julilili42/papers huggingface dataset:
The STArgardt Remofuscin Treatment Trial (STARTT): design and baseline characteristics of enrolled Stargardt patients
2022-09-27

<ns3:p><ns3:bold>Background: </ns3:bold>This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT).</ns3:p><ns3:p> <ns3:bold>Methods: </ns3:bold>In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF<ns3:sub>8</ns3:sub>). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP), spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index.</ns3:p><ns3:p> <ns3:bold>Results: </ns3:bold>Mean age of participants was 35±11 years with 49 (56%) female. Median qAF<ns3:sub>8</ns3:sub> value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 μm (range 72-265) and median macular volume of 1.65 mm<ns3:sup>3</ns3:sup> (range 1.13-2.19). Compared to persons without vision impairment,<ns3:sup> </ns3:sup>both reading performance and patient-reported visual function were significantly lower (p&lt;0.001, one sample t-test). Mean reading speed was 108±39 words/minute with logRAD-score of 0.45±0.28. Mean VFQ-25 composite score was 72±13. Mean FRI Index score 2.8±0.6.</ns3:p><ns3:p> <ns3:bold>Conclusions: </ns3:bold>This trial design may serve as reference for future clinical trials as it explores the utility of qAF<ns3:sub>8</ns3:sub> as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1.</ns3:p><ns3:p> <ns3:bold>EudraCT registration:</ns3:bold> 2018-001496-20 (09/05/2019)</ns3:p>
Physical activity improves body image of sedentary adults. Exploring the roles of interoception and affective response
2022-09-27

Abstract To reduce the number of sedentary people, an improved understanding of effects of exercise in this specific group is needed. The present project investigates the impact of regular aerobic exercise uptake on body image, and how this effect is associated with differences in interoceptive abilities and affective response to exercise. Participants were 29 sedentary adults who underwent a 12-week aerobic physical activity intervention comprised of 30–36 sessions. Body image was improved with large effect sizes. Correlations were observed between affective response to physical activity and body image improvement, but not with interoceptive abilities. Explorative mediation models suggest a neglectable role of a priori interoceptive abilities. Instead, body image improvement was achieved when positive valence was assigned to interoceptive cues experienced during exercise.
PO.3.67 Measuring IFNA2 levels by a single-molecule array in clinical practice of childhood-onset sle patients does matter; results from a single center longitudinal study
2022-09-27

<h3>Introduction</h3> Type-I interferon (IFN-I) pathway activation plays a pivotal role in the pathogenesis of SLE and has been proposed as biomarker for disease activity. IFN-I pathway activation can be measured by determining the expression of IFN-I stimulated genes or a so-called IFN signature. Ultrasensitive single-molecule array (Simoa) technology enables measurement of IFN protein concentrations at subfemtomolar concentrations. Parallel use of these measuring methods in longitudinal cohorts of childhood-onset SLE (cSLE) patients in relation to disease activity could help in translating the most relevant technique for use in clinical practice. <h3>Objective</h3> To determine the association of serum IFNa2 levels and whole blood IFN-I stimulated gene expression with disease activity and study their potential to mark specific disease activity states in a longitudinal cohort of cSLE patients. <h3>Methods</h3> Serum IFNa2 levels were measured in 338 samples from 48 cSLE patients and 67 healthy controls using an IFN-a2 Simoa assay (Quanterix) on an HD-X analyser. A 5 gene IFN-I signature was measured by RT-PCR in paired whole blood samples. Disease activity was assessed by the clinical SELENA-SLEDAI (cSLEDAI) and BILAG-2004. Low disease activity was defined by the Low Lupus Disease Activity State (LLDAS) and flares were characterized by the SELENA-SLEDAI flare index. Analysis was performed using linear mixed effect models. <h3>Results</h3> A clear positive correlation was present between serum IFNa2 levels and the IFN-I gene signature (r=0.78, p&lt;0.0001). Serum IFNa2 levels and the IFN-I gene signature showed the same significant negative trend in the first three years after diagnosis. In this timeframe, mean baseline serum IFNa2 levels decreased with 55.1% (delta 172 fg/mL, p&lt;0.001) to a mean value of 164fg/mL, which was below the calculated threshold of 219.4 fg/mL. In the linear mixed model, serum IFNa2 levels were significantly associated with both the cSLEDAI and the BILAG-2004 (p&lt;0.001 and p&lt;0.01), while the IFN-I gene signature did not show this association (p=0.35 and p=0.23). Moreover, 69.7% of the time points in LLDAS had a serum IFNa2 level under the calculated threshold, while only 31.9% of the time points in LLDAS reached an IFN-I gene signature below the calculated threshold. Both techniques were equally capable of marking disease flares (79.2% above threshold vs 87.5% above threshold). <h3>Conclusions</h3> Serum IFNa2 levels measured by Simoa, but not the type-I IFN gene signature, are associated with disease activity scores and characterize disease activity states in cSLE patients. Hence, this technique has the potential to be implemented in clinical practice.
Hemispheric differences of 1Hz rTMS over motor and premotor cortex in modulation of neural processing and hand function
2022-09-27

Abstract Introduction: Non-invasive brain stimulation can modulate both neural processing and behavioral performance. Its effects may by influenced by the stimulated area and hemisphere. In this study (EC no. 09083), repetitive transcranial magnetic stimulation (rTMS) was applied to the primary motor cortex (M1) or dorsal premotor cortex (dPMC) of either the right or left hemisphere, while evaluating cortical neurophysiology and hand function. Methods: Fifteen healthy subjects participated in this placebo-controlled crossover study. Four sessions of real 1Hz rTMS (110% of rMT, 900 pulses) over (i) left M1, (ii) right M1, (iii) left dPMC, (iv) right dPMC, and one session of (v) placebo 1Hz rTMS (0% of rMT, 900 pulses) over the left M1 were applied in randomized order. Motor function of both hands(Jebsen-Taylor Hand Function Test (JTHFT)) and neural processing within both hemispheres (motor evoked potentials (MEPs), cortical silent period (CSP) and ipsilateral silent period (ISP)) were evaluated prior and after each intervention session. Results: A lengthening of CSP and ISP durations within the right hemisphere were induced by 1Hz rTMS over both areas and hemispheres. No such intervention-induced neurophysiological changes were detected within the left hemisphere. Regarding JTHFT and MEP, no intervention-induced changes ensued. Changes of hand function correlated with neurophysiological changes within both hemispheres, more often for the left than the right hand. Conclusions: Effects of 1Hz rTMS can be better captured by neurophysiological than behavioral measures. Hemispheric differences need to be considered for this intervention.
Myeloid hypoxia-inducible factor HIF1A provides cardio-protection during ischemia and reperfusion via induction of netrin-1
2022-09-28

The transcription factor hypoxia-inducible factor HIF1A induces cardioprotection from ischemia and reperfusion injury. Here, we investigate tissue-specific pathways that are critical for HIF1A-elicited tissue protection. Initial studies showed that mice with induced global Hif1a deletion ( Hif1a loxP/loxP UbiquitinCre+) have exaggerated myocardial injury during in situ ischemia and reperfusion. Surprisingly, this phenotype was mirrored only in mice with myeloid-specific Hif1a deletion (Hif1a loxP/loxP LysM Cre+). In contrast, mice with myocardial specific ( Hif1a loxP/loxP Myosin Cre+), or vascular Hif1a deletion ( Hif1a loxP/loxP VEcadherin Cre+) experienced similar levels of injury as controls. Subsequent studies using adoptive transfer of Hif1a- deficient polymorphonuclear neutrophils (PMNs) prior to myocardial injury demonstrated increased reperfusion injury. On the contrary, the adoptive transfer of PMNs treated ex vivo with the hypoxia inducible factor (HIF) stabilizer dimethyloxalylglycine (DMOG) was associated with attenuated myocardial injury. Furthermore, DMOG-mediated cardioprotection was abolished in Hif1a loxP/loxP LysM Cre+ mice, but not in Hif2a loxP/loxP LysM Cre+ mice. Finally, studies of PMN-dependent HIF1A target genes implicated the neuronal guidance molecule netrin-1 in mediating the cardioprotective effects of myeloid HIF1A. Taken together, the present studies identified a functional role for myeloid-expressed HIF1A in providing cardioprotection during ischemia and reperfusion injury, which is mediated, at least in part, by the induction of the netrin-1 neuronal guidance molecule in neutrophils.
Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas
2022-09-28

CD19CAR T cells facilitate a transformational treatment in various relapsed and refractory aggressive B-lineage cancers. In general, encouraging response rates have been observed in B-lineage-derived non-Hodgkin’s lymphomas treated with CD19CAR T cells. The major cause of death in heavily pretreated NHL patients is lymphoma progression and lymphoma recurrence. Inefficient CAR T cell therapy is the result of the limited potency of the CAR T cell product or is due to loss of the targeted antigen. Target antigen loss has been identified as the key factor that can be addressed stringently by dual- or multitargeted CAR T cell approaches. We have developed a versatile adapter CAR T cell technology (AdCAR) that allows multitargeting. Screening of three different B-lineage lymphoma cell lines has revealed distinct immune target profiles. Cancer-specific adapter molecule combinations may be utilized to prevent antigen immune escape. In general, CD19CAR T cells become non-functional in CD19 negative lymphoma subsets; however, AdCAR T cells can be redirected to alternative target antigens beyond CD19, such as CD20, CD22, CD79B, and ROR-1. The capability to flexibly shift CAR specificity by exchanging the adapter molecule’s specificity broadens the application and significantly increases the anti-leukemic and anti-lymphoma activity. The clinical evaluation of AdCAR T cells in lymphoma as a new concept of CAR T cell immunotherapy may overcome treatment failure due to antigen immune escape in monotargeted conventional CAR T cell therapies.
Ties between reading faces, bodies, eyes, and autistic traits
2022-09-28

While reading covered with masks faces during the COVID-19 pandemic, for efficient social interaction, we need to combine information from different sources such as the eyes (without faces hidden by masks) and bodies. This may be challenging for individuals with neuropsychiatric conditions, in particular, autism spectrum disorders. Here we examined whether reading of dynamic faces, bodies, and eyes are tied in a gender-specific way, and how these capabilities are related to autistic traits expression. Females and males accomplished a task with point-light faces along with a task with point-light body locomotion portraying different emotional expressions. They had to infer emotional content of displays. In addition, participants were administered the Reading the Mind in the Eyes Test, modified and Autism Spectrum Quotient questionnaire. The findings show that only in females, inferring emotions from dynamic bodies and faces are firmly linked, whereas in males, reading in the eyes is knotted with face reading. Strikingly, in neurotypical males only, accuracy of face, body, and eyes reading was negatively tied with autistic traits. The outcome points to gender-specific modes in social cognition: females rely upon merely dynamic cues while reading faces and bodies, whereas males most likely trust configural information. The findings are of value for examination of face and body language reading in neuropsychiatric conditions, in particular, autism, most of which are gender/sex-specific. This work suggests that if male individuals with autistic traits experience difficulties in reading covered with masks faces, these deficits may be unlikely compensated by reading (even dynamic) bodies and faces. By contrast, in females, reading covered faces as well as reading language of dynamic bodies and faces are not compulsorily connected to autistic traits preventing them from paying high costs for maladaptive social interaction.
Experimental exposure assessment of designed chemical mixtures in cell-based in vitro bioassays
2022-09-28

Cell-based bioassays are useful tools for the effect assessment of complex mixtures, but so far exposure assessment has not been performed for mixtures of chemicals. In the present study, cytotoxicity and activation of oxidative stress response were measured for three designed chemical mixtures with up to twelve components. The measurements of biological responses were complemented by concentration measurements using solid-phase microextraction to derive the freely dissolved concentrations of the mixtures ( C free,mix ). The tested mixtures showed slightly higher cytotoxic effects than predicted by the concentration addition model. Nominal and freely dissolved effect concentrations of the mixtures were very similar (within a factor of 1.5), but nominal concentrations ( C nom ) and C free of the individual mixture components were only similar for the hydrophilic chemicals (e.g., caffeine, coumarin, lamotrigine). For hydrophobic (e.g., fluoranthene) and acidic chemicals (e.g., diclofenac, naproxen) C free was up to 648 times lower than C nom . Chemicals were dosed in equipotent nominal concentration ratios and therefore contributed equally to the detected effects. Hydrophilic chemicals with low potency dominated C nom,mix (up to 95%) and C free,mix (up to 99%). Several mixture components (e.g., diclofenac, ibuprofen, naproxen and warfarin) showed increasing free fractions with increasing C nom,mix and therefore also a concentration-dependent contribution to C free,mix . Based on the findings of this study, we concluded that C nom,mix will be sufficient for evaluating the toxicity of mixtures that contain chemicals with diverse physicochemical properties at low concentration levels. In contrast, for risk assessment purposes and quantitative in vitro to in vivo extrapolations, C free,mix is a better parameter because the in vitro responses can be related to freely dissolved concentrations in human plasma.
Administrative data in pediatric critical care research—Potential, challenges, and future directions
2022-09-28

Heterogenous patient populations with small case numbers constitute a relevant barrier to research in pediatric critical care. Prospective studies bring along logistic barriers and—if interventional—ethical concerns. Therefore, retrospective observational investigations, mainly multicenter studies or analyses of registry data, prevail in the field of pediatric critical care research. Administrative health care data represent a possible alternative to overcome small case numbers and logistic barriers. However, their current use is limited by a lack of knowledge among clinicians about the availability and characteristics of these data sets, along with required expertise in the handling of large data sets. Specifically in the field of critical care research, difficulties to assess the severity of the acute disease and estimate organ dysfunction and outcomes pose additional challenges. In contrast, trauma research has shown that classification of injury severity from administrative data can be achieved and chronic disease scores have been developed for pediatric patients, nurturing confidence that the remaining obstacles can be overcome. Despite the undoubted challenges, interdisciplinary collaboration between clinicians and methodologic experts have resulted in impactful publications from across the world. Efforts to enable the estimation of organ dysfunction and measure outcomes after critical illness are the most urgent tasks to promote the use of administrative data in critical care. Clever analysis and linking of different administrative health care data sets carry the potential to advance observational research in pediatric critical care and ultimately improve clinical care for critically ill children.
Modeling the Dynamics of Mixture Toxicity and Effects of Organic Micropollutants in a Small River under Unsteady Flow Conditions
2022-09-28

The presence of anthropogenic organic micropollutants in rivers poses a long-term threat to surface water quality. To describe and quantify the in-stream fate of single micropollutants, the advection-dispersion-reaction (ADR) equation has been used previously. Understanding the dynamics of the mixture effects and cytotoxicity that are cumulatively caused by micropollutant mixtures along their flow path in rivers requires a new concept. Thus, we extended the ADR equation from single micropollutants to defined mixtures and then to the measured mixture effects of micropollutants extracted from the same river water samples. Effects (single and mixture) are expressed as effect units and toxic units, the inverse of effect concentrations and inhibitory concentrations, respectively, quantified using a panel of in vitro bioassays. We performed a Lagrangian sampling campaign under unsteady flow, collecting river water that was impacted by a wastewater treatment plant (WWTP) effluent. To reduce the computational time, the solution of the ADR equation was expressed by a convolution-based reactive transport approach, which was used to simulate the dynamics of the effects. The dissipation dynamics of the individual micropollutants were reproduced by the deterministic model following first-order kinetics. The dynamics of experimental mixture effects without known compositions were captured by the model ensemble obtained through Bayesian calibration. The highly fluctuating WWTP effluent discharge dominated the temporal patterns of the effect fluxes in the river. Minor inputs likely from surface runoff and pesticide diffusion might contribute to the general effect and cytotoxicity pattern but could not be confirmed by the model-based analysis of the available effect and chemical data.
Systematic analysis of in-source modifications of primary metabolites during flow-injection time-of-flight mass spectrometry
2022-09-28

Abstract Flow-injection mass spectrometry (FI-MS) enables metabolomics studies with a very high sample-throughput. However, FI-MS is prone to in-source modifications of analytes because samples are directly injected into the electrospray ionization source of a mass spectrometer without prior chromatographic separation. Here, we spiked authentic standards of 160 primary metabolites individually into an Escherichia coli metabolite extract and measured the thus derived 160 spike-in samples by FI-MS. Our results demonstrate that FI-MS can capture a wide range of chemically divers analytes within 30 seconds measurement time. However, the data also revealed extensive in-source modifications. Across all 160 spike-in samples, we identified significant increases of 11,013 ion peaks in positive and negative mode combined. To explain these unknown m/z features, we connected them to the m/z feature of the (de-)protonated metabolite using information about mass differences and MS2 spectra. This resulted in networks that explained on average 49 % of all significant features. The networks showed that a single metabolite undergoes compound specific and often sequential in-source modifications like adductions, chemical reactions, and fragmentations. Our results show that FI-MS generates complex MS1 spectra, which leads to an overestimation of significant features, but neutral losses and MS2 spectra explain many of these features. Highlights FI-MS enables measurements of chemically divers metabolites. Extensive in-source modifications during electrospray ionization are detected by FI-MS. A network approach explains 49 % of all recorded in-source modifications.
Ancient implications for today’s precision medicine: How the first Near East farmers shaped the European genetic risk architecture for IBD
2022-09-28

<title>Abstract</title> Inflammatory bowel disease (IBD) is often described as a model for modern civilization diseases in which environmental factors trigger disease manifestation in genetically compromised individuals. Little is known about the evolutionary history of variants associated with IBD in modern Europeans. Here, we analysed 610 IBD-variants in 2445 ancient datasets from human remains spanning the last 12,000 years, including genotypes generated from 172 newly collected individuals from the European Neolithic. We found statistically significant differences in the frequencies of 97 IBD variants between Neolithic and modern populations that can be explained by the adoption of an agricultural lifestyle and behaviour and concomitant possible microbiome changes in the earliest farmers. Later admixture events and selection against pathogens largely influenced the genetic risk architecture of IBD in contemporary Europeans. A better understanding of the evolutionary history of disease variants is an important first step in translating genetic findings into preventive health care.
Extreme brain sagging and transtentorial herniation in spontaneous intracranial hypotension
2022-09-28

Introduction: Spontaneous intracranial hypotension often results in a new-onset headache that is worse with upright posture, along with other neurologic signs and symptoms. It is less rare than once thought and is not usually considered in the differential diagnosis of chronic daily headaches for months.
Polarization constraints on the X-ray corona in Seyfert Galaxies: MCG-05-23-16
2022-09-29

ABSTRACT We report on the first observation of a radio-quiet active galactic nucleus (AGN) in polarized X-rays: the Seyfert 1.9 galaxy MCG-05-23-16. This source was pointed at with the Imaging X-ray Polarimetry Explorer (IXPE) starting on 2022 May 14 for a net observing time of 486 ks, simultaneously with XMM-Newton (58 ks) and NuSTAR (83 ks). A polarization degree Π smaller than 4.7 per cent (at the 99 per cent confidence level) is derived in the 2–8 keV energy range, where emission is dominated by the primary component ascribed to the hot corona. The broad-band spectrum, inferred from a simultaneous fit to the IXPE, NuSTAR, and XMM-Newton data, is well reproduced by a power law with photon index Γ = 1.85 ± 0.01 and a high-energy cutoff EC = 120 ± 15 keV. A comparison with Monte Carlo simulations shows that a lamp-post and a conical geometry of the corona are consistent with the observed upper limit, a slab geometry is allowed only if the inclination angle of the system is less than 50°.