bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesizing and Applying Molecular Targeted Imaging Results in Patients With Prostate Cancer (RADAR VII)
Authors: Crawford E. David , Harris Richard G. , Slovin Susan F. , Concepcion Raoul S. , Albala David M. , Gomella Leonard G. , Orio Peter F. , Sellinger Scott B. , Petrylak Daniel P. , Koo Phillip J.
Published: March 2023

Purpose:

Molecular targeted imaging (MTI) is one of the most powerful new tools in the prostate cancer arsenal, but incorporation of MTI results into treatment decision making continues to be a challenge. Guidance is available for clinicians to determine when and how frequently MTI should be used, but clinicians also need to know how MTI results should influence management decisions.

Materials and methods:

In this review, the Radiographic Assessments for Detection of Advanced Recurrence (RADAR) VII group has developed consensus guidance for the use of MTI in clinical decision making. RADAR VII sought to include all physicians involved in the management of prostate cancer, including urologists, medical oncologists, radiation oncologists, and nuclear medicine specialists.

Results:

Recommendations were developed for the management of localized, biochemically recurrent, or nonmetastatic castrate-resistant prostate cancer (nmCRPC) by conventional imaging and metastatic disease by MTI. Recommendations were also developed for the treatment of patients with equivocal MTI results. These recommendations are based largely on clinical experience and limited clinical data because of a lack of high-quality, prospective studies regarding the role of MTI in clinical decision making. As such, the RADAR VII group also provides a framework for the incorporation of MTI into ongoing and future clinical trials to support the development of more robust recommendations.

Conclusions:

We developed several recommendations for the interpretation and application of MTI results for patients with localized disease, biochemical recurrence, and nmCRPC on conventional imaging. These recommendations should be viewed within the context of the limited available evidence and the dynamic nature of prostate cancer research.
Analysis of the Gene Therapies Authorized by the United States Food and Drug Administration and the European Medicines Agency
Authors: Ghanem Buthainah , Seoane-Vazquez Enrique , Brown Lawrence , Rodriguez-Monguio Rosa
Published: March 2023

Background:

Gene therapy, altering the genes inside human cells, has recently emerged as an alternative for preventing and treating disease. Concerns have been expressed about the clinical value and the high cost of gene therapies.

Objective:

This study assessed the characteristics of the clinical trials, authorizations, and prices of gene therapies in the United States and the European Union.

Research Design:

We collected regulatory information from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and manufacturer-listed prices from the United States, UK, and Germany. Descriptive statistics and t tests were conducted in the study.

Results:

As of January 1, 2022, the FDA and EMA authorized 8 and 10 gene therapies, respectively. The FDA and EMA granted orphan designation to all gene therapies except talimogene laherparepvec. Pivotal clinical trials were nonrandomized, open level, uncontrolled, phase I–III, and included a limited number of patients. Study primary outcomes were mainly surrogate endpoints without demonstration of direct patient benefit. The price of gene therapies at market entry ranged from $200,064 to $2,125,000 million.

Conclusions:

Gene therapy is used to treat incurable diseases that affect only a small number of patients (orphan diseases). Based on this, they are approved by the EMA and FDA with insufficient clinical evidence to ensure safety and efficacy, in addition to the high cost.
POSTTRAUMATIC RUPTURED AXILLARY MONONEUROPATHY WITHOUT SHOULDER DISLOCATION IN AN AMERICAN FOOTBALL PLAYER: A CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Meiling James B. , Bishop Allen T. , Young Nathan P.
Published: March 2023

A high-school-aged right-handed male presented with a 5-month history of persistent proximal right arm weakness and numbness after an American football stinger injury without a documented history of a shoulder dislocation or humeral fracture. He developed diffuse deltoid muscle atrophy, persistent shoulder abduction weakness, and reduced pinprick sensation confined to the axillary distribution over 5 months. Needle electromyography demonstrated dense fibrillation potentials and no voluntary activation in all three deltoid muscle heads, indicating a severe posttraumatic ruptured axillary mononeuropathy. The patient then underwent a complex 3-cable sural nerve graft repair for attempted reinnervation of the axillary-innervated muscles. Isolated axillary nerve injuries are usually associated with anterior shoulder dislocations; however, a severe isolated persistent axillary mononeuropathy from a ruptured axillary nerve may occur in trauma patients without a clear history of shoulder dislocation. These patients may present with only mild persistent weakness of shoulder abduction. Electrodiagnostic testing to fully assess axillary nerve function should still be considered to identify patients with high grade nerve injuries that may benefit from sural nerve grafting. The rapid recovery of our patient’s initial symptoms with persistent severe axillary injury suggests a unique vulnerability of the nerve due to the neuroanatomy and possibly other factors.
Adding weight shift training to weight reduction decreases the risk of falling in obese females: A prospective randomized controlled trial
Authors: Abdel-Aal Nabil Mahmoud , Ibrahim Amal Hassan , Samaha Hanan El-Sayed , Mohamed Hanaa Samir
Published: March 2023

Objective

To examine the effect of adding weight shift training to a weight loss program on the risk of falling, fear of falling, overall stability, anteroposterior stability, mediolateral stability, and isometric knee torque in young obese women.

Design

A single-blinded, randomized controlled study was performed. Sixty females, 18-46 years, were randomly assigned either to the study or the control groups. The participants in the study group were given weight-shifting training plus a weight reduction program; the control group received only a weight-reduction program. The interventions were performed for 12 weeks. At baseline and after 12 weeks of training, the risk of falling, fear of falling, overall stability, anteroposterior stability, mediolateral stability, and isometric knee torque were all examined.

Results

There were statistically significant differences in risk of falling, fear of falling, isometric knee torque, and overall, anteroposterior, and mediolateral stability indices, in favor of the study group, after three months of training (P < 0.001).

Conclusions

Weight shift training combined with weight reduction was more beneficial than weight reduction alone in decreasing the risk of falling, fear of falling, and improving isometric knee torque, and overall, anteroposterior, and mediolateral stability indices. It could be used for treating balance problems and weakness around the knee joint in obese females.
Investigation of the relevant factors in the complexity of chronic low back pain patients with a physiotherapy prescription. A network analysis approach, comparing chronic-pain free individuals and chronic patients
Authors: Carta Giacomo , Costantini Giulio , Garzonio Stefano , Romano Daniele
Published: March 2023

Objective

Chronic Low Back Pain (CLBP) is the leading cause of disability worldwide, and several factors have been proposed as potential causes or co-factors. We aimed to explore their direct and indirect relations to understand CLBP and identify relevant rehabilitation targets.

Methods

119 CLBP patients and 117 chronic-pain free individuals were assessed. A network analysis approach was employed to explore the complexity of CLBP by assessing the relations between pain intensity, disability, functionality (physical, social and psychological), age, body mass index, and education level.

Results

The network analysis revealed the independence of pain and disability related to CLBP from age, sex, and BMI. Crucially, pain intensity and disability are directly and strongly connected in chronic-pain free individuals, but not in CLBP patients. Psychosocial functioning is related to pain intensity and disability indirectly through the mediation of one’s general health perception and perceived physical functionality.

Conclusion

Clinicians should pay more attention to perceived physical functionality and psychosocial factors as they are tightly linked to CLBP. Indeed, pain intensity seems a sub-optimal rehabilitation target. Our study suggests that a biopsychosocial approach is much needed to investigate CLBP, but it also warns against overestimating the direct impact of each potential contributor.
Feeding morphology and body size shape resource partitioning in an eared seal community
Authors: Valenzuela-Toro Ana M. , Mehta Rita , Pyenson Nicholas D. , Costa Daniel P. , Koch Paul L.
Published: March 2023

Body size and feeding morphology influence how animals partition themselves within communities. We tested the relationships among sex, body size, skull morphology and foraging in sympatric otariids (eared seals) from the eastern North Pacific Ocean, the most diverse otariid community in the world. We recorded skull measurements and stable carbon (
δ
13
C) and nitrogen (
δ
15
N) isotope values (proxies for foraging) from museum specimens in four sympatric species: California sea lions (
Zalophus californianus
), Steller sea lions (
Eumetopias jubatus
), northern fur seals (
Callorhinus ursinus
) and Guadalupe fur seals (
Arctocephalus townsendi
). Species and sexes had statistical differences in size, skull morphology and foraging significantly affecting the
δ
13
C values. Sea lions had higher
δ
13
C values than fur seals, and males of all species had higher values than females. The
δ
15
N values were correlated with species and feeding morphology; individuals with stronger bite forces had higher
δ
15
N values. We also found a significant community-wide correlation between skull length (indicator of body length), and foraging, with larger individuals having nearshore habitat preferences, and consuming higher trophic level prey than smaller individuals. Still, there was no consistent association between these traits at the intraspecific level, indicating that other factors might account for foraging variability.
Did AI get more negative recently?
Authors: Beese Dominik , Altunbaş Begüm , Güzeler Görkem , Eger Steffen
Published: March 2023

In this paper, we classify scientific articles in the domain of natural language processing (NLP) and machine learning (ML), as core subfields of artificial intelligence (AI), into whether (i) they extend the current state-of-the-art by the introduction of novel techniques which beat existing models or whether (ii) they mainly criticize the existing state-of-the-art, i.e. that it is deficient with respect to some property (e.g. wrong evaluation, wrong datasets, misleading task specification). We refer to contributions under (i) as having a ‘positive stance’ and contributions under (ii) as having a ‘negative stance’ (to related work). We annotate over 1.5 k papers from NLP and ML to train a SciBERT-based model to automatically predict the stance of a paper based on its title and abstract. We then analyse large-scale trends on over 41 k papers from the last approximately 35 years in NLP and ML, finding that papers have become substantially more positive over time, but negative papers also got more negative and we observe considerably more negative papers in recent years. Negative papers are also more influential in terms of citations they receive.
Sprinting performance of individuals with unilateral transfemoral amputation: compensation strategies for lower limb coordination
Authors: Hu Mingyu , Kobayashi Toshiki , Hisano Genki , Murata Hiroto , Ichimura Daisuke , Hobara Hiroaki
Published: March 2023

Understanding the sprinting patterns of individuals with unilateral transfemoral amputation (uTFA) is important for designing improved running-specific prostheses and for prosthetic gait rehabilitation. Continuous relative phase (CRP) analysis acquires clues from movement kinematics and obtains insights into the sprinting coordination of individuals with uTFA. Seven individuals with uTFA sprinted on a 40 m runway. The spatio-temporal parameters, joint and segment angles of the lower limbs were obtained, and CRP analysis was performed on thigh-shank and shank-foot couplings. Subsequently, the asymmetry ratios of the parameters were calculated. Statistical analyses were performed between the lower limbs. Significant differences in the stance time, stance phase percentage, ankle joint angles and CRP of the shank-foot coupling (
p
< 0.05) were observed between the lower limbs. The primary contributor to these differences could be the structural differences between the lower limbs. Despite the presence of different coordination features in the stance and swing phases between the lower limbs, no significant difference in the coordination patterns of the thigh-shank coupling was observed. This may be a compensation strategy for achieving coordination patterns with improved symmetry between the lower limbs. The results of this study provide novel insights into the sprinting movement patterns of individuals with uTFA.
Estimation of reinforced urn processes under left-truncation and right-censoring
Authors: Souto Arias Luis A. , Cirillo Pasquale , Oosterlee Cornelis W.
Published: March 2023

We propose a non-parametric estimator for bivariate left-truncated and right-censored observations that combines the expectation–maximization algorithm and the reinforced urn process. The resulting expectation-reinforcement algorithm allows for the inclusion of experts’ knowledge in the form of a prior distribution, thus belonging to the class of Bayesian models. This can be relevant in applications where the data is incomplete, due to biases in the sampling process, as in the case of left-truncation and right-censoring. With this new approach, the distribution of the truncation variables is also recovered, granting further insight into those biases, and playing an important role in applications like prevalent cohort studies. The estimators are tested numerically using artificial and empirical datasets, and compared with other methodologies such as copula models and the Kaplan–Meier estimator.
Stiff skin, soft core: soft backings enhance the conformability and friction of fibre-reinforced adhesives
Authors: Glaser Niels C. , Langowski Julian K. A.
Published: March 2023

Biomimetic adhesives with a stiff fibre-reinforced base layer generate strong attachment, even without bioinspired micropatterning of the contact surface. However, current fibre-reinforced adhesive designs are still less versatile with respect to substrate variability than their biological counterparts. In this study, we enhance the comformability of a fibre-reinforced adhesive on curved substrates by adding bioinspired soft backings. We designed and fabricated soft backing variations (polyurethane foams and silicone hydroskeletons) with varying compressive stiffnesses that mimic the soft viscoelastic structures in the adhesive appendages of tree frogs, geckos and other animals. The backings were mounted on a smooth silicone layer enforced with a polyester mesh, and we experimentally investigated the contact area and friction performance of these adhesives on a curved substrate. The results show that the contact area and friction created by a fibre-reinforced adhesive with a soft backing in contact with a non-flat substrate scale inversely with backing stiffness. The integration of stiff fibre-reinforcement with a compressible backing represents an important step in bringing bioinspired adhesives out of the laboratory and into the real world, for example in soft robotic grippers. Moreover, our findings stimulate further research into the role of soft tissues in biological adhesive systems.
Cuisine in transition? Organic residue analysis of domestic containers from 9th-14th century Sicily
Authors: Lundy Jasmine , Drieu Lea , Orecchioni Paola , Meo Antonino , Aniceti Veronica , Fiorentino Girolamo , Primavera Milena , Talbot Helen , Molinari Alessandra , Carver Martin O. H. , Craig Oliver E.
Published: March 2023

From the 9th to 14th centuries AD, Sicily experienced a series of rapid and quite radical changes in political regime, but the impact of these regime changes on the lives of the people that experienced them remains largely elusive within the historical narrative. We use a multi-faceted lipid residue approach to give direct chemical evidence of the use of 248 everyday domestic ceramic containers from Islamic and post-Islamic contexts in western Sicily to aid our understanding of daily habits throughout this period of political change. A range of commodities was successfully identified, including animal fats, vegetable products, fruit products (potentially including wine) and plant resins. The study highlights the complexity of residues in early medieval Mediterranean society as, in many cases, mixtures of commodities were observed reflecting sequential cooking events and/or the complex mixtures reflective of medieval recipes. However, overall, there were no clear changes in the composition of the residues following the imposition of Norman control over the island and through subsequent periods, despite some differences between urban centres and rural sites. Thus, lending to the idea that post-Islamic populations largely flourished and benefited from the agricultural systems, resources and recipes left by their predecessors.
The blending effect of natural polysaccharides with nano-zirconia towards the removal of fluoride and arsenate from water
Authors: Shanika Fernando M. , Wimalasiri A. K. D. V. K. , Dziemidowicz Karolina , Williams Gareth R , Rasika Koswattage K. , Dissanayake D. P. , Nalin De Silva K. M. , De Silva Rohini M.
Published: March 2023

Nano-zirconia (ZO) was synthesized using a microwave-assisted one-pot precipitation route. Two biopolymers, chitosan (CTS) and carboxymethyl cellulose were blended with ZO at different w/w ratios. The formulation with 30% w/w chitosan (ZO-CTS) was found to give enhanced uptake of F
−
and As(V). ZO and the most effective ZO-CTS system were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. These confirmed the formation of a composite system containing nanoparticles of 50 nm in size, in which ZO was present in the amorphous form. It was observed that the combination of ZO with CTS improved the F
−
and As(V) adsorption capacity most notably at pH 5.5. Fluoride adsorption by ZO-CTS followed the Freundlich isotherm model, with an adsorption capacity of 120 mg g
−1
. Adsorption of As(V) by ZO-CTS could be fitted with both the Langmuir and Freundlich isotherm models and was found to have a capacity of 14.8 mg g
−1
. Gravity filtration studies conducted for groundwater levels indicated the effectiveness of ZO-CTS in adsorbing As(V) and F
−
at a pH of 5.5. The ability of the ZO-CTS in removing Cd(II) and Pb(II) was also investigated, and no such enhancement was observed, and found the neat ZO was the most potent sorbent here.
Bone histology of Neogene angulate tortoises (Testudines: Testudinidae) from South Africa: palaeobiological and skeletochronological implications
Authors: Bhat Mohd Shafi , Chinsamy Anusuya , Parkington John
Published: March 2023

Here we examine the tibial microstructure of modern and fossil angulate tortoises to assess the histology and growth from the late Miocene–early Pliocene, Pleistocene through to modern forms. The cross-sections of all the tibiae sampled revealed highly vascularized, uninterrupted, fibrolamellar bone tissue during early ontogeny, which suggests that early growth was fast. However, later in ontogeny, growth was slower, as indicated by the deposition of parallel-fibred bone tissue in the outer cortex, and even ceased periodically, as indicated by lines of arrested growth. Comparative analyses of the growth rates of the tortoises from different time periods showed that the tortoises from the late Miocene–early Pliocene Langebaanweg locality and from Diepkloof Rock Shelter had relatively slower growth rates under less optimal growth conditions. Additionally, these prehistoric specimens show extensive remodelling, and several generations of secondary osteons further suggest functional and/or metabolic stresses on the skeleton. Palaeoenvironmental reconstructions suggest that it was mostly cooler and drier with seasonal fluctuations in late Miocene–early Pliocene, and it is likely that
Chersina
responded to these conditions by having a lower rate of growth as compared with their modern counterparts, which thrive in the current prevailing more favourable Mediterranean type of climate.
Diagnosis of left atrial appendage thrombus using cardiac computed tomography: new insights from thrombi locations
Authors: Guo Chuxian , Jiang Zhi , He Jionghong , Ma Haiyan , Wang Yuquan , Tan Jing , Ou Qiaoqiao , Tian Ye , Tian Longhai , Liu Qifang , Huang Jing , Yang Long
Published: March 2023

Background

Cardiac computed tomography (CCT) is an emerging non-invasive modality for assessing left atrial appendage (LAA) thrombus, but the results were conflicting. Our study aims to evaluate the accuracy of CCT for detecting LAA thrombus in patients undergoing catheter ablation of atrial fibrillation (AF), using transesophageal echocardiography (TEE) as the reference standard.

Methods

From May 2017 to December 2022, 726 patients (male: 60.2%, age: 61±11 years) who had both TEE and CCT before catheter ablation of AF were retrospectively included. The CCT protocol consisted of one angiographic phase and one delayed scan 30 seconds later. LAA thrombi were defined as solid masses on TEE or persistent defects on CCT. The thrombus dimension and location, the LAA filling and emptying flow velocity were assessed by TEE.

Results

Of the 57(7.9%) patients with LAA thrombi identified by TEE, 29(50.9%) were located at the LAA ostium, and 28(49.1%) were in the LAA. The former showed higher motility following blood flow and heartbeats than the latter. The CCT detected 14(48.3%) of the LAA-ostium thrombi but 25(89.3%) of those in the LAA (p= 0.001). The LAA-ostium thrombi with the LAA mean flow velocity higher than 0.35m/s and maximum diameters shorter than 10mm were more prone to have CCT false-negative results.

Conclusion

For patients undergoing catheter ablation for AF, CCT with a 30s delay scan is less sensitive to LAA thrombi than TEE, especially LAA-ostium thrombi with smaller sizes and higher LAA flow velocity.

Clinical perspective section

What are new?

Over half of the LAA thrombi were located at the LAA ostium.

The CCT was less sensitive to the LAA-ostium thrombi with smaller sizes and higher LAA flow velocity.

What is the clinical implication?

1. The CCT using a 30s delay scan did not reliably exclude the LAA thrombi for the patients scheduled for pulmonary vein isolation, especially those located at the LAA ostium.
Development of a self-monitoring system for lung transplant patients using information and communication technology: a pilot study
Authors: Shinohara Yoshikazu , Yamamoto Kazumichi , Wannous Muhammad , Yanagiya Masahiro , Nagano Masaaki , Kitano Kentaro , Sato Masaaki , Konoeda Chihiro , Nakajima Jun
Published: March 2023

Background

Lung transplantation is the final option for end-stage respiratory diseases. Postoperative monitoring of patients’ physical condition and performance of appropriate interventions for any abnormalities are important to improve the long-term success of lung transplantation. In Japan, patients’ handwritten self-management charts are widely used to record data for home spirometry, vital signs, and medication dosages. However, handwritten data are not suitable for assessment. We developed an internet-based real-time monitoring system (LT-FollowUp) that can easily assess patient data and detect any abnormalities that arise without delay. The aim of this pilot study was to examine the acceptability of LT-FollowUp to patients.

Methods

This was a prospective single-arm pilot cohort study. Lung transplant patients were recruited consecutively at regular outpatient visits from October 2020. Patients were instructed to enter their self-measurements (pulmonary functions and vital signs) and immunosuppressant dosages twice a day.

Acceptability was assessed by the data filling rate. The changes in filling rate over time were evaluated using a linear mixed-effects model for repeated measurements.

Results

A total of 19 patients were included in the study. There were no significant differences in the filling rates between the handwritten charts and LT-FollowUp.

Conclusion

LT-FollowUp is an acceptable system for patients. Further development of the LT-FollowUp system may lead to better long-term clinical outcomes of lung transplantation.
Detection ofP. malariaeusing a new rapid isothermal amplification lateral flow assay
Authors: Assefa Ashenafi , Wamae Kevin K. , Hennelly Chris M. , Ngasala Billy , Muller Meredith , Kalonji Albert , Phanzu Fernandine , Cunningham Clark H. , Lin Jessica T. , Parr Jonathan B.
Published: March 2023

P. malariaeis found worldwide and causes chronic parasitism in its human hosts. We developed aP. malariae (Pm)diagnostic assay that uses rapid, isothermal recombinase polymerase amplification (RPA) and lateral-flow-strip detection. Using 18S rRNA plasmid DNA, the assay demonstrates a detection limit of 10 copies /µL (∼1.7 genome equivalents) and 100% analytical specificity. Testing in field samples showed 95% clinical sensitivity and 88% specificity compared to qPCR. Total assay time was 35 minutes. Combined with simplified DNA extraction methods, the assay has potential for future field-deployable point-of-care use to detect a parasite species that remains largely undiagnosed.
NovelCYP1B1-RMDN2Alzheimer’s disease locus identified by genome-wide association analysis of cerebral tau deposition on PET
Authors: Nho Kwangsik , Risacher Shannon L. , Apostolova Liana , Bice Paula J. , Brosch Jared , Deardorff Rachael , Faber Kelley , Farlow Martin R. , Foroud Tatiana , Gao Sujuan , Rosewood Thea , Kim Jun Pyo , Nudelman Kelly , Yu Meichen , Aisen Paul , Sperling Reisa , Hooli Basavaraj , Shcherbinin Sergey , Svaldi Diana , Jack Clifford R. , Jagust William J. , Landau Susan , Vasanthakumar Aparna , Waring Jeffrey F. , Doré Vincent , Laws Simon M. , Masters Colin L. , Porter Tenielle , Rowe Christopher C. , Villemagne Victor L , Dumitrescu Logan , Hohman Timothy J. , Libby Julia B. , Mormino Elizabeth , Buckley Rachel F. , Johnson Keith , Yang Hyun-Sik , Petersen Ronald C. , Ramanan Vijay K. , Vemuri Prashanthi , Cohen Ann D. , Fan Kang-Hsien , Kamboh M. Ilyas , Lopez Oscar L. , Bennett David A. , Ali Muhammad , Benzinger Tammie , Cruchaga Carlos , Hobbs Diana , De Jager Philip L. , Fujita Masashi , Jadhav Vaishnavi , Lamb Bruce T. , Tsai Andy P. , Castanho Isabel , Mill Jonathan , Weiner Michael W. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI),   the Alzheimer’s Disease Neuroimaging Initiative – Department of Defense,   the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study),   Australian Imaging, Biomarker & Lifestyle Study (AIBL), Saykin Andrew J.
Published: March 2023

Determining the genetic architecture of Alzheimer’s disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. TheCYP1B1-RMDN2locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, whileAPOE4rs429358 accounted for 3.6%. rs2113389 was associated with higher tau and faster cognitive decline. Additive effects, but no interactions, were observed between rs2113389 and diagnosis,APOE4, and Aβ positivity.CYP1B1expression was upregulated in AD. rs2113389 was associated with higherCYP1B1expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship betweenCYP1B1and tau deposition but not Aβ. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.
External Validation of DeepBleed: The first open-source 3D Deep Learning Network for the Segmentation of Intracerebral and Intraventricular Hemorrhage
Authors: Cao Haoyin , Morotti Andrea , Mazzacane Federico , Desser Dmitriy , Schlunk Frieder , Güttler Christopher , Kniep Helge , Penzkofer Tobias , Fiehler Jens , Hanning Uta , Dell’Orco Andrea , Nawabi Jawed
Published: March 2023

Objectives

DeepBleed is the first publicly available deep neural network model for the 3D segmentation of acute intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) on non-enhanced CT scans (NECT). The aim of this study was to evaluate the generalizability in an independent heterogenous ICH cohort and to improve the prediction accuracy by retraining the model.

Methods

This retrospective study included patients from three European stroke centers diagnosed with acute spontaneous ICH and IVH on NECT between January 2017 and June 2020. Patients were divided into a training-, validation- and test cohort according to the initial study. Model performance was evaluated using metrics of dice score (DSC), sensitivity, and positive predictive values (PPV) in the original model (OM) and the retrained model (RM) for each ICH location. Students’ t-test was used to compare the DSC between the two models. A multivariate linear regression model was used to identify variables associated with the DSC. Pearson correlation coefficients (r) were calculated to evaluate the volumetric agreement with the manual reference (ground truth: GT). Intraclass correlation coefficients (ICC) were calculated to evaluate segmentation agreement with the GT compared to expert raters.

Results

In total, 1040 patients were included. Segmentations of the OM had a median DSC, sensitivity, and PPV of 0.84, 0.79, and 0.93, compared to 0.83, 0.80, and 0.91 in the RM, adjusted p-values > 0.05. Performance metrics for infratentorial ICH improved from a median DSC of 0.71 for brainstem and 0.48 for cerebellar ICH in the OM to 0.77 and 0.79 in the RM. ICH volume and location were significantly associated with the DSC, p-values < 0.05. Volumetric measurements showed strong agreement with the GT (r > 0.90), p-value >0.05. Agreement of the automated segmentations with the GT were excellent (ICC ≥ 0.9, p-values <0.001), however worse if compared to the human expert raters (p-values <0.0001).

Conclusions

DeepBleed demonstrated an overall good generalization in an independent validation cohort and location specific variances improved significantly after model retraining. Segmentations and volume measurements showed a strong agreement with the manual reference; however, the quality of segmentations was lower compared to human expert raters. This is the first publicly available external validation of the open-source DeepBleed network for spontaneous ICH introduced by Sharrock et al.
Discrepancies between registered protocol and final publication in exercise interventions for chronic low back pain: a meta-research study
Authors: Bargeri Silvia , Basso Giacomo , Geraci Ignazio , Castellini Greta , Chiarotto Alessandro , Gianola Silvia , Ostelo Raymond , Testa Marco , Innocenti Tiziano
Published: March 2023

Background

Evidence of selective reporting bias is common in randomized controlled trials (RCTs) of various medical fields, undermining their integrity and credibility. However, this has not yet been assessed in exercise for chronic low back pain (cLBP) RCTs. Therefore, we will aim to assess the prevalence of discrepancies between the registered protocol and final publication in this field and the characteristics of RCTs with and without such discrepancies.

Methods

We will start from the RCTs included in the 2021 Cochrane review (n=249) and identified in its update (n=172) to select all RCTs reporting a protocol registration. Standardized data collection form will be developed to record information from both registration and publication. We will then detect discrepancies for primary and secondary outcomes, outcomes measures, timepoints, number of arms and statistical analysis plans between the registered protocol and final publication. We will use descriptive statistics to assess the proportion of RCTs with and without a discrepancy as well as to compare their characteristics.

Ethics and dissemination

We will offer insights and recommendations for future RCTs avoiding selective reporting that can reflect in subsequent inaccuracies in systematic reviews or guidelines for clinical practice. Results of this study will be shared through conference presentations and publication in a peer-reviewed journals.
Scleral appearance is not a correlate of domestication in mammals
Authors: Caspar Kai R. , Hüttner Lisa , Begall Sabine
Published: March 2023

Numerous hypotheses try to explain the unusual appearance of the human eye with its bright sclera and transparent conjunctiva and how it could have evolved from a dark-eyed phenotype, as is present in many non-human primates. Recently, it has been argued that pigmentation defects induced by self-domestication may have led to bright-eyed ocular phenotypes in humans and some other primate lineages, such as marmosets. However, it has never been systematically studied whether actual domesticated mammals consistently deviate from wild mammals in regard to their conjunctival pigmentation and if this trait might therefore be part of a domestication syndrome. Here, we test this idea by drawing phylogenetically informed comparisons from a photographic dataset spanning 13 domesticated mammal species and their closest living wild relatives. We did not recover significant differences in scleral appearance or irido-scleral contrast between domesticated and wild forms, suggesting that conjunctival depigmentation, unlike cutaneous pigmentation disorders, is not a general correlate of domestication. Regardless of their domestication status, macroscopically depigmented conjunctivae were observed in carnivorans and lagomorphs, whereas ungulates generally displayed darker eyes. Based on our dataset, we also present preliminary evidence for a general increase of conjunctival pigmentation with eye size in mammals. Our findings suggest that conjunctival depigmentation in humans is not a byproduct of self-domestication, even if we assume that our species has undergone such a process in its recent evolutionary history.
Comparative analysis of amphibian genomes: an emerging resource for basic and applied research
Authors: Kosch Tiffany A. , Crawford Andrew J. , Mueller Rachel Lockridge , Wollenberg Valero Katharina C. , Power Megan L. , Rodríguez Ariel , O’Connell Lauren A. , Young Neil D. , Skerratt Lee F.
Published: March 2023

Amphibians are the most threatened group of vertebrates and are in dire need of conservation intervention to ensure their continued survival. They exhibit unique features including a high diversity of reproductive strategies, permeable and specialized skin capable of producing toxins and antimicrobial compounds, multiple genetic mechanisms of sex determination, and in some lineages, the ability to regenerate limbs and organs. Although genomics approaches would shed light on these unique traits and aid conservation, sequencing and assembly of amphibian genomes has lagged behind other taxa due to their comparatively large genome sizes. Fortunately, the development of long-read sequencing technologies and initiatives has led to a recent burst of new amphibian genome assemblies. Although growing, the field of amphibian genomics suffers from the lack of annotation resources, tools for working with challenging genomes, and lack of high-quality assemblies in multiple clades of amphibians. Here we analyze 51 publicly available amphibian genomes to evaluate their usefulness for functional genomics research. We report considerable variation in genome assembly quality and completeness, and report some of the highest transposable element and repeat contents of any vertebrate. Additionally, we detected an association between transposable element content and climatic variables. Our analysis provides evidence of conserved genome synteny despite the long divergence times of this group, but we also highlight inconsistencies in chromosome naming and orientation across genome assemblies. We discuss sequencing gaps in the phylogeny and suggest key targets for future sequencing endeavors. Finally, we propose increased investment in amphibian genomics research to promote their conservation.
A distinct class of pan-cancer susceptibility genes revealed by alternative polyadenylation transcriptome-wide association study
Authors: Chen Hui , Wang Zeyang , Wang Jia , Chen Wenyan , Ma Xuelian , Zou Xudong , Plass Mireya , Lian Cheng , Ni Ting , Wei Gong-Hong , Li Wei , Deng Lin , Li Lei
Published: March 2023

Alternative polyadenylation (APA) plays an important role in cancer initiation and progression; however, current genome- and transcriptome-wide association studies (GWAS and TWAS, respectively) mostly ignore APA when identifying putative cancer susceptibility genes. Here, we performed a pan-cancer 3′untranslated region (UTR) APA TWAS (3′aTWAS) by integrating 80 well-powered (n>50,000) GWAS datasets across 23 major cancer types with APA quantification from 17,330 RNA sequencing samples across 49 tissue types and 949 individuals. We found that genetic variants associated with APA represent around 24.4% of cancer GWAS variants and are more likely to be causal variants explaining a large portion of cancer heritability. We further identified 413 significant APA-linked cancer susceptibility genes. Of these, 77.4% have been overlooked by traditional expression- and splicing-studies, given that APA may regulate translation, protein localization, and protein–protein interactions independent of the expression level of the genes or splicing isoforms. As proof of principle validation, modulation of four novel APA-linked breast-cancer susceptibility genes significantly altered cancer cell proliferation. Our study highlights the significant role of APA in discovering new cancer susceptibility genes and provides a strong foundational framework for enhancing our understanding of the etiology underlying human cancers.
Multifunctional Materials Strategies for Enhanced Safety of Wireless, Skin-Interfaced Bioelectronic Devices
Authors: Liu Claire , Kim Jin-Tae , Yang Da Som , Cho Donghwi , Yoo Seonggwang , Madhvapathy Surabhi R. , Jeong Hyoyoung , Yang Tianyu , Luan Haiwen , Avila Raudel , Park Jihun , Wu Yunyun , Bryant Kennedy , Cho Min , Lee JiYong , Kwak Jay , Ryu WonHyoung , Huang Yonggang , Nuzzo Ralph G. , Rogers John A.
Published: March 2023

Many recently developed classes of wireless, skin-interfaced bioelectronic devices rely on conventional thermoset silicone elastomer materials, such as poly(dimethylsiloxane) (PDMS), as soft encapsulating structures around collections of electronic components, radio frequency antennas and, commonly, rechargeable batteries. In optimized layouts and device designs, these materials provide attractive features, most prominently in their gentle, noninvasive interfaces to the skin even at regions of high curvature and large natural deformations. Past work, however, overlooks opportunities for developing variants of these materials for multimodal means to enhance the safety of the devices against failure modes that range from mechanical damage to thermal runaway. This paper presents a self-healing PDMS dynamic covalent matrix embedded with chemistries that provide thermochromism, mechanochromism, strain-adaptive stiffening, and thermal insulation, as a collection of attributes relevant to safety. Demonstrations of this materials system and associated encapsulation strategy involve a wireless, skin-interfaced device that captures mechanoacoustic signatures of health status. The concepts introduced here can apply immediately to many other related bioelectronic devices.
A unique symbiosome in an anaerobic single-celled eukaryote
Authors: Jerlström-Hultqvist Jon , Gallot-Lavallée Lucie , Salas-Leiva Dayana E. , Curtis Bruce A. , Záhonová Kristína , Čepička Ivan , Stairs Courtney W. , Pipaliya Shweta , Dacks Joel B. , Archibald John M. , Roger Andrew J.
Published: March 2023

Symbiotic relationships drive evolutionary change and are important sources of novelty. Here we demonstrate a highly structured syntrophic symbiosis between species of the anaerobic protistAnaeramoeba(Anaeramoebae, Metamonada) and bacterial ectosymbionts. We dissected this symbiosis with long-read metagenomics, transcriptomics of host and symbiont cells coupled with fluorescent in situ hybridization (FISH), and microscopy. Genome sequencing, phylogenomic analyses and FISH show that the symbionts belong to theDesulfobacteraceaeand were acquired independently in two differentAnaeramoebaspecies. We show that ectosymbionts likely reside deep within cell surface invaginations in a symbiosomal membrane network that is tightly associated with cytoplasmic hydrogenosomes. Metabolic reconstructions based on the genomes and transcriptomes of the symbionts suggest a highly evolved syntrophic interaction. Host hydrogenosomes likely produce hydrogen, acetate, and propionate that are consumed by the symbionts dissimilatory sulfate reduction, Wood-Ljungdahl and methylmalonyl pathways, respectively. Because the host genome sequences encode several vitamin B12-dependent enzymes but appear to lack the ability to biosynthesize this vitamin, we hypothesize that the symbionts supply their hosts with B12. We detected numerous lateral gene transfers from diverse bacteria toAnaeramoeba, including genes involved in oxygen defense and anaerobic metabolism. Gene families encoding membrane-trafficking components that regulate the phagosomal maturation machinery are notably expanded inAnaeramoebaspp. and may be involved in organizing and/or stabilizing the symbiosomal membrane system. Overall, the Anaeramoebae have evolved a dynamic symbiosome comprised of a vacuolar system that facilitates positioning and maintenance of sulfate-reducing bacterial ectosymbionts.
A role for retro-splenial cortex in the task-related P3 network
Authors: Das Diptyajit , Shaw Marnie E. , Hämäläinen Matti S. , Dykstra Andrew R. , Doll Laura , Gutschalk Alexander
Published: March 2023

Objective

The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified.

Methods

We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm.

Results

Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses.

Conclusion

The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG.

Significance

These results provide a new perspective for the interpretation of the extensive research based on the P3 response.
Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells
Authors: Kirk Jason S , Wang Jie , Tracz Amanda , Long Mark , Rosario Spencer R , Ji Yibing , Kumar Rahul , Liu Xiaozhuo , Singh Prashant K , Puzanov Igor , Chatta Gurkamal , Cheng Qing , Huang Jiaoti , Wrana Jeffrey L , Lovell Jonathan , Yu Han , Liu Song , Shen Michael M , Liu Tao , Tang Dean G
Published: March 2023

Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate JUN/FOS, WNT/B-Catenin, FOXQ1, NFkB, and JAK/STAT pathways as the major drivers of castration-resistant luminal populations with high relevance to human PCa. Importantly, we demonstrate the utility of our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), to aid in developing novel combination treatments with ARSI for advanced PCa patients.
Delayed formation of neural representations of space in aged mice
Authors: McDermott Kelsey D. , Frechou M. Agustina , Jordan Jake T. , Martin Sunaina S. , Gonçalves J. Tiago
Published: March 2023

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Usingin vivotwo-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.
Continuous optical detection of small-molecule analytes in complex biomatrices
Authors: Hariri Amani A. , Cartwright Alyssa P. , Dory Constantin , Gidi Yasser , Yee Steven , Fu Kaiyu , Yang Kiyoul , Wu Diana , Thompson Ian A. P. , Maganzini Nicolò , Feagin Trevor , Young Brian E. , Afshar Behrad Habib , Eisenstein Michael , Digonnet Michel , Vuckovic Jelena , Soh H. Tom
Published: March 2023

Current technology for measuring specific biomarkers – continuously in complex samples, without sample preparation – is limited to just handful of molecules such as glucose and blood oxygen. In this work, we present the first optical biosensor system that enables continuous detection of a wide range of biomarkers in complex samples, such as human plasma. Our system employs a modular duplex-bubble switch (DBS) architecture that converts aptamers into structure-switching fluorescence probes whose affinity and kinetics can be readily tuned. These DBS constructs are coupled to a fiber-optic detector that measures the fluorescence change only within an evanescent field, thereby minimizing the impact of background autofluorescence and enabling direct detection of analytes at physiologically relevant concentrations even in interferent-rich sample matrices. Using our system, we achieved continuous detection of dopamine in artificial cerebrospinal fluid for >24 hours with sub-second resolution and a limit of detection (LOD) of 1 µM. We subsequently demonstrated the system’s generalizability by configuring it to detect cortisol with nanomolar sensitivity in undiluted human plasma. Both sensors achieved LODs orders of magnitude lower than theKDof the DBS element, highlighting the potential to achieve sensitive detection even when using aptamers with modest affinity.