bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut Microbiota in Monozygotic Twins Discordant for Parkinson's Disease
Authors: Bolliri Carlotta , Fontana Alessandra , Cereda Emanuele , Barichella Michela , Cilia Roberto , Ferri Valentina , Caronni Serena , Calandrella Daniela , Morelli Lorenzo , Pezzoli Gianni
Published: July 2022

Differences in gut microbiota between Parkinson's disease patients and controls seem to depend on multiple—frequently unmeasured—confounders. Monozygotic twins offer a unique model for controlling several factors responsible for interpersonal variation in gut microbiota. Fecal samples from 20 monozygotic twin pairs (n = 40) discordant for Parkinson's disease were studied (metagenomic shotgun analysis). Paired data analysis detected minimal differences in bacterial taxa abundance at species level (Bacteroides pectinophilus [p = 0.037], Bifidobacterium pseudocatenulatum [p = 0.050], and Bifidobacterium catenulatum [p = 0.025]) and in predicted metabolic pathways (primary bile acid biosynthesis [p = 0.037]). Additional studies are warranted to understand the role of gut microbiota in the pathogenesis of Parkinson's disease. ANN NEUROL 2022;92:631–636
Tandem synthesis, cytotoxicity, and in silico study of new 1,3,4‐oxadiazoles as potential thymidylate synthase inhibitors
Authors: Sanad Sherif M. H. , Mekky Ahmed E. M. , Ahmed Ahmed A. M.
Published: July 2022

A new series of pyrrole‐linked mono‐ and bis(1,3,4‐oxadiazole) hybrids, attached to various arene units, was prepared using a two‐step tandem protocol. Therefore, a benzohydrazide derivative was condensed with the appropriate aldehydes in ethanol at 80°C for 60–150 min to give the corresponding N‐(benzoylhydrazones). Without isolation, the previous intermediates underwent intramolecular oxidative cyclization in dimethyl sulfoxide at 180°C for 90–200 min in the presence of chloramine trihydrate to afford the target hybrids. The cytotoxicity of all hybrids was examined in vitro against the MCF‐7, HEPG2, and Caco2 cell lines. Arene‐linked hybrids 4i and 4j, attached to p‐nitro and p‐acetoxy units, were the most potent ones, with IC50 values ranging from 5.47 to 8.80 and 12.75 to 21.22 μM, respectively, when tested on the above cell lines. At the tested concentrations of 5 and 7.5 μM, hybrid 4i inhibited thymidylate synthase (TS) with the best inhibition percentages of 72.3 and 91.3, whereas hybrid 4j displayed comparable inhibitory activity to the reference pemetrexed. Hybrid 4j had inhibition percentages of 62.7 and 82.6, whereas pemetrexed had inhibition percentages of 59.2 and 80.2, respectively. The capability of hybrids 4i and 4j as potential TS inhibitors is supported by molecular docking studies, while SwissADME predicts their efficacy as drug‐like scaffolds.
Therapeutic management of arthritis: A review on structural and target‐based approaches
Authors: Mahore Anjali , Kamboj Payal , Kaleem Mohammad , Amir Mohammad
Published: July 2022

Inflammation is the natural defense mechanism against any external stimuli in the human body and it saves us from foreign entities that may alter our bodies' normal functioning. Any anomaly in this natural defense system leads to the development of different pathological conditions associated with chronic inflammation like rheumatoid arthritis, osteoarthritis, atopy, asthma, allergic rhino‐conjunctivitis, coronary artery disease, cardiac arrhythmias, obesity, insulin resistance and type‐2 diabetes, depression, and aging. These disorders impair the quality of life of affected people in different ways. Among these, rheumatoid arthritis and osteoarthritis are the most common chronic inflammation‐associated disorders. Different therapeutic strategies are already available for the treatment of rheumatoid arthritis and osteoarthritis, but all with pros and cons. Here, we discuss the emergence of several antiarthritic analogs developed by different researchers which could provide the basis for the evolution of newer therapeutic strategies with better activity and safety profiles.
Multivariate dynamic modeling for Bayesian forecasting of business revenue
Authors: Yanchenko Anna K. , Tierney Graham , Lawson Joseph , Hellmayr Christoph , Cron Andrew , West Mike
Published: July 2022

Forecasting enterprise‐wide revenue is critical to many companies and presents several challenges and opportunities for significant business impact. This case study is based on model developments to address these challenges for forecasting in a large‐scale retail company. Focused on multivariate revenue forecasting across collections of supermarkets and product categories, hierarchical dynamic models are natural: these are able to couple revenue streams in an integrated forecasting model, while allowing conditional decoupling to enable relevant and sensitive analysis together with scalable computation. Structured models exploit multi‐scale modeling to cascade information on price and promotion activities as predictors relevant across categories and groups of stores. With a context‐relevant focus on forecasting revenue 12 weeks ahead, the study highlights product categories that benefit from multi‐scale information, defines insights into when, how, and why multivariate models improve forecast accuracy, and shows how cross‐category dependencies can relate to promotion decisions in one category impacting others. Bayesian modeling developments underlying the case study are accessible in custom code for interested readers.
Study on luminescent properties of orange phosphor NaCaPO4:Eu3+
Authors: Shi Rong , Wang Xigui
Published: July 2022

The NaCaPO4:Eu3+ phosphor was synthesized by the sol–gel method. The structure and luminescence properties of the phosphor were analyzed by thermogravimetric‐differential thermal analysis (TG‐DTA), Fourier‐transform infrared (FTIR) spectroscopy, X‐ray diffraction (XRD), transmission electron microscopy (TEM) and fluorescence spectroscopy. TG‐DTA results show that NaCaPO4 phase can be formed after 700°C. FTIR spectra confirmed the existence of PO4 units. XRD results show that the sample is a pure NaCaPO4 orthorhombic crystal phase. The TEM diagram shows that the sample has good uniformity. The NaCaPO4:Eu3+ emits orange light under 394 nm excitation. The optimal doping concentration is 3 mol%. The reason for concentration quenching is caused by multipolar interaction. Through further analysis of the charge transfer band and the spectrum at 5D0 → 7F0 transition of the NaCaPO4:Eu3+ phosphor, the reason for the orange light of the phosphor is owing to the different Eu3+ occupancy which is explained in detail.
Epstein–Barr virus DNA change level combined with tumor volume reduction ratio after inductive chemotherapy as a better prognostic predictor in locally advanced nasopharyngeal carcinoma
Authors: Xiang Zhong‐zheng , He Tao , Zeng Yuan‐yuan , Liu Fang , Shao Bian‐fei , Yang Tian , Ma Jia‐chun , Wang Xi‐ran , Yu Si‐ting , Liu Lei
Published: July 2022

Background

To explore the prognosis predicting ability of the combined factors, Epstein–Barr virus DNA change level (EBVCL) and tumor volume reduction ratio (TVRR) after inductive chemotherapy (IC), in locally advanced nasopharyngeal carcinoma (LANPC).

Methods

From 2010 to 2018, 299 LANPC patients were included in this retrospective study. Receiver operating characteristic (ROC) curve analysis was performed to acquire the best critical values. According to the best critical values of EBVCL and TVRR, patients were stratified into low‐ and high‐risk groups. Kaplan–Meier and ROC curve analyses were utilized to verify the prognostic ability of the new predictor (EBVCL+TVRR). The prognostic values among EBVCL+TVRR, EBVCL, TVRR, TNM stage, and the RECIST 1.1 criteria were compared by ROC curve. The primary end points were overall survival (OS), progression‐free survival (PFS), distant metastasis‐free survival (DMFS), and locoregional failure‐free survival (LRFFS).

Results

ROC curve analyses of TVRR on three‐year survival showed the best critical values of TVRR was 32.72% for OS, 30.21% for PFS and LRFFS, 29.87% for DMFS. The best critical value of EBVCL was 127 copies/ml for OS, and 87.7 copies/ml for PFS, DMFS, and LRFFS. The three‐year OS, PFS, DMFS, and LRFFS for low‐ and high‐risk groups were 97.7% versus 78.3% (hazard ratio [HR] = 0.2398; 95% confidence interval [CI]: 0.1277–0.4502; p < 0.0001), 91.1% versus 60.9% (HR = 0.3294; 95% CI: 0.2050–0.5292; p < 0.0001), 94.2% versus 68.7% (HR = 0.2413; 95% CI: 0.1284–0.4535; p < 0.0001) and 97.8% versus 77.9% (HR = 0.3078; 95% CI: 0.1700–0.5573; p = 0.0001), respectively. The maximal area under ROC curve of EBVCL+TVRR, EBVCL, TVRR, TNM stage, and RECIST 1.1 criteria for three‐year OS was 0.829, 0.750, 0.711, 0.555, and 0.605, respectively.

Conclusion

The new‐developed indicator (EBVCL+TVRR) could better predict the LANPC patient's survival after IC compared with TNM stage system or RECIST 1.1 criteria.
A case–control study to evaluate the impact of the breast screening programme on breast cancer incidence in England
Authors: Blyuss Oleg , Dibden Amanda , Massat Nathalie J. , Parmar Dharmishta , Cuzick Jack , Duffy Stephen W. , Sasieni Peter
Published: July 2022

Background

There is uncertainty about overdiagnosis in mammography screening.

Methods

We aimed to estimate the effect of screening on breast cancer incidence and overdiagnosis in the NHS Breast Screening Programme in England. The study included 57,493 cases and 105,653 controls, with cases defined as women diagnosed at ages 47–89 with primary breast cancer, invasive or ductal carcinoma in situ, in 2010 or 2011. Where possible, two controls were selected per case, matched on date of birth and screening area.

Conditional logistic regression was used to estimate the effect of screening on breast cancer risk, with adjustment for potential self‐selection bias. Results were combined with national incidence data to estimate absolute rates of overdiagnosis. Overdiagnosis was calculated as the cumulative excess of cancers diagnosed in the age group 50–77 in a woman attending three‐yearly screening between ages 50 and 70 compared with a woman attending no screens.

Results

The estimated number of cases overdiagnosed in women attending all screens in the programme was 679.3 per 100,000 without adjustment for self‐selection bias and 261.2 per 100,000 with adjustment. These corresponded to an estimated 9.5% of screen‐detected cancers overdiagnosed without adjustment and 3.7% with adjustment for self‐selection.

Conclusions

The NHS Breast Screening Programme in England confers at worst modest levels of overdiagnosis.
Mechanical properties of thermoplastic polymers in fused filament fabrication (FFF)
Authors: Bhardwaj Nancy , Henein Hani , Wolfe Tonya
Published: July 2022

Fused filament fabrication (FFF) is a method used to fabricate initial prototypes out of polymeric materials, with printed parts often being used as load‐carrying elements. The mechanical properties of various polymer materials produced under certain printing conditions exhibit superior strength and ductility and may serve as an inexpensive replacement for metal or wooden parts. To gain knowledge of 3D‐printed part strength and compare the quality of filament material from several manufacturers, this study characterizes the mechanical properties of parts printed from various commercial FFF feedstocks. Uniaxial tensile testing is performed to determine the ultimate tensile strength, Young's modulus, and fracture strain of polymer and composite materials. This study, thus, demonstrates the importance and necessity of evaluating the filament feedstock prior to printing, as polymeric filaments of the same type of polymer can have different mechanical properties.
A peptide interfering with the dimerization of oncogenic KITENIN protein and its stability suppresses colorectal tumour progression
Authors: Kim Sung Jin , Sun Eun Gene , Bae Jeong A , Park Sehoon , Hong Chang‐Soo , Park Zee‐Yong , Kim Hangun , Kim Kyung Keun
Published: July 2022

The stability of a protein, as well as its function and versatility, can be enhanced through oligomerization. KITENIN (KAI1 C‐terminal interacting tetraspanin) is known to promote the malignant progression of colorectal cancer (CRC). How KITENIN maintains its structural integrity and stability are largely unknown, however. Here we investigated the mechanisms regulating the stability of KITENIN with the aim of developing therapeutics blocking its oncogenic functions. We found that KITENIN formed a homo‐oligomeric complex and that the intracellular C‐terminal domain (KITENIN‐CTD) was needed for this oligomerization. Expression of the KITENIN‐CTD alone interfered with the formation of the KITENIN homodimer, and the amino acid sequence from 463 to 471 within the KITENIN‐CTD was the most effective. This sequence coupled with a cell‐penetrating peptide was named a KITENIN dimerization‐interfering peptide (KDIP). We next studied the mechanisms by which KDIP affected the stability of KITENIN. The KITENIN‐interacting protein myosin‐X (Myo10), which has oncogenic activity in several cancers, functioned as an effector to stabilize the KITENIN homodimer in the cis formation. Treatment with KDIP resulted in the disintegration of the homodimer via downregulation of Myo10, which led to increased binding of RACK1 to the exposed RACK1‐interacting motif (463–471 aa), and subsequent autophagy‐dependent degradation of KITENIN and reduced CRC cell invasion. Intravenous injection of KDIP significantly reduced the tumour burden in a syngeneic mouse tumour model and colorectal liver metastasis in an intrasplenic hepatic metastasis model. Collectively, our present results provide a new cancer therapeutic peptide for blocking colorectal liver metastasis, which acts by inducing the downregulation of Myo10 and specifically targeting the stability of the oncogenic KITENIN protein.
A comprehensive survey on software‐defined networking for smart communities
Authors: Chaudhary Rajat , Aujla Gagangeet Singh , Kumar Neeraj , Chouhan Pushpinder Kaur
Published: July 2022

The need to provide services closer to the end‐user proximity leads to the exchange of a large volume of data generated from the smart devices deployed at different geo‐distributed sites. The massive amount of data generated from the smart devices need to be transmitted, analyzed, and processed. This requires seamless data exchanges among geo‐separated nodes, which results in a considerable burden on the underlying network infrastructure and can degrade the performance of any implemented solution. Therefore, a dynamic, agile, and programmable network management paradigm is required. To handle the challenges mentioned above, software‐defined networking (SDN) gained much attention from academia, researchers, and industrial sectors. Shifting the computational load from forwarding devices to a logically centralized controller is a dream of every network operator who wants to have complete control and global visibility of the network. Also, the concept of network functions virtualization (NFV) in SDN controller is required to increase resource utilization efficiency. Thus, in this paper, a comprehensive survey on SDN for various smart applications is presented. This survey covers the infrastructural details of SDN hardware and OpenFlow switches, controllers, simulation tools, programming languages, open issues, and challenges in SDN implementation with advanced technologies such as 5G and microservices. In addition, the challenges on the control plane and data plane are highlighted in detail, such as fault tolerance, routing, scheduling of flows, and energy consumption on OpenFlow switches. Finally, various open issues and challenges future scope of SDN are discussed and analyzed in the proposal.
A flexible three‐dimensional heterophase computed tomography hepatocellular carcinoma detection algorithm for generalizable and practical screening
Authors: Cheng Chi‐Tung , Cai Jinzheng , Teng Wei , Zheng Youjing , Huang Yu‐Ting , Wang Yu‐Chao , Peng Chien‐Wei , Tang Youbao , Lee Wei‐Chen , Yeh Ta‐Sen , Xiao Jing , Lu Le , Liao Chien‐Hung , Harrison Adam P.
Published: July 2022

Hepatocellular carcinoma (HCC) can be potentially discovered from abdominal computed tomography (CT) studies under varied clinical scenarios (e.g., fully dynamic contrast‐enhanced [DCE] studies, noncontrast [NC] plus venous phase [VP] abdominal studies, or NC‐only studies). Each scenario presents its own clinical challenges that could benefit from computer‐aided detection (CADe) tools. We investigate whether a single CADe model can be made flexible enough to handle different contrast protocols and whether this flexibility imparts performance gains. We developed a flexible three‐dimensional deep algorithm, called heterophase volumetric detection (HPVD), that can accept any combination of contrast‐phase inputs with adjustable sensitivity depending on the clinical purpose. We trained HPVD on 771 DCE CT scans to detect HCCs and evaluated it on 164 positives and 206 controls. We compared performance against six clinical readers, including two radiologists, two hepatopancreaticobiliary surgeons, and two hepatologists. The area under the curve of the localization receiver operating characteristic for NC‐only, NC plus VP, and full DCE CT yielded 0.71 (95% confidence interval [CI], 0.64–0.77), 0.81 (95% CI, 0.75–0.87), and 0.89 (95% CI, 0.84–0.93), respectively. At a high‐sensitivity operating point of 80% on DCE CT, HPVD achieved 97% specificity, which is comparable to measured physician performance. We also demonstrated performance improvements over more typical and less flexible nonheterophase detectors. Conclusion: A single deep‐learning algorithm can be effectively applied to diverse HCC detection clinical scenarios, indicating that HPVD could serve as a useful clinical aid for at‐risk and opportunistic HCC surveillance.
A cell penetrating peptide‐modified magnetic/fluorescent probe for in vivo tracking of mesenchymal stem cells
Authors: Xie Xing , Liu Wei , Zhu Wanzong , Zhang Gongyuan , Dai Yiyao , Wu Jiumei , Nie Hemin , Lei Lei
Published: July 2022

Difficulty in precise tracking of the in vivo distribution and migration of transplanted stem cells in a noninvasive way is a great hurdle in regenerative medicine research. Paramagnetic element‐doped upconversion nanoparticles (UCNPs) emerge as a kind of promising dual‐modal imaging agents owing to the possibility in combining strong contrast of MR imaging and high efficiency of fluorescence imaging. Herein a kind of Mn‐doped NaYF4‐based UCNPs (NaYF4: 20%Yb, 2%Er, 30%Mn) was developed and then hydrophilized by various coatings, including cell penetrating peptide, DNA, and SiO2. The UCNPs were denoted as Pep/UCNPs, DNA/UCNPs, and SiO2/UCNPs, respectively. Their potential in cell labeling and in vivo tracking applications was comprehensively explored. The results show that the Mn‐doped UCNPs possess high biocompatibility, high cell labeling efficiency, high MR resolution, and importantly a single emission at 660 nm, within optical window for in vivo imaging of biological targets. Particularly, mesenchymal stem cells (MSCs) pre‐labeled by cell penetrating peptide‐modified UCNPs (Pep/UCNPs) can be precisely monitored in terms of their distribution in mice over a long period of time by simultaneous MR and fluorescent imaging, which provided a noninvasive and double‐checking tool for investigating the destination of stem cells in tissue regeneration.
Approaches to accelerating the study of new antiretrovirals in pregnancy
Authors: Abrams Elaine J. , Calmy Alexandra , Fairlie Lee , Mahaka Imelda C. , Chimula Lameck , Flynn Patricia M. , Kinuthia John , Myer Landon , Khoo Saye H. , Musoke Philippa , Zwerski Sheryl , Zech Jennifer M. , Lockman Shahin , Siberry George K.
Published: July 2022

Introduction

Women who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available.

Discussion

The World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year‐long workshop on “Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women.” Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre‐ and post‐licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non‐pregnant adults, provided that drug levels in pregnancy are similar. However, short‐term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre‐clinical studies is essential for pregnancy short‐term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post‐marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two‐drug regimens, long‐acting ARVs and ARVs administered through novel delivery systems.

Conclusions

Implementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.
What to consider when tailoring benign prostatic hyperplasia treatment
Authors: Sze Christina , Chughtai Bilal , Kaplan Steven A
Published: July 2022

While there is a prolific list of minimally invasive procedures for lower urinary tract symptoms due to benign prostatic obstruction, the American Urological Association has yet to define their roles in the treatment algorithm. Therefore, it remains a challenge for urologists to identify the most appropriate treatment option for a particular patient.
Busting for change: a care pathway for overactive bladder
Authors: Kovacic James , Chung Amanda
Published: July 2022

Overactive bladder is common, underdiagnosed and undertreated. It is challenging to manage but evidence‐based guidelines provide a pathway to effective treatments that will help people with the disease.
Myths and misunderstanding about personality disorder
Authors: Tyrer Peter
Published: July 2022

Ideas promulgated in social media about personality disorder being a misogynistic diagnosis are far from true. Nevertheless, healthcare professionals should realise that personality problems are ubiquitous and cannot be ignored. With understanding they can be overcome.
Digital Credential Evolution
Authors: West Richard E. , Cheng Zui
Published: July 2022

In this chapter, we discuss open recognition as a key part of the digital learning/open education revolution, and open microcredentials a method for open recognition to disrupt traditional educational practices surrounding how we recognize and certify learning. We begin with definitions of open microcredentials, badges, verifiable credentials, and similar concepts. Then, we discuss the potential of open microcredentials to impact teaching and learning at the micro-, meso-, and macrolevels. We then conclude with recommendations for practice and the suggestion of a framework to guide research.
Topological invariant of 4-manifolds based on a 3-group
Authors: Radenković T. , Vojinović M.
Published: July 2022

Abstract

We study a generalization of 4-dimensional BF-theory in the context of higher gauge theory. We construct a triangulation independent topological state sum Z, based on the classical 3BF action for a general 3-group and a 4-dimensional spacetime manifold $$ \mathcal{M} $$
M
4. This state sum coincides with Porter’s TQFT for d = 4 and n = 3. In order to verify that the constructed state sum is a topological invariant of the underlying 4-dimensional manifold, its behavior under Pachner moves is analyzed, and it is obtained that the state sum Z remains the same. This paper is a generalization of the work done by Girelli, Pfeiffer, and Popescu for the case of state sum based on the classical 2BF action with the underlying 2-group structure.
3d $$ \mathcal{N} $$ = 2 brane webs and quiver matrices
Authors: Cheng Shi
Published: July 2022

Abstract

We discuss 3d brane webs and effective Chern-Simons levels for 3d $$ \mathcal{N} $$
N
= 2 gauge theories. We find that turning on real masses for chiral multiplets leads to various equivalent brane webs that are related by flipping positions of D5-branes. We interpret flips as ST-transformations for chiral multiplets. ST-transformations could turn abelian theories into dual theories with mixed Chern-Simons levels that are interpreted as quiver matrices Cij encoding DT-invariants. We notice that each brane web corresponds to a quiver matrix. ST-transformations of holomorphic blocks are discussed to verify results. We also discuss the movement of flavor D5-branes, which leads to double-layer brane webs and manifests fiber-base duality. In the second part, we compute refined vortex partition functions of nonabelian theories with the gauge group U(N) and find corresponding quiver matrices. The computation shows that on Higgs branch nonabelian groups are broken to abelian groups.
Activation of the hypoxia response protects mice from amyloid-β accumulation
Authors: Ollonen Teemu , Kurkela Margareta , Laitakari Anna , Sakko Samuli , Koivisto Henna , Myllyharju Johanna , Tanila Heikki , Serpi Raisa , Koivunen Peppi
Published: July 2022

Alzheimer’s disease (AD) is the most common cause of dementia with limited treatment options affecting millions of people and the prevalence increasing with the aging population. The current knowledge on the role of the hypoxia/hypoxia-inducible factor (HIF) in the AD pathology is restricted and controversial. We hypothesized based on benefits of the genetic long-term inactivation of HIF prolyl 4-hydroxylase-2 (HIF-P4H-2) on metabolism, vasculature and inflammatory response that prolonged moderate activation of the hypoxia response could hinder AD pathology. We used an aging model to study potential spontaneous accumulation of amyloid-β (Aβ) in HIF-P4H-2-deficient mice and a transgenic APP/PSEN1 mouse model subjected to prolonged sustained environmental hypoxia (15% O2 for 6 weeks) at two different time points of the disease; at age of 4 and 10 months. In both settings, activation of the hypoxia response reduced brain protein aggregate levels and this associated with higher vascularity. In the senescent HIF-P4H-2-deficient mice metabolic reprogramming also contributed to less protein aggregates while in APP/PSEN1 mice lesser Aβ associated additionally with hypoxia-mediated favorable responses to neuroinflammation and amyloid precursor protein processing. In conclusion, continuous, non-full-scale activation of the HIF pathway appears to mediate protection against neurodegeneration via several mechanisms and should be studied as a treatment option for AD.

Graphical abstract
Retinal microvascular associations with cardiometabolic risk factors differ by diabetes status: results from the UK Biobank
Authors: Tapp Robyn J. , Owen Christopher G. , Barman Sarah A. , Strachan David P. , Welikala Roshan A. , Foster Paul J. , Whincup Peter H. , Rudnicka Alicja R. ,   on behalf of the UK Biobank Eyes and Vision Consortium
Published: July 2022

Aims/hypothesis

The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status.

Methods

The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering).

Results

A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction <0.01) for total fat mass index, HbA1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a −0.92 μm difference (95% CI −0.96 to −0.88 μm) in arteriolar diameter for those without diabetes, and a −0.58 μm difference (95% CI −0.76 to −0.41 μm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters.

Conclusions/interpretation

We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications.

Data Availability

The data supporting the results reported here are available through the UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access).

Graphical abstract
Simulation im Wahlfach Rechtsmedizin im Dritten Abschnitt der Ärztlichen Prüfung
Authors: Stoevesandt Dietrich , Woydt Lina , Steglich Jonas , Lessig Rüdiger , Rudzki Mathias , Schlitt Axel , Weber Marko
Published: July 2022

In der COVID-19-Pandemie konnte der Dritte Abschnitt der Ärztlichen Prüfung an Simulationspersonen und Simulatoren durchgeführt werden. Auch im Fach Rechtsmedizin ist deren Einsatz sinnvoll, da eine höhere Standardisierung und Vergleichbarkeit von Prüfungsleistungen erreicht wird und die Verwendung von echten Leichnamen aus medikolegalen Gründen oft nicht vertretbar ist. Der vorliegende Fall berichtet über die Vor- und Nachteile einer Simulation im Staatsexamen, in der anhand einer Leichenschau am Simulator und einer Fremdanamnese eine Todesbescheinigung vollständig ausgefüllt werden sollte.
Quantitative evaluation of a deep learning-based framework to generate whole-body attenuation maps using LSO background radiation in long axial FOV PET scanners
Authors: Sari Hasan , Teimoorisichani Mohammadreza , Mingels Clemens , Alberts Ian , Panin Vladimir , Bharkhada Deepak , Xue Song , Prenosil George , Shi Kuangyu , Conti Maurizio , Rominger Axel
Published: July 2022

Purpose

Attenuation correction is a critically important step in data correction in positron emission tomography (PET) image formation. The current standard method involves conversion of Hounsfield units from a computed tomography (CT) image to construct attenuation maps (µ-maps) at 511 keV. In this work, the increased sensitivity of long axial field-of-view (LAFOV) PET scanners was exploited to develop and evaluate a deep learning (DL) and joint reconstruction-based method to generate µ-maps utilizing background radiation from lutetium-based (LSO) scintillators.

Methods

Data from 18 subjects were used to train convolutional neural networks to enhance initial µ-maps generated using joint activity and attenuation reconstruction algorithm (MLACF) with transmission data from LSO background radiation acquired before and after the administration of 18F-fluorodeoxyglucose (18F-FDG) (µ-mapMLACF-PRE and µ-mapMLACF-POST respectively). The deep learning-enhanced µ-maps (µ-mapDL-MLACF-PRE and µ-mapDL-MLACF-POST) were compared against MLACF-derived and CT-based maps (µ-mapCT). The performance of the method was also evaluated by assessing PET images reconstructed using each µ-map and computing volume-of-interest based standard uptake value measurements and percentage relative mean error (rME) and relative mean absolute error (rMAE) relative to CT-based method.

Results

No statistically significant difference was observed in rME values for µ-mapDL-MLACF-PRE and µ-mapDL-MLACF-POST both in fat-based and water-based soft tissue as well as bones, suggesting that presence of the radiopharmaceutical activity in the body had negligible effects on the resulting µ-maps. The rMAE values µ-mapDL-MLACF-POST were reduced by a factor of 3.3 in average compared to the rMAE of µ-mapMLACF-POST. Similarly, the average rMAE values of PET images reconstructed using µ-mapDL-MLACF-POST (PETDL-MLACF-POST) were 2.6 times smaller than the average rMAE values of PET images reconstructed using µ-mapMLACF-POST. The mean absolute errors in SUV values of PETDL-MLACF-POST compared to PETCT were less than 5% in healthy organs, less than 7% in brain grey matter and 4.3% for all tumours combined.

Conclusion

We describe a deep learning-based method to accurately generate µ-maps from PET emission data and LSO background radiation, enabling CT-free attenuation and scatter correction in LAFOV PET scanners.
mCRPC patients with PSA fluctuations under radioligand therapy have comparable survival benefits relative to patients with sustained PSA decrease
Authors: Hartrampf Philipp E. , Bundschuh Ralph A. , Weinzierl Franz-Xaver , Serfling Sebastian E. , Kosmala Aleksander , Seitz Anna Katharina , Kübler Hubert , Buck Andreas K. , Essler Markus , Werner Rudolf A.
Published: July 2022

Introduction

In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy.

Materials and methods

In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan–Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle).

Results

Sixty-one out of one hundred seventy-six (34.7%) patients showed a sustained increase and 86/176 (48.8%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95% CI 0.22–0.56; P < 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95% CI 0.30–0.80; P < 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95% CI 0.78–2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95% CI 0.38–4.05; P = 0.68).

Conclusion

Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.
Association of Abdominal Arterial Calcification Score with Patients’ Survival and Kidney Allograft Function after Kidney Transplant
Authors: Jarmi Tambi , Spaulding Aaron C. , Jebrini Abdullah , Sella David M. , Alexander Lauren F. , Nussbaum Samuel , Shoukry Mira , White Launia , Wadei Hani M. , Farres Houssam
Published: July 2022

Background

Abdominal arterial calcification (AAC) is common among candidates for kidney transplant. The aim of this study is to correlate AAC score value with post‐kidney transplant outcomes.

Methods

We modified the coronary calcium score by changing the intake data points and used it to quantitate the AAC. We conducted a retrospective clinical study of all adult patients who were transplanted at our center, between 2010 and 2013, and had abdominal computed tomography scan done before transplantation. Outcomes included mortality, pulse pressure (PP) measured by 24 h ambulatory blood pressure monitoring system, and kidney allograft function measured by iothalamate clearance.

Results

For each 1000 increase of AAC score value, there is an associated 1.05 increase in the risk of death (95% CI 1.02, 1.08) (p < 0.001). Overall median AAC value for all patients was 1784; Kaplan–Meier curve showed reduced survival of all‐cause mortality for patients with AAC score value above median and reduced survival among patients with cardiac related mortality. The iothalamate clearance was lower among patients with total AAC score value above the median. Patients with abnormal PP (< 40 or > 60 mmHg) had an elevated median AAC score value at 4319.3 (IQR 1210.4, 11097.1) compared to patients with normal PP with AAC score value at 595.9 (IQR 9.9, 2959.9) (p < 0.001).

Conclusion

We showed an association of AAC with patients’ survival and kidney allograft function after kidney transplant. The AAC score value could be used as a risk stratification when patients are considered for kidney transplant.
Applications of machine learning for imaging-driven diagnosis of musculoskeletal malignancies—a scoping review
Authors: Hinterwimmer Florian , Consalvo Sarah , Neumann Jan , Rueckert Daniel , von Eisenhart-Rothe Rüdiger , Burgkart Rainer
Published: July 2022

Musculoskeletal malignancies are a rare type of cancer. Consequently, sufficient imaging data for machine learning (ML) applications is difficult to obtain. The main purpose of this review was to investigate whether ML is already having an impact on imaging-driven diagnosis of musculoskeletal malignancies and what the respective reasons for this might be. A scoping review was conducted by a radiologist, an orthopaedic surgeon and a data scientist to identify suitable articles based on the PRISMA statement. Studies meeting the following criteria were included: primary malignant musculoskeletal tumours, machine/deep learning application, imaging data or data retrieved from images, human/preclinical, English language and original research. Initially, 480 articles were found and 38 met the eligibility criteria. Several continuous and discrete parameters related to publication, patient distribution, tumour specificities, ML methods, data and metrics were extracted from the final articles. For the synthesis, diagnosis-oriented studies were further examined by retrieving the number of patients and labels and metric scores. No significant correlations between metrics and mean number of samples were found. Several studies presented that ML could support imaging-driven diagnosis of musculoskeletal malignancies in distinct cases. However, data quality and quantity must be increased to achieve clinically relevant results. Compared to the experience of an expert radiologist, the studies used small datasets and mostly included only one type of data. Key to critical advancement of ML models for rare diseases such as musculoskeletal malignancies is a systematic, structured data collection and the establishment of (inter)national networks to obtain substantial datasets in the future.

Key Points

• Machine learning does not yet significantly impact imaging-driven diagnosis for musculoskeletal malignancies compared to other disciplines such as lung, breast or CNS cancer.

• Research in the area of musculoskeletal tumour imaging and machine learning is still very limited.

• Machine learning in musculoskeletal tumour imaging is impeded by insufficient availability of data and rarity of the disease.
Breast MRI: does a clinical decision algorithm outweigh reader experience?
Authors: Pötsch Nina , Korajac Aida , Stelzer Philipp , Kapetas Panagiotis , Milos Ruxandra-Iulia , Dietzel Matthias , Helbich Thomas H. , Clauser Paola , Baltzer Pascal A. T.
Published: July 2022

Objectives

Due to its high sensitivity, DCE MRI of the breast (MRIb) is increasingly used for both screening and assessment purposes. The Kaiser score (KS) is a clinical decision algorithm, which formalizes and guides diagnosis in breast MRI and is expected to compensate for lesser reader experience. The aim was to evaluate the diagnostic performance of untrained residents using the KS compared to off-site radiologists experienced in breast imaging using only MR BI-RADS.

Methods

Three off-site, board-certified radiologists, experienced in breast imaging, interpreted MRIb according to the MR BI-RADS scale. The same studies were read by three residents in radiology without prior training in breast imaging using the KS. All readers were blinded to clinical information. Histology was used as the gold standard. Statistical analysis was conducted by comparing the AUC of the ROC curves.

Results

A total of 80 women (median age 52 years) with 93 lesions (32 benign, 61 malignant) were included. The individual within-group performance of the three expert readers (AUC 0.723–0.742) as well as the three residents was equal (AUC 0.842–0.928), p > 0.05, respectively. But, the rating of each resident using the KS significantly outperformed the experts’ ratings using the MR BI-RADS scale (p ≤ 0.05).

Conclusion

The KS helped residents to achieve better results in reaching correct diagnoses than experienced radiologists empirically assigning MR BI-RADS categories in a clinical “problem solving MRI” setting. These results support that reporting breast MRI benefits more from using a diagnostic algorithm rather than expert experience.

Key Points

• Reporting breast MRI benefits more from using a diagnostic algorithm rather than expert experience in a clinical “problem solving MRI” setting.

• The Kaiser score, which provides a clinical decision algorithm for structured reporting, helps residents to reach an expert level in breast MRI reporting and to even outperform experienced radiologists using MR BI-RADS without further formal guidance.
3D finite-element brain modeling of lateral ventricular wall loading to rationalize periventricular white matter hyperintensity locations
Authors: Caçoilo Andreia , Rusinek Henry , Weickenmeier Johannes
Published: July 2022

Aging-related periventricular white matter hyperintensities (pvWMHs) are a common observation in medical images of the aging brain. The underlying tissue damage is part of the complex pathophysiology associated with age-related microstructural changes and cognitive decline. PvWMH formation is linked to blood–brain barrier dysfunction from cerebral small vessel disease as well as the accumulation of cerebrospinal fluid in periventricular tissue due to progressive denudation of the ventricular wall. In need of a unifying theory for pvWMH etiology, image-based finite-element modeling is used to demonstrate that ventricular expansion from age-related cerebral atrophy and hemodynamic loading leads to maximum mechanical loading of the ventricular wall in the same locations that show pvWMHs. Ventricular inflation, induced via pressurization of the ventricular wall, creates significant ventricular wall stretch and stress on the ependymal cells lining the wall, that are linked to cerebrospinal fluid leaking from the lateral ventricles into periventricular white matter tissue. Eight anatomically accurate 3D brain models of cognitively healthy subjects with a wide range of ventricular shapes are created. For all models, our simulations show that mechanomarkers of mechanical wall loading are consistently highest in pvWMHs locations (p < 0.05). Maximum principal strain, the ependymal cell thinning ratio, and wall curvature are on average 14%, 8%, and 24% higher in pvWMH regions compared to the remaining ventricular wall, respectively. Computational modeling provides a powerful framework to systematically study pvWMH formation and growth with the goal to develop pharmacological interventions in the future.
Real-time monitoring of intravenous thrombolysis in acute ischemic stroke using rotational thromboelastometry: a feasibility pilot study
Authors: Tinchon Alexander , Freydl Elisabeth , Fitzgerald Robert D. , Duarte Christina , Weber Michael , Calabek-Wohinz Bernadette , Waiß Christoph , Oberndorfer Stefan
Published: July 2022

Introduction

Rotational thromboelastometry (ROTEM) records whole blood coagulation in vitro. Data on dynamic changes of clot patterns during intravenous thrombolysis (IVT) in acute ischemic stroke is scarce. We investigated the feasibility of ROTEM as a potential point-of-care assessment tool for IVT.

Methods

In this prospective pilot study, patients with acute stroke symptoms received IVT. Whole blood coagulation was tracked on the ROTEM analyzer. Blood samples were analyzed before, and then 2, 15, 30 and 60 min after beginning IVT. In vitro clots (iCLs) were described by their maximum clot firmness (MCF), the time needed to reach MCF (MCF-t), as well as the area under the curve (AR10). National Institutes of Health Stroke Scale (NIHSS) was used as early clinical outcome parameter.

Results

We analyzed 288 iCLs from 12 patients undergoing IVT. In all iCLs, an early fibrinolysis (91% within the first 10 min) was detected during IVT. Three different curve progression patterns were observed: a low-responder pattern with a continuous clot increase, a high-responder pattern with a sustained clot decrease or total clotting suppression and an intermediate-responder pattern with alternating clot characteristics. There was a difference among these groups in early clinical outcome (AR10 and MCF each p = 0.01, MCF-t p = 0.02, Kruskal–Wallis Test).

Conclusion

The fibrinolysis patterns determined using ROTEM allow for the monitoring of IVT in patients with acute ischemic stroke. This pilot study found a correlation between the in vitro fibrinolysis patterns and early clinical outcomes. These findings support a potential for individualization of IVT in the future.