bluuebunny/crossref_metadata_2025 huggingface dataset:
An online global survey and follow-up expert groups on the scope and needs related to training, research, and mentorship among early-career addiction medicine professionals
Authors: Bhad Roshan , Achab Sophia , Rafei Parnian , Kathiresan Preethy , Ardabili Hossein Mohaddes , Butner Jenna , Orsolini Laura , Melby Katrine , Farokhnia Mehdi , Narasimha Venkata Lakshmi , Ridley Kelly , Tolomeo Serenella , Kanabar Mitika , Matanje Beatrice , Grandinetti Paolo ,   ISAM NExT Consortium, Potenza Marc , Ekhtiari Hamed , Baldacchino Alexander
Published: July 2023

Addiction medicine is a rapidly growing field with many young professionals seeking careers in this field. However, early-career professionals (ECPs) face challenges such as a lack of competency-based training due to a shortage of trainers, limited resources, limited mentorship opportunities, and establishment of suitable research areas. The International Society of Addiction Medicine (ISAM) New Professionals Exploration, Training & Education (NExT) committee, a global platform for early-career addiction medicine professionals (ECAMPs), conducted a two-phase online survey using a modified Delphi-based approach among ECAMPs across 56 countries to assess the need for standardized training, research opportunities, and mentorship. A total of 110 respondents participated in Phase I (online key informant survey), and 28 respondents participated in Phase II (online expert group discussions on three themes identified in Phase I). The survey found that there is a lack of standardized training, structured mentorship programs, research funding, and research opportunities in addiction medicine for ECAMPs. There is a need for standardized training programs, improving research opportunities, and effective mentorship programs to promote the next generation of addiction medicine professionals and further development in the entire field. The efforts of ISAM NExT are well-received and give a template of how this gap can be addressed.
A longitudinal analysis of the hot hand and gambler’s fallacy biases
Authors: Polin Brian A. , Benisaac Eyal
Published: July 2023

Researchers have found evidence of both hot hand and gambler’s fallacy biases in lottery number selection. Which of the two opposite effects is observed is often dependent upon the nature of the lottery game, the particular sample, the local culture of the participants, or the time transpired since the seed event. By observing hundreds of millions of lottery entries over 118 consecutive semiweekly drawings, we present evidence of both effects and their longitudinal properties. With respect to the selection ofindividualnumbers, lottery participants tend to avoid recently selected winning numbers. This gambler’s fallacy effect diminishes and the number becomes increasingly ‘hot’ until it is selected again. With respect to winning numbercombinations, we found strong evidence of a small but persistent hot hand bias. This bias gradually diminishes over time, but remains detectable and highly consistent for a number of years.
The hunt for the Kármán ‘constant’ revisited
Authors: Monkewitz Peter A. , Nagib Hassan M.
Published: July 2023

The log law of the wall, joining the inner, near-wall mean velocity profile (MVP) in wall-bounded turbulent flows to the outer region, has been a permanent fixture of turbulence research for over hundred years, but there is still no general agreement on the value of the prefactor, the inverse of the Kármán ‘constant’

$\kappa$

, or on its universality. The choice diagnostic tool to locate logarithmic parts of the MVP is to look for regions where the indicator function

$\varXi$

(equal to the wall-normal coordinate

$y^+$

times the mean velocity derivative

$\mathrm {d} U^+/\mathrm {d} y^+$

) is constant. In pressure-driven flows, however, such as channel and pipe flows,

$\varXi$

is significantly affected by a term proportional to the wall-normal coordinate, of order

$O({Re}_{\tau }^{-1})$

in the inner expansion, but moving up across the overlap to the leading

$O(1)$

in the outer expansion. Here we show that, due to this linear overlap term,

${Re}_{\tau }$

values well beyond

$10^5$

are required to produce one decade of near constant

$\varXi$

in channels and pipes. The problem is resolved by considering the common part of the inner asymptotic expansion carried to

$O({Re}_{\tau }^{-1})$

, and the leading order of the outer expansion. This common part contains a superposition of the log law and a linear term

$S_0 \,y^+{Re}_{\tau }^{-1}$

, and corresponds to the linear part of

$\varXi$

, which, in channel and pipe, is concealed up to

$y^+ \approx 500\unicode{x2013}1000$

by terms of the inner expansion. A new and robust method is devised to simultaneously determine

$\kappa$

and

$S_0$

in pressure-driven flows at currently accessible

${Re}_{\tau }$

values, yielding

$\kappa$

values which are consistent with the

$\kappa$

values deduced from the Reynolds number dependence of centreline velocities. A comparison with the zero-pressure-gradient turbulent boundary layer, further clarifies the issues and improves our understanding.
Slippery rheotaxis: new regimes for guiding wall-bound microswimmers
Authors: Ghosh Soumyajit , Poddar Antarip
Published: July 2023

The near-surface locomotion of microswimmers under the action of background flows has been studied extensively, whereas the intervening effects of complex surface properties remain hitherto unknown. Intending to delineate the shear-driven dynamics near a planar slippery wall, we adopt the squirmer model of microswimmers and employ a three-dimensional analytical-numerical framework in bispherical coordinates. It is interpreted that both the self-propulsion and the external shear flow are redistributed due to hydrodynamic slippage, followed by modulations in the thrust torque on the microswimmer. Phase portraits of the quasi-steady dynamics indicate that the stable upstream swimming states, known as ‘rheotaxis’, are significantly modulated by the slip length compared with the no-slip case. For puller swimmers, an intricate interplay among the modulated interfacial friction near a slippery surface, velocity gradients of the shear flow and the strength of the squirmer parameter promotes a critical shear rate beyond which a wide range of new rheotactic states exist. Consequently, an escaping microswimmer may exhibit rheotaxis or an existing rheotactic state annihilates due to crashing. Although stable states are absent for pushers without steric interactions, transitions from escaping and undamped oscillations to ‘rheotaxis’ occur in the presence of wall repulsion, but only until the other characteristics are overwhelmed by escape due to enhanced shear. Disclosing the ability of hydrodynamic slippage in broadening the scope of migration against a background flow for a wide range of parameters, the present work paves the way for investigations on the entrapment of microswimmers near complex pathways or sorting using selective rheotaxis.
ON THE DENSITY OF SUMSETS, II
Authors: LEONETTI PAOLO , TRINGALI SALVATORE
Published: July 2023

Arithmetic quasidensities are a large family of real-valued set functions partially defined on the power set of
$\mathbb {N}$
, including the asymptotic density, the Banach density and the analytic density. Let
$B \subseteq \mathbb {N}$
be a nonempty set covering
$o(n!)$
residue classes modulo
$n!$
as
$n\to \infty $
(for example, the primes or the perfect powers). We show that, for each
$\alpha \in [0,1]$
, there is a set
$A\subseteq \mathbb {N}$
such that, for every arithmetic quasidensity
$\mu $
, both A and the sumset
$A+B$
are in the domain of
$\mu $
and, in addition,
$\mu (A + B) = \alpha $
. The proof relies on the properties of a little known density first considered by Buck [‘The measure theoretic approach to density’, Amer. J. Math.68 (1946), 560–580].
ON CERTAIN CLOSE-TO-CONVEX FUNCTIONS
Authors: ALI MD FIROZ , NUREZZAMAN MD
Published: July 2023

Let
$\mathcal {K}_u$
denote the class of all analytic functions f in the unit disk
$\mathbb {D}:=\{z\in \mathbb {C}:|z|<1\}$
, normalised by
$f(0)=f'(0)-1=0$
and satisfying
$|zf'(z)/g(z)-1|<1$
in
$\mathbb {D}$
for some starlike function g. Allu, Sokól and Thomas [‘On a close-to-convex analogue of certain starlike functions’, Bull. Aust. Math. Soc.108 (2020), 268–281] obtained a partial solution for the Fekete–Szegö problem and initial coefficient estimates for functions in
$\mathcal {K}_u$
, and posed a conjecture in this regard. We prove this conjecture regarding the sharp estimates of coefficients and solve the Fekete–Szegö problem completely for functions in the class
$\mathcal {K}_u$
.
Impact of Point-of-Care Ultrasound on Prehospital Decision Making by HEMS Physicians in Critically Ill and Injured Patients: A Prospective Cohort Study
Authors: Vianen Niek J. , Van Lieshout Esther M.M. , Vlasveld Koen H.A. , Maissan Iscander M. , Gerritsen Patricia C. , Den Hartog Dennis , Verhofstad Michael H.J. , Van Vledder Mark G.
Published: July 2023

Introduction:

Several studies have shown the additional benefit of point-of-care ultrasound (POCUS) by prehospital Emergency Medical Services (EMS). Since organization of EMS may vary significantly across countries, the value of POCUS likely depends on the prehospital system in which it is used. In order to be able to optimally implement POCUS and develop a tailored training curriculum, it is important to know how often POCUS is currently used, for which indications it is used, and how it affects decision making. The aims of this study were: (1) to determine the percentage of patients in whom POCUS was used by Dutch Helicopter Emergency Medical Services (HEMS) crews; (2) to determine how often POCUS findings led to changes in on-scene management; and (3) what these changes were.

Methods:

Patients who received prehospital care from December 1, 2020 through March 31, 2021 by a single HEMS crew were included in this prospective cohort study. Clinical data and specific data on POCUS examination, findings, and therapeutic consequences were collected and analyzed.

Results:

During the study period, on-scene HEMS care was provided to 612 patients, of which 211 (34.5%) patients underwent POCUS. Of these, 209 (34.2%) patients with a median age of 45 years were included. There were 131 (62.7%) trauma patients, and 70 (33.7%) of the included patients underwent cardiopulmonary resuscitation (CPR). The median reported time of POCUS examination was three (P25-P75 2-5) minutes. Median prolongation of on-scene time was zero (P25-P75 0-1) minutes. In 85 (40.7%) patients, POCUS examination had therapeutic consequence: POCUS was found to impact treatment decisions in 34 (26.0%) trauma patients and 51 (65.4%) non-trauma patients. In patients with cardiac arrest, POCUS was most often used to aid decision making with regard to terminating or continuing resuscitation (28 patients; 13.4%).

Conclusion:

During the study period, POCUS examination was used in 34.5% of all prehospital HEMS patients and had a therapeutic consequence in 40.7% of patients. In trauma patients, POCUS seems to be most effective for patient triage and evaluation of treatment effectiveness. Moreover, POCUS can be of significant value in patients undergoing CPR. A tailored HEMS POCUS training curriculum should include ultrasound techniques for trauma and cardiac arrest.
Seismogenic Structure of the 2014 M6.5 Ludian Earthquake From Three‐Dimensional Joint Inversion of Magnetotelluric Data and Seismic Arrival Times
Authors: Huang Yuqi , Moorkamp Max , Gao Ji , Zhang Haijiang
Published: July 2023

On 3 August 2014, a destructive earthquake with a magnitude of 6.5 occurred in the Ludian region in Yunan, China, causing heavy casualties. However, the seismogenic structure of the Ludian earthquake is still unclear. To address this issue, we have developed a three‐dimensional joint inversion algorithm for magnetotelluric data and seismic body wave arrival times based on the cross gradient structural similarity constraint, which utilizes the complementary advantages of the two different datasets. We use arrival times of P‐ and S‐waves from 6,369 local earthquakes recorded by 30 seismic stations and magnetotelluric impedances from 127 MT stations to perform the joint inversion to construct a combined 3‐D P‐wave velocity (Vp), S‐wave velocity (Vs), and resistivity models and the locations of relocated aftershocks in the source region of the Ludian earthquake. Our models show significant low Vp/Vs ratios and low resistivity in the upper crust of the main shock zone, and the relocated aftershocks form an L‐shaped zone. Based on petrophysical studies and analysis of the cross‐plots of different physical properties, we infer the existence of cracks/fractures and fluids as well as high quartz contents in the source region. These fluids may play a key role in promoting the Ludian earthquake by reducing the effective normal stress of the fault zone, and the existence of high quartz contents further makes the crustal rocks in the source region more brittle. Our study provides a new evidence how the properties of the crust in the focal area have some control on the genesis of moderate to large earthquakes.
The Proximal Ejecta Around the Marine‐Target Lockne Impact Structure, Sweden
Authors: Sturkell Erik , Ormö Jens , Hegardt Eric Austin , Stockmann Gabrielle , Meland Erik , Wikström Torbjörn
Published: July 2023

Very few impact craters on Earth have preserved proximal ejecta (ejecta blanket), which when present help us to better understand the cratering processes when asteroid hits Earth. The 458 Ma old Lockne impact structure consists of a 7.5‐km wide nested crater in the crystalline basement surrounded by an approximately 3‐km wide brim developed in the upper sedimentary target. The asteroid struck a marine environment with 500 m sea water, 50‐m lithified limestone, and 30 m of Cambrian clay covering a peneplainized crystalline basement. The transient crater that developed in rock and water obtained a “soup‐plate” shape and reached about 7 km from the impact crater center, the farthest on the down‐range side. The brim of the soup‐plate was partially stripped of Ordovician limestone and water before the emplacement of inner impact crater ejecta. Most of the ejecta rest upon the Cambrian clay (today shale). The asteroid struck obliquely from the east, which is reflected in the ejecta distribution. The proximal ejecta field is divided into two crescent‐shaped areas to the northwest and southwest of the nested crater and covers 26 km2. Resistivity profiles, mapping, and core drilling show that the thickness of the ejecta masses range between 30 and 50 m with a total volume of about 1 km3. They were not re‐worked by the resurge. They represent roughly 26 vol% of the calculated excavated volume of crystalline rocks. Thus, it can be concluded that the Lockne impact crater has a well‐preserved ejecta blanket.
Diffusion-free valve for preprogrammed immunoassay with capillary microfluidics
Authors: Azizian Pooya , Casals-Terré Jasmina , Ricart Jordi , Cabot Joan M.
Published: July 2023

By manipulating the geometry and surface chemistry of microfluidic channels, capillary-driven microfluidics can move and stop fluids spontaneously without external instrumentation. Furthermore, complex microfluidic circuits can be preprogrammed by synchronizing the capillary pressures and encoding the surface tensions of microfluidic chips. A key component of these systems is the capillary valve. However, the main concern for these valves is the presence of unwanted diffusion during the valve loading and activation steps that can cause cross-contamination. In this study, we design and validate a novel diffusion-free capillary valve: the π-valve. This valve consists of a 3D structure and a void area. The void acts as a spacer between two fluids to avoid direct contact. When the valve is triggered, the air trapped within the void is displaced by pneumatic suction induced from the capillary flow downstream without introducing a gas bubble into the circuit. The proposed design eliminates diffusive mixing before valve activation. Numerical simulation is used to study the function and optimize the dimensions of the π-valve, and 3D printing is used to fabricate either the mould or the microfluidic chip. A comparison with a conventional valve (based on a constriction-expansion valve) demonstrates that the π-valve eliminates possible backflow into the valve and reduces the mixing and diffusion during the loading and trigger steps. As a proof-of-concept, this valve is successfully implemented in a capillary-driven circuit for the determination of benzodiazepine, achieving the successive release of 3 solutions in a 3D-printed microfluidic chip without external instrumentation. The results show a 40% increase in the fluorescence intensity using the π-valve relative to the conventional value. Overall, the π-valve prevents cross-contamination, minimizes sample use, and facilitates a sophisticated preprogrammed release of fluids, offering a promising tool for conducting automated immunoassays applicable at point-of-care testing.
Bifidobacterium infantis as a probiotic in preterm infants: a systematic review and meta-analysis
Authors: Batta Vamsi K. , Rao Shripada C. , Patole Sanjay K.
Published: July 2023

Background

Bifidobacterium infantishas special abilities to utilise human milk oligosaccharides. Hence we hypothesised that probiotic supplements containingB. infantismay confer greater benefits to preterm infants than probiotic supplements withoutB. infantis.

Methods

A systematic review with meta-analysis was conducted according to standard guidelines. We selected RCTs evaluating probiotics compared to placebo or no treatment in preterm and/or low birth weight infants. Probiotic effects on Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS) and Mortality were analysed separately for RCTs in which the supplemented probiotic product containedB. infantisand those that did not containB. infantis.

Results

67 RCTs were included (n = 14,606), of which 16 used probiotics containingB. infantis(Subgroup A) and 51 RCTs did not (Subgroup B) Meta-analysis of all RCTs indicated that probiotics reduced the risk of NEC, LOS, and mortality. The subgroup meta-analysis demonstrated greater reduction in the incidence of NEC in subgroup A than subgroup B [(relative risk in subgroup A: 0.38; 95% CI, 0.27–0.55) versus (0.67; 95% CI, 0.55–0.81) in subgroup B;pvalue for subgroup difference: 0.01].

Conclusions

These results provide indirect evidence that probiotic supplements that includeB. infantismay be more beneficial for preterm infants. Well-designed RCTs are necessary to confirm these findings.

Impact

Evidence is emerging that beneficial effects of probiotics are species and strain specific.

This systematic review analyses ifB. infantissupplementation provides an advantage to preterm infants.

This is the first systematic review evaluating the effects of probiotics containingB.infantisin preterm infants.

The results of this systematic review provides indirect evidence that probiotics that includeB. infantismay be more beneficial for preterm infants. These results will help in guiding future research and clinical practice for usingB. infantisas a probiotic in preterm infants.
Establishment and identification of an animal model of Hirschsprung disease in suckling mice
Authors: Lan Chaoting , Wu Yuxin , Liu Yanqing , Wang Ning , Su Meiling , Qin Dingjiang , Zhong Weiyong , Zhao Xinying , Zhu Yun , He Qiuming , Xia Huimin , Zhang Yan
Published: July 2023

Background

Hirschsprung disease (HSCR) is a congenital intestinal malformation. Previous HSCR animal model needs invasive operation on adult animal. The aim of this study is to establish an early-onset animal model which is consistent with the clinical manifestation of HSCR patients.

Methods

The neonatal mice were randomly divided into the benzalkonium chloride (BAC) group, treated with BAC via enema, and the control group, treated with saline. Weight changes, excretion time of carmine, CT scan, hematoxylin-eosin staining and immunofluorescence staining were used to evaluate the effect of the model. Differentially expressed genes (DEGs) in the HSCR mice were analyzed by using DAVID 6.8 database and compared with DEGs from HSCR patients.

Results

The weight of mice was lower and the excretion time of carmine was longer in the BAC group. Moreover, distal colon stenosis and proximal colon enlargement appeared in the BAC group. Neurons in the distal colon decreased significantly after 4 weeks of BAC treatment and almost disappeared completely after 12 weeks. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression.

Conclusions

An economical and reliable HSCR animal model which has similar clinical characteristics to HSCR patients was successfully established.

Impact

The animal model of Hirschsprung disease was first established in BALB/c mice.

This model is an animal model of early-onset HSCR that is easy to operate and consistent with clinical manifestations.

Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression.
Altered brain dynamic in major depressive disorder: state and trait features
Authors: Javaheripour Nooshin , Colic Lejla , Opel Nils , Li Meng , Maleki Balajoo Somayeh , Chand Tara , Van der Meer Johan , Krylova Marina , Izyurov Igor , Meller Tina , Goltermann Janik , Winter Nils R. , Meinert Susanne , Grotegerd Dominik , Jansen Andreas , Alexander Nina , Usemann Paula , Thomas-Odenthal Florian , Evermann Ulrika , Wroblewski Adrian , Brosch Katharina , Stein Frederike , Hahn Tim , Straube Benjamin , Krug Axel , Nenadić Igor , Kircher Tilo , Croy Ilona , Dannlowski Udo , Wagner Gerd , Walter Martin
Published: July 2023

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity.
Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions
Authors: Bernardi Paolo , Gerle Christoph , Halestrap Andrew P. , Jonas Elizabeth A. , Karch Jason , Mnatsakanyan Nelli , Pavlov Evgeny , Sheu Shey-Shing , Soukas Alexander A.
Published: July 2023

The mitochondrial permeability transition (mPT) describes a Ca2+-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel, the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outer mitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However, transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrial bioenergetics and rapid Ca2+ efflux. Since its discovery decades ago, intensive efforts have been made to identify the exact pore-forming structure of the mPT. Both the adenine nucleotide translocase (ANT) and, more recently, the mitochondrial F1FO (F)-ATP synthase dimers, monomers or c-subunit ring alone have been implicated. Here we share the insights of several key investigators with different perspectives who have pioneered mPT research. We critically assess proposed models for the molecular identity of the mPTP and the mechanisms underlying its opposing roles in the life and death of cells. We provide in-depth insights into current controversies, seeking to achieve a degree of consensus that will stimulate future innovative research into the nature and role of the mPTP.
Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids
Authors: Ai Zongyong , Niu Baohua , Yin Yu , Xiang Lifeng , Shi Gaohui , Duan Kui , Wang Sile , Hu Yingjie , Zhang Chi , Zhang Chengting , Rong Lujuan , Kong Ruize , Chen Tingwei , Guo Yixin , Liu Wanlu , Li Nan , Zhao Shumei , Zhu Xiaoqing , Mai Xuancheng , Li Yonggang , Wu Ze , Zheng Yi , Fu Jianping , Ji Weizhi , Li Tianqing
Published: July 2023

Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage development as well as underlying mechanisms remains obscure. Using 3D-cultured human embryos, herein we report a complete cell atlas of the early post-implantation lineages and decipher cellular composition and gene signatures of the epiblast and hypoblast derivatives. In addition, we develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs and extraembryonic cells. Using human embryos and E-assembloids, we reveal that WNT, BMP and Nodal signaling pathways synergistically, but functionally differently, orchestrate human peri-implantation lineage development. Specially, we dissect mechanisms underlying extraembryonic mesoderm and extraembryonic endoderm specifications. Finally, an improved E-assembloid is developed to recapitulate the epiblast and hypoblast development and tissue architectures in the pre-gastrulation human embryo. Our findings provide insights into human peri-implantation development, and the E-assembloid offers a useful model to disentangle cellular behaviors and signaling interactions that drive human embryogenesis.
Show don’t tell: assessing the impact of co-developed patient information videos in paediatric uveitis
Authors: Khalil Rana , Kellett Salomey , Petrushkin Harry , Twomey Christine , Rahi Jugnoo , Solebo Ameenat Lola
Published: July 2023

Background/Objectives

There is a paucity of online educational content targeting children and young people with uveitis. We evaluated the impact of a co-designed patient education video on subjective and objective understanding of childhood uveitis.

Subjects/Methods

Co-designed patient education media were produced in collaboration with the Childhood Uveitis Studies steering group and the Great Ormond Street Hospital Generation R Young People’s Advisory Group and narrated by children. Patients managed within the Uveitis service at GOSH were invited to take part in a pre–post survey, undertaken immediately prior to and following viewing of a patient education video.

Results

Forty-three patients participated. These were stratified according to age, duration of disease, and treatment type for analysis. Self-rated knowledge improved across all groups (p = 0.001), particularly in those with a new diagnosis of uveitis (Z = −8.124, p < 0.001). Objective knowledge scores improved across all questions, especially in younger children, those with new disease, and those on steroid only treatment (Z = −3.847, p < 0.001, Z = −3.975, p < 0.001, Z = −3.448, p < 0.001; respectively). Most participants reported the videos to be easy to understand and with the right amount of information. All stated that they learned something new.

Conclusions

Patient understanding of disease and treatment is crucial to achieving the best possible outcomes for this chronic, relapsing remitting and potentially blinding disorder. Our findings data shows the potential value of co-designed patient information videos, specifically in our study benefitting younger patients and those recently diagnosed. We suggest that other clinical teams could collaborate fruitfully with patient groups to develop similar videos to target possible misinformation and potentially improve patient outcomes.
Integrating full and partial genome sequences to decipher the global spread of canine rabies virus
Authors: Holtz Andrew , Baele Guy , Bourhy Hervé , Zhukova Anna
Published: July 2023

Despite the rapid growth in viral genome sequencing, statistical methods face challenges in handling historical viral endemic diseases with large amounts of underutilized partial sequence data. We propose a phylogenetic pipeline that harnesses both full and partial viral genome sequences to investigate historical pathogen spread between countries. Its application to rabies virus (RABV) yields precise dating and confident estimates of its geographic dispersal. By using full genomes and partial sequences, we reduce both geographic and genetic biases that often hinder studies that focus on specific genes. Our pipeline reveals an emergence of the present canine-mediated RABV between years 1301 and 1403 and reveals regional introductions over a 700-year period. This geographic reconstruction enables us to locate episodes of human-mediated introductions of RABV and examine the role that European colonization played in its spread. Our approach enables phylogeographic analysis of large and genetically diverse data sets for many viral pathogens.
Maternal TDP-43 interacts with RNA Pol II and regulates zygotic genome activation
Authors: Nie Xiaoqing , Xu Qianhua , Xu Chengpeng , Chen Fengling , Wang Qizhi , Qin Dandan , Wang Rui , Gao Zheng , Lu Xukun , Yang Xinai , Wu Yu , Gu Chen , Xie Wei , Li Lei
Published: July 2023

Zygotic genome activation (ZGA) is essential for early embryonic development. However, the regulation of ZGA remains elusive in mammals. Here we report that a maternal factor TDP-43, a nuclear transactive response DNA-binding protein, regulates ZGA through RNA Pol II and is essential for mouse early embryogenesis. Maternal TDP-43 translocates from the cytoplasm into the nucleus at the early two-cell stage when minor to major ZGA transition occurs. Genetic deletion of maternal TDP-43 results in mouse early embryos arrested at the two-cell stage. TDP-43 co-occupies with RNA Pol II as large foci in the nucleus and also at the promoters of ZGA genes at the late two-cell stage. Biochemical evidence indicates that TDP-43 binds Polr2a and Cyclin T1. Depletion of maternal TDP-43 caused the loss of Pol II foci and reduced Pol II binding on chromatin at major ZGA genes, accompanied by defective ZGA. Collectively, our results suggest that maternal TDP-43 is critical for mouse early embryonic development, in part through facilitating the correct RNA Pol II configuration and zygotic genome activation.
Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
Authors: Yeh Yu-Te , Sona Chandan , Yan Xin , Li Yunxiao , Pathak Adrija , McDermott Mark I. , Xie Zhigang , Liu Liangwen , Arunagiri Anoop , Wang Yuting , Cazenave-Gassiot Amaury , Ghosh Adhideb , von Meyenn Ferdinand , Kumarasamy Sivarajan , Najjar Sonia M. , Jia Shiqi , Wenk Markus R. , Traynor-Kaplan Alexis , Arvan Peter , Barg Sebastian , Bankaitis Vytas A. , Poy Matthew N.
Published: July 2023

Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation.PITPNAin beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion ofPitpnain the beta-cells ofIns-Cre, Pitpnaflox/floxmice leads to hyperglycemia resulting from decreasing glucose-stimulated insulin secretion (GSIS) and reducing pancreatic beta-cell mass. Furthermore,PITPNAsilencing in human islets confirms its role in PtdIns-4-P synthesis and leads to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration ofPITPNAin islets of T2D human subjects reverses these beta-cell defects and identifyPITPNAas a critical target linked to beta-cell failure in T2D.
Engineering tumoral vascular leakiness with gold nanoparticles
Authors: Setyawati Magdiel Inggrid , Wang Qin , Ni Nengyi , Tee Jie Kai , Ariga Katsuhiko , Ke Pu Chun , Ho Han Kiat , Wang Yucai , Leong David Tai
Published: July 2023

Delivering cancer therapeutics to tumors necessitates their escape from the surrounding blood vessels. Tumor vasculatures are not always sufficiently leaky. Herein, we engineer therapeutically competent leakage of therapeutics from tumor vasculature with gold nanoparticles capable of inducing endothelial leakiness (NanoEL). These NanoEL gold nanoparticles activated the loss of endothelial adherens junctions without any perceivable toxicity to the endothelial cells. Microscopically, through real time live animal intravital imaging, we show that NanoEL particles induced leakiness in the tumor vessels walls and improved infiltration into the interstitial space within the tumor. In both primary tumor and secondary micrometastases animal models, we show that pretreatment of tumor vasculature with NanoEL particles before therapeutics administration could completely regress the cancer. Engineering tumoral vasculature leakiness represents a new paradigm in our approach towards increasing tumoral accessibility of anti-cancer therapeutics instead of further increasing their anti-cancer lethality.
The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils
Authors: Toller-Kawahisa Juliana Escher , Hiroki Carlos Hiroji , Silva Camila Meirelles de Souza , Nascimento Daniele Carvalho , Públio Gabriel Azevedo , Martins Timna Varela , Damasceno Luis Eduardo Alves , Veras Flávio Protásio , Viacava Paula Ramos , Sukesada Fábio Yuji , Day Emily Anne , Zotta Alessia , Ryan Tristram Alexander Jasper , Moreira da Silva Rodrigo , Cunha Thiago Mattar , Lopes Norberto Peporine , Cunha Fernando de Queiroz , O’Neill Luke Anthony John , Alves-Filho José Carlos
Published: July 2023

Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2 (PKM2) is a glycolytic enzyme known to be involved in metabolic reprogramming and gene transcription in many immune cell types, its role in neutrophils remains poorly understood. Here, we report that PKM2 regulates ROS production and microbial killing by neutrophils. Zymosan-activated neutrophils showed increased cytoplasmic expression of PKM2. Pharmacological inhibition or genetic deficiency of PKM2 in neutrophils reduced ROS production andStaphylococcus aureuskilling in vitro. In addition, this also resulted in phosphoenolpyruvate (PEP) accumulation and decreased dihydroxyacetone phosphate (DHAP) production, which is required for de novo synthesis of diacylglycerol (DAG) from glycolysis. In vivo, PKM2 deficiency in myeloid cells impaired the control of infection withStaphylococcus aureus. Our results fill the gap in the current knowledge of the importance of lower glycolysis for ROS production in neutrophils, highlighting the role of PKM2 in regulating the DHAP and DAG synthesis to promote ROS production in neutrophils.
A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury
Authors: Yang Chen , Xu Huidie , Yang Dong , Xie Yunhao , Xiong Mingrui , Fan Yu , Liu XiKai , Zhang Yu , Xiao Yushuo , Chen Yuchen , Zhou Yihao , Song Liangliang , Wang Chen , Peng Anlin , Petersen Robert B. , Chen Hong , Huang Kun , Zheng Ling
Published: July 2023

Acute kidney injury (AKI) exhibits high morbidity and mortality. Kidney injury molecule-1 (KIM1) is dramatically upregulated in renal tubules upon injury, and acts as a biomarker for various renal diseases. However, the exact role and underlying mechanism of KIM1 in the progression of AKI remain elusive. Herein, we report that renal tubular specific knockout ofKim1attenuates cisplatin- or ischemia/reperfusion-induced AKI in male mice. Mechanistically, transcription factor Yin Yang 1 (YY1), which is downregulated upon AKI, binds to the promoter ofKIM1and represses its expression. Injury-induced KIM1 binds to the ECD domain of death receptor 5 (DR5), which activates DR5 and the following caspase cascade by promoting its multimerization, thus induces renal cell apoptosis and exacerbates AKI. Blocking the KIM1-DR5 interaction with rationally designed peptides exhibit reno-protective effects against AKI. Here, we reveal a YY1-KIM1-DR5 axis in the progression of AKI, which warrants future exploration as therapeutic targets.
Impact of cognitive performance and negative symptoms on psychosocial functioning in Czech schizophrenia patients
Authors: Kalisova L. , Michalec J. , Dechterenko F. , Silhan P. , Hyza M. , Chlebovcova M. , Brenova M. , Bezdicek O.
Published: July 2023

Schizophrenia has a profound influence on the real-life functioning of patients. There are several factors inherent to the disease course affecting the level of psychosocial functioning. Our study focused on the impact of cognitive deficit and severity of negative symptoms (i.e., the experiential domain (avolition, asociality, and anhedonia) and the expressive domain (blunted affect and alogia)) to explore psychosocial functioning in schizophrenia. Schizophrenia patients (n = 211) were tested for the presence of cognitive impairment using the NIMH-MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Cattery (MCCB; MATRICS Consensus Cognitive Battery) and the extent of negative symptoms using the PANSS (PANSS; Positive and Negative Syndrome Scale—selected items). The level of psychosocial functioning was measured with the Personal and Social Performance Scale (PSP). The path analysis using three regression models was used to analyse variables influencing psychosocial functioning (PSP). One of these models analyzed influence of cognitive functioning (MCCB) and negative schizophrenia symptoms (PANSS selected items reflecting expressive and experiential deficits) as predictors and NART/CRT and disease length as confounders. R2 was 0.54. The direct effect of the MCCB (β = 0.09) on the PSP was suppressed by the strong effect of the negative symptoms (β = −0.64). The presence of cognitive deficits and negative symptoms in our sample of schizophrenia patients significantly influences the level of their psychosocial functioning, a key factor in remission and recovery.
Short-term high-fat diet consumption impairs synaptic plasticity in the aged hippocampus via IL-1 signaling
Authors: González Olmo Brigitte M. , Bettes Menaz N. , DeMarsh James W. , Zhao Fangli , Askwith Candice , Barrientos Ruth M.
Published: July 2023

More Americans are consuming diets higher in saturated fats and refined sugars than ever before. These trends could have serious consequences for the older population because high-fat diet (HFD) consumption, known to induce neuroinflammation, has been shown to accelerate and aggravate memory declines. We have previously demonstrated that short-term HFD consumption, which does not evoke obesity-related comorbidities, produced profound impairments to hippocampal-dependent memory in aged rats. These impairments were precipitated by increases in proinflammatory cytokines, primarily interleukin-1 beta (IL-1β). Here, we explored the extent to which short-term HFD consumption disrupts hippocampal synaptic plasticity, as measured by long-term potentiation (LTP), in young adult and aged rats. We demonstrated that (1) HFD disrupted late-phase LTP in the hippocampus of aged, but not young adult rats, (2) HFD did not disrupt early-phase LTP, and (3) blockade of the IL-1 receptor rescued L-LTP in aged HFD-fed rats. These findings suggest that hippocampal memory impairments in aged rats following HFD consumption occur through the deterioration of synaptic plasticity and that IL-1β is a critical driver of that deterioration.
Robust estimation of cortical similarity networks from brain MRI
Authors: Sebenius Isaac , Seidlitz Jakob , Warrier Varun , Bethlehem Richard A. I. , Alexander-Bloch Aaron , Mallard Travis T. , Garcia Rafael Romero , Bullmore Edward T. , Morgan Sarah E.
Published: July 2023

Structural similarity is a growing focus for magnetic resonance imaging (MRI) of connectomes. Here we propose Morphometric INverse Divergence (MIND), a new method to estimate within-subject similarity between cortical areas based on the divergence between their multivariate distributions of multiple MRI features. Compared to the prior approach of morphometric similarity networks (MSNs) onn > 11,000 scans spanning three human datasets and one macaque dataset, MIND networks were more reliable, more consistent with cortical cytoarchitectonics and symmetry and more correlated with tract-tracing measures of axonal connectivity. MIND networks derived from human T1-weighted MRI were more sensitive to age-related changes than MSNs or networks derived by tractography of diffusion-weighted MRI. Gene co-expression between cortical areas was more strongly coupled to MIND networks than to MSNs or tractography. MIND network phenotypes were also more heritable, especially edges between structurally differentiated areas. MIND network analysis provides a biologically validated lens for cortical connectomics using readily available MRI data.
Clinical relevance of deep learning models in predicting the onset timing of cancer pain exacerbation
Authors: Bang Yeong Hak , Choi Yoon Ho , Park Mincheol , Shin Soo-Yong , Kim Seok Jin
Published: July 2023

Cancer pain is a challenging clinical problem that is encountered in the management of cancer pain. We aimed to investigate the clinical relevance of deep learning models that predict the onset of cancer pain exacerbation in hospitalized patients. We defined cancer pain exacerbation (CPE) as the pain with a numerical rating scale (NRS) score of ≥ 4. We investigated the performance of the deep learning models using the Matthews correlation coefficient (MCC) with different input lengths and time binning. All the pain records were obtained from the electronic medical records of the hematology-oncology wards in a Samsung Medical Center between July 2016 and February 2020. The model was externally validated using the holdout method with 20% of the datasets. The most common type of cancer was lung cancer (n = 745, 21.7%), and the median CPE per day was 1.01. The NRS pain records showed circadian patterns that correlated with NRS pain patterns of the previous days. The correlation of the NRS scores showed a positive association with the closeness of the NRS pattern of the day with forecast date and size of time binning. The long short-term memory-based model exhibited a good performance by demonstrating 9 times the best performance and 8 times the second-best performance among 21 different settings. The best performance was achieved with 120 h input and 12 h bin lengths (MCC: 0.4927). Our study demonstrated the possibility of predicting CPE using deep learning models, thereby suggesting that preemptive cancer pain management using deep learning could potentially improve patients’ daily life.
Explainable ML models for a deeper insight on treatment decision for localized prostate cancer
Authors: Han Jang Hee , Lee Sungyup , Lee Byounghwa , Baek Ock-kee , Washington Samuel L. , Herlemann Annika , Lonergan Peter E. , Carroll Peter R. , Jeong Chang Wook , Cooperberg Matthew R.
Published: July 2023

Although there are several decision aids for the treatment of localized prostate cancer (PCa), there are limitations in the consistency and certainty of the information provided. We aimed to better understand the treatment decision process and develop a decision-predicting model considering oncologic, demographic, socioeconomic, and geographic factors. Men newly diagnosed with localized PCa between 2010 and 2015 from the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting database were included (n = 255,837). We designed two prediction models: (1) Active surveillance/watchful waiting (AS/WW), radical prostatectomy (RP), and radiation therapy (RT) decision prediction in the entire cohort. (2) Prediction of AS/WW decisions in the low-risk cohort. The discrimination of the model was evaluated using the multiclass area under the curve (AUC). A plausible Shapley additive explanations value was used to explain the model’s prediction results. Oncological variables affected the RP decisions most, whereas RT was highly affected by geographic factors. The dependence plot depicted the feature interactions in reaching a treatment decision. The decision predicting model achieved an overall multiclass AUC of 0.77, whereas 0.74 was confirmed for the low-risk model. Using a large population-based real-world database, we unraveled the complex decision-making process and visualized nonlinear feature interactions in localized PCa.
Simple algorithm for judging equivalence of differential-algebraic equation systems
Authors: Kato Shota , Zhang Chunpu , Kano Manabu
Published: July 2023

Mathematical formulas play a prominent role in science, technology, engineering, and mathematics (STEM) documents; understanding STEM documents usually requires knowing the difference between equation groups containing multiple equations. When two equation groups can be transformed into the same form, we call the equation groups equivalent. Existing tools cannot judge the equivalence of two equation groups; thus, we develop an algorithm to judge such an equivalence using a computer algebra system. The proposed algorithm first eliminates variables appearing only in either equation group. It then checks the equivalence of the equations one by one: the equations with identical algebraic solutions for the same variable are judged equivalent. If each equation in one equation group is equivalent to an equation in the other, the equation groups are judged equivalent; otherwise, non-equivalent. We generated 50 pairs of equation groups for evaluation. The proposed method accurately judged the equivalence of all pairs. This method is expected to facilitate comprehension of a large amount of mathematical information in STEM documents. Furthermore, this is a necessary step for machines to understand equations, including process models.