bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Clinical Severity, Neuroimaging, and Electroencephalographic Findings in Children with Subacute Sclerosing Panencephalitis
Authors: Panda Prateek Kumar , Elwadhi Aman , Gupta Diksha , Gupta Swati Kumari , Dasgupta Soura , Singh Garima , Sherwani Poonam , Sharawat Indar Kumar
Published: August 2024

Background

Children diagnosed with subacute sclerosing panencephalitis (SSPE) display a range of neuroimaging abnormalities during different stages of the disease, but their exact clinical significance remains unclear.

Methods

In this retrospective cohort study, our objective was to examine magnetic resonance imaging (MRI) abnormalities in the brains of patients aged 18 years or younger with subacute sclerosing panencephalitis. We aimed to correlate these MRI abnormalities with clinical severity, sociodemographic variables, electroencephalographic (EEG) abnormalities, and cerebrospinal anti-measles antibody titers.

Results

The study included 112 cases of subacute sclerosing panencephalitis (mean age at onset: 8.9 ± 2.6 years). MRI analysis at the time of presentation revealed the following abnormalities: subcortical white matter signal changes (n = 95), periventricular white matter signal changes (n = 76), splenium of corpus callosum involvement (n = 39), diffuse corpus callosum involvement (n = 27), cerebral atrophy (n = 35), basal ganglia involvement (n = 10), and brain stem involvement (n = 2). Notably, subcortical white matter involvement, periventricular white matter involvement, diffuse corpus callosum involvement, and basal ganglia involvement were more prevalent in patients with stage III and IV subacute sclerosing panencephalitis ( P < .05 for all). Cerebral atrophy was also significantly more common in patients with stage III compared to those with stage IV subacute sclerosing panencephalitis ( P < .0001). However, no substantial positive or negative associations were found between MRI findings and EEG abnormalities, other sociodemographic/clinical variables, and cerebrospinal fluid measles-specific antibody titers ( P > .05).

Conclusion

Early in the disease progression of subacute sclerosing panencephalitis, the temporoparietal and parietooccipital regions of the subcortical white matter are affected. Neuroimaging abnormalities exhibit a stronger association with Jabbour's clinical staging, but do not show significant associations with other clinical, sociodemographic, and EEG features.
Optimizing passengers’ experience: A goal-oriented reinforcement learning speed control approach for urban railway trains
Authors: Liu Wangyang , Feng Qingsheng , Li Hong
Published: August 2024

Prolonged vibration can be uncomfortable for passengers utilizing urban rail transit systems. This study proposes an automatic speed control framework for urban railway trains to reduce vertical vibrations experienced by passengers. We suggest the concept of the “segmented comfort speed limit” to represent the vertical passing comfort of oncoming sections. This speed limit is calculated from 1/3 octave band acceleration and smoothed through lag-type speed control mode. The deep deterministic policy gradient algorithm with hindsight experience replay mechanism (HER-DDPG) is designed, to balance safety, comfort, and energy efficiency driving. Verify the speed control framework based on HER-DDPG through the rail data collected from Dalian Metro Line 12. Compared with the DDPG-based model, the vertical comfort is improved by 2.34%, and the longitudinal acceleration and total energy consumption are reduced by 45% and 8.1%. Compared with the real-world train control trajectory, HER-DDPG improves vertical comfort by 9.76% and reduces energy consumption by 12.4%. The results show that the proposed framework can effectively improve the ride experience of passengers.
Microcrack behavior in bone: Stress field analysis at osteon cement line tips
Authors: Ji Chunhui , Yang Xiuyan , Zhang Liang , Chen Xicheng , Sun Yadi , Lin Bin
Published: August 2024

Bone microstructure governs microcrack propagation complexity. Current research, relying on linear elastic fracture mechanics, inadequately considers authentic multi-level structures, like cement lines and osteons, impacting stress intensity at cracks. This study, by constructing models encompassing single or multiple osteons, delves into the influence of factors like crack length, osteon radius, and modulus ratio on the stress intensity factor at the crack tip. Employing a fracture mechanics phase-field approach to simulate crack propagation paths, it particularly explores the role of cement lines as weak interfaces in crack extension. The aim is to comprehensively and systematically elucidate the critical factors of bone microstructure in the context of crack propagation.
Does Digital Orientation Enhance Firm Performance?
Authors: Brahmana Rayenda Khresna , Kontesa Maria
Published: August 2024

This research examines the effect of digital orientation on firm performance within the framework of organizational orientation theory. Focusing on a sample of Malaysian listed companies from 2012 to 2019, we employed robust panel regression alongside dynamic generalized method of moments panel and panel quantile regression models as supplementary analyses. The digital orientation was evaluated using Python-based text analysis. Surprisingly, our findings challenge conventional wisdom: Contrary to expectations, digital orientation exhibited no significant influence on firm performance metrics such as returns on assets, returns on equity and Tobin’s Q. This contradicts organizational orientation theory, suggesting that transitioning towards digitalization might not inherently enhance performance. Our study argues that adopting digitalized business practices may not ensure improved firm performance, particularly in emerging economies like Malaysia.
Advancing Internationalization in the Formal Curriculum: Content Integration and Inclusive Design
Authors: Liang Siyin
Published: August 2024

Despite the growing attention of Canadian universities to curriculum development as part of their internationalization efforts, there is still a lack of understanding of what constitutes an internationalized formal curriculum from the perspectives of diverse community members. This exploratory, interpretive case study aims to contribute to the ongoing internationalization efforts to foster an enriched education experience that benefits both domestic and international students. It highlights perspectives from international postgraduate students regarding the approach of internationalizing formal curricula in a Canadian university. The findings presented in this article elaborate on these students’ earnest request for content integration in an internationalized formal curriculum. The findings also emphasize the importance of being aware of practice traditions in a learning site and incorporating inclusive course design to reduce potential inequalities and the risk of system exclusion.
A grounded exploration of regulatory dynamics and competitive forces in the Indian telecom network industry
Authors: Gandhi Ravi , Hasti Charru , Sagar Mahim
Published: August 2024

This research studies the disassociation phenomenon between network and data services that has disrupted the telecom sector in India. We employed grounded theory approach to explore this phenomenon and its impact on the Telecommunication Service Providers (TSPs). We have derived the insights and developed a coding paradigm via a judgmental sample of 19 senior experts at decision-making positions in the Indian telecom sector. Through literature review, we identified the fundamental changes in the Indian telecom sector from 2013 to 2019, when this phenomenon was widely observed. The findings indicate the technology evolution’s role in driving the data-network disassociation in the presence of regulatory forbearance, 4G spectrum availability, hyper-competition, and evolving device ecosystem. These conditions have proved advantageous to Over-The-Top (OTT) players, caused financial stress to the TSPs, and forced them to resort to consolidation measures and shift from voice-based to data-based business models. The study’s insights will help the Industry understand the phenomena, regulatory issues in technology adoption, survival challenges, and decision-making strategies for pre-empting technical disruptions. It also emphasizes being watchful of the competing non-conventional industries from a regulatory perspective.
Patient Opportunities to Self-Schedule in a Large Multisite, Multispecialty Medical Practice: Program Description and Uptake of 7 Unique Processes for Patients to Successfully Self-Schedule (and Reschedule) Their Medical Appointments
Authors: North Frederick , Buss Rebecca , Nelson Elissa M. , Thompson Matthew C. , Pecina Jennifer , Crum Brian A.
Published: August 2024

Introduction

Patient self-scheduling of medical appointments is becoming more common in many medical institutions. However, the complexity of scheduling multiple specialties, following scheduling guidelines, and managing appointment access requires a variety of processes for a diverse inventory of self-schedulable appointment types.

Methods

From 7 unique patient self-scheduling methods, we captured counts of successfully self-scheduled and completed appointments. A process map was created to show the paths of 5 different primary self-scheduling processes (new appointment self-scheduling) and 2 secondary self-scheduling processes (existing appointment self-rescheduling).

Results

There were 7 unique processes that led to 733,651 successfully self-scheduled completed visits from January 1 to December 31, 2023 at a multisite, multispecialty clinic. The self-scheduling processes consisted of the following: (1) Ticket offer (appointment “ticket” offers for specific visits generated by a provider order or system rules), the software “ticket” sent to the patient permits “admission” to self-schedule calendar templates (341,591 uses, 46.6%); (2) direct self-scheduled visit for prequalified visit types (203,593 uses, 27.6%); (3) self-reschedule option (patient option to reschedule existing appointment, 79,706 uses, 10.9%); (4) new patient self-scheduled visit via clinic website (does not require portal access, 54,367 uses, 7.4%). (5) automated waitlist self-rescheduled visit (38,649 uses, 5.3%); (6) automated waitlist self-scheduled visit of previously unscheduled visit (10,939 uses, 1.5%); and (7) self-triage self-scheduled visit (4806 uses, 0.7%).

Conclusion

The processes for self-scheduling are expanding. Our multispecialty clinic has implemented 7 different processes to help patients successfully self-schedule medical appointments. Some of the processes occur before initial scheduling (such as self-triage), and some are implemented after successful scheduling has already occurred (self-rescheduling option and self-rescheduling aided by an automated waitlist). Continued research is needed to look for measures of success beyond the ability to complete a self-scheduled visit, including the accuracy of the booking (right provider, location, and length of visit).
Patients Presenting with Acute Stroke During COVID-19 Pandemic Era: A Multicenter Retrospective Study
Authors: Hashmi Amal M. Al , Imam Yahia , Saqqur Maher , Ozdemir Atilla Ozcan , Farhoudi Mehdi , Wasay Mohammad , Mushtaq Faiza , Jose Sachin , Mansur Ossama Yassin , Shuaib Ashfaq ,   the MENA-SINO Organization (http://mena-sino.org)
Published: August 2024

Background

Coronavirus disease-2019 (COVID-19) infection originated in China and was very quickly seen in the Middle East North Africa (MENA) region. This study was undertaken to evaluate COVID-19-related cerebrovascular involvement in the MENA+ region.

Methods

Retrospective observational regional multicenter study aiming to identify acute stroke presentation and functional independency in patients with COVID-19 infection in the MENA region. The diagnosis of COVID-19 was established by polymerase chain reaction testing in all patients. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the severity of stroke symptoms. Functional independency was assisted by a modified Rankin Scale (mRS) at 90 days.

Results

There were 209 patients including 65 COVID-19-related stroke group (CRSG). The mean age was 62.85 ± 15.94 for (CRSG) and 58.69 ± 14.73 in non-COVID-19 stroke group (NCSG). The most prevalent risk factor for both groups was hypertension 45 (69.2%) and 105 (72.9) respectively. Intravenous thrombolysis therapy was delivered to 6/65 (9.2%) in (CRSG) compared to 11 (7.6) in (NCSG). The mean NIHSS at baseline for the (CRSG) was 12.94 ± 9.46, versus 6.08 ± 4.9 in (NCSG). This was statistically significant ( P < 0.001). Functional outcome at the 90-day measured using mRS was worse in the (CRSG) compared to (NCSG) 3.61 ± 2.53, 2.20 ± 2.60 respectively and this was statistically significant ( P = 0.001).

Conclusion

In this study from multiple countries from the MENA+ region, we showed that acute stroke in patients with active COVID-19 had more severe symptoms at onset and worse 90 days’ outcomes despite the young age. There were no regional differences noted in severity and outcome in the MENA region.
Towards greener city logistics: an application of agile routing algorithms to optimize the distribution of micro-hubs in Barcelona
Authors: Castillo C. , Panadero J. , Alvarez-Palau E. J. , Juan A. A.
Published: August 2024

The COVID-19 pandemic accelerated the shift towards online shopping, reshaping consumer habits and intensifying the impact on urban freight distribution. This disruption exacerbated traffic congestion and parking shortages in cities, underscoring the need for sustainable distribution models. The European Union's common transport policy advocates for innovative UFD approaches that promote intermodal transportation, reduce traffic, and optimize cargo loads. Our study addresses these challenges by proposing an agile routing algorithm for an alternative UFD model in Barcelona. This model suggests strategically located micro-hubs selected from a set of railway facilities, markets, shopping centers, district buildings, pickup points, post offices, and parking lots (1057 points in total). It also promotes intermodality through cargo bikes and electric vans. The study has two main objectives: (i) to identify a network of intermodal micro-hubs for the efficient delivery of parcels in Barcelona and (ii) to develop an agile routing algorithm to optimize their location. The algorithm generates adaptive distribution plans considering micro-hub operating costs and vehicle routing costs, and using heuristic and machine learning methods enhanced by parallelization techniques. It swiftly produces high-quality routing plans based on transportation infrastructure, transportation modes, and delivery locations. The algorithm adapts dynamically and employs multi-objective techniques to establish the Pareto frontier for each plan. Real-world testing in Barcelona, using actual data has shown promising results, providing potential scenarios to reduce CO2 emissions and improve delivery times. As such, this research offers an innovative and sustainable approach to UFD, that will contribute significantly to a greener future for cities.
Clinical incidence and relevance of incomplete endothelialization in atrial fibrillation patients with Left Atrial Appendage Closure
Authors: Zhu Jini , Wang Yanpeng , Li Meifang , Huang Dong , Li Shuai , Li Jingbo
Published: August 2024

Background

The objective of this study is to investigate the incidence, potential risk factors, and clinical outcomes of incomplete device endothelialization (IDE) in atrial fibrillation (AF) patients undergoing Watchman left atrial appendage closure (LAAC).

Methods

In this study, 68 AF patients who underwent successful implantation of the Watchman device without peri-device leak (PDL) during follow-up were included. The endothelialization status was assessed using Transesophageal echocardiography (TEE) and LAA computed tomography angiography (CTA) at 6 weeks and 6 months post-implantation. Adverse cerebro-cardiac events were documented at one-year follow-up. Baseline characteristics, including age, device sizes, and clinical indicators, were analyzed as potential predictors for IDE.

Results

IDE was observed in 70.6% and 67.6% of patients at 6 weeks and 6 months after implantation, respectively. Higher levels of high-density lipoprotein cholesterol (HDL-C) [odds ratio (OR): 15.109, 95% confidence interval (CI): 1.637-139.478, p = 0.017 and OR: 11.015, 95% CI: 1.365–88.896, p = 0.024] and lower aspartate aminotransferase (AST) (OR 0.924, 95% CI: 0.865–0.986, p = 0.017 and OR: 0.930, 95% CI: 0.874–0.990, p = 0.023) at baseline were found to be significantly associated with IDE at 6 weeks and 6 months, respectively, although no significant difference in adverse cerebro-cardiac events was noted between incomplete and complete DE groups during 1-year follow-up

Conclusions

IDE is found to be a prevalent occurrence in humans following LAAC. Elevated HDL-C and reduced AST levels are shown to be linked to an increased risk of IDE after LAAC
Test-enhanced learning in Neuroanesthesia for the First Year anesthetic residents: a randomized controlled trial
Authors: Raksakietisak Manee , Lertsiripatarajit Vasu , Aroonpruksakul Naiyana , Plailaharn Narin , Raksamani Kasana
Published: August 2024

Background

Test enhancing learning (TEL) had shown a significant effect in promoting the learning of many learning contents. However, its effect on the postgraduate medical level was unclear. This study aimed to investigate the effect of TEL in 1st year anesthesiology residents learning neuroanesthesia.

Method

The residents were randomized to either group A, which was assigned to do the intervention exam (exam A) for two times during learning in neuroanesthesia, or group B, which studied in the same environment without doing the exam. All participants were assigned to do the assessment exam (exam B) at one month after the end of the rotation. All of the exams were ten multiple choice questions (MCQ). Since the anesthesia residents rotated to neuroanesthesia for two weeks twice during the first year, we conducted the experiments twice, using exams that covered both basic science (BS) and clinical science (CS) topics.

Results

There was no significant difference in mean ± SD of the scores for assessment exams asking about the basic science topic (BS_B) [group A (5.25 ± 2.05) VS group B (4.90 ± 1.80); p = 0.570] and the clinical science topic (CS_B) [group A (6.30 ± 1.26) VS group B (5.95 ± 1.61); p = 0.448].

Conclusion

This study showed null findings on the effect of TEL on learning in residents of the first year of anesthesiology. More studies on TEL were required to confirm the effect of TEL and find the appropriate test format that could enhance learning for post-graduate medical trainees.
A mixed method study exploring similarities and differences in general and social services-specific barriers to treatment-seeking among individuals with a problematic use of alcohol, cannabis, or gambling
Authors: Schettini Greta , Lindner Philip , Ekström Veronica , Johansson Magnus
Published: August 2024

Introduction

The treatment gap for addictive disorders is one of the largest in health care. Several studies have investigated barriers to treatment for different addictive disorders, but very few studies conducted have explored whether the barriers differ depending on substance or behavior or if they are common among all addictive disorders. In Sweden, addiction care is provided both by the healthcare and social services, where the latter is common, but also less popular. To our knowledge, there are no studies exploring whether the barriers are different depending on where the treatment is given.

Aim

The aim was to thoroughly explore both which general and social services-specific barriers to treatment that are common, which barriers that differs, and how the barriers are described among individuals with a problematic use of alcohol, cannabis and/or gambling.

Method

A mixed method convergent parallel design was conducted. For the quantitative measures, surveys including the validated Barriers to Treatment Inventory as well as questions regarding barriers in the Swedish multi-provider landscape, were collected from individuals with a problematic use of alcohol (n = 207), cannabis (n = 51), and gambling (n = 37). In parallel, 17 semi-structured interviews from the same population were conducted and analyzed with thematic analysis. Thereafter, the quantitative and qualitative data was compared, contrasted, and at last, interpreted.

Results

The quantitative data showed that the largest general barriers in all groups were privacy concern and poor availability, and the largest barriers for seeking help from the social services was stigma, unawareness of what is offered, and fear of consequences for all groups. The qualitative data resulted in five general barriers: stigma, ambivalence, accessibility, fear of consequences, and lack of knowledge about addiction and its’ treatments, and three barriers specifically towards social services: social services reputation, fear of meeting acquaintances, and lack of knowledge. The themes were developed from data from all groups, but different aspects of the themes were mentioned by different groups.

Conclusion

There are details and aspects that differentiates both the general and social service-specific barriers to treatment between individuals with a problematic use of alcohol, cannabis, and gambling, but in large they perceive similar barriers.
Inhibition of IRP2-dependent reprogramming of iron metabolism suppresses tumor growth in colorectal cancer
Authors: Hwang Jieon , Park Areum , Kim Chinwoo , Kim Chang Gon , Kwak Jaesung , Kim Byungil , Shin Hyunjin , Ku Minhee , Yang Jaemoon , Baek Ayoung , Choi Jiwon , Lim Hocheol , No Kyoung Tai , Zhao Xianghua , Choi Uyeong , Kim Tae Il , Jeong Kyu-Sung , Lee Hyuk , Shin Sang Joon
Published: August 2024

Background

Dysregulation of iron metabolism is implicated in malignant transformation, cancer progression, and therapeutic resistance. Here, we demonstrate that iron regulatory protein 2 (IRP2) preferentially regulates iron metabolism and promotes tumor growth in colorectal cancer (CRC).

Methods

IRP2 knockdown and knockout cells were generated using RNA interference and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 methodologies, respectively. Cell viability was evaluated using both CCK-8 assay and cell counting techniques. Furthermore, IRP2 inhibition was determined by surface plasmon resonance (SPR) and RNA immunoprecipitation (IP). The suppressive effects of IRP2 were also corroborated in both organoid and mouse xenograft models, providing a comprehensive validation of IRP2’s role.

Results

We have elucidated the role of IRP2 as a preferential regulator of iron metabolism, actively promoting tumorigenesis within CRC. Elevated levels of IRP2 expression in patient samples are correlated with diminished overall survival, thereby reinforcing its potential role as a prognostic biomarker. The functional suppression of IRP2 resulted in a pronounced delay in tumor growth. Building on this proof of concept, we have developed IRP2 inhibitors that significantly reduce IRP2 expression and hinder its interaction with iron-responsive elements in key iron-regulating proteins, such as ferritin heavy chain 1 (FTH1) and transferrin receptor (TFRC), culminating in iron depletion and a marked reduction in CRC cell proliferation. Furthermore, these inhibitors are shown to activate the AMPK-ULK1-Beclin1 signaling cascade, leading to cell death in CRC models.

Conclusions

Collectively, these findings highlight the therapeutic potential of targeting IRP2 to exploit the disruption of iron metabolism in CRC, presenting a strategic advancement in addressing a critical area of unmet clinical need.
ΔNp63 bookmarks and creates an accessible epigenetic environment for TGFβ-induced cancer cell stemness and invasiveness
Authors: Vasilaki Eleftheria , Bai Yu , Ali Mohamad Moustafa , Sundqvist Anders , Moustakas Aristidis , Heldin Carl-Henrik
Published: August 2024

Background

p63 is a transcription factor with intrinsic pioneer factor activity and pleiotropic functions. Transforming growth factor β (TGFβ) signaling via activation and cooperative action of canonical, SMAD, and non-canonical, MAP-kinase (MAPK) pathways, elicits both anti- and pro-tumorigenic properties, including cell stemness and invasiveness. TGFβ activates the ΔNp63 transcriptional program in cancer cells; however, the link between TGFβ and p63 in unmasking the epigenetic landscape during tumor progression allowing chromatin accessibility and gene transcription, is not yet reported.

Methods

Small molecule inhibitors, including protein kinase inhibitors and RNA-silencing, provided loss of function analyses. Sphere formation assays in cancer cells, chromatin immunoprecipitation and mRNA expression assays were utilized in order to gain mechanistic evidence. Mass spectrometry analysis coupled to co-immunoprecipitation assays revealed novel p63 interactors and their involvement in p63-dependent transcription.

Results

The sphere-forming capacity of breast cancer cells was enhanced upon TGFβ stimulation and significantly decreased upon ΔNp63 depletion. Activation of TGFβ signaling via p38 MAPK signaling induced ΔNp63 phosphorylation at Ser 66/68 resulting in stabilized ΔNp63 protein with enhanced DNA binding properties. TGFβ stimulation altered the ratio of H3K27ac and H3K27me3 histone modification marks, pointing towards higher H3K27ac and increased p300 acetyltransferase recruitment to chromatin. By silencing the expression of ΔNp63, the TGFβ effect on chromatin remodeling was abrogated. Inhibition of H3K27me3, revealed the important role of TGFβ as the upstream signal for guiding ΔNp63 to the TGFβ/SMAD gene loci, as well as the indispensable role of ΔNp63 in recruiting histone modifying enzymes, such as p300, to these genomic regions, regulating chromatin accessibility and gene transcription. Mechanistically, TGFβ through SMAD activation induced dissociation of ΔNp63 from NURD or NCOR/SMRT histone deacetylation complexes, while promoted the assembly of ΔNp63-p300 complexes, affecting the levels of histone acetylation and the outcome of ΔNp63-dependent transcription.

Conclusions

ΔNp63, phosphorylated and recruited by TGFβ to the TGFβ/SMAD/ΔNp63 gene loci, promotes chromatin accessibility and transcription of target genes related to stemness and cell invasion.
IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency
Authors: Dong Qiyu , Yin Xiaojie , Fan Shuanglong , Zhong Sheng , Yang Wenxin , Chen Keer , Wang Qian , Ma Xue , Mahlatsi Refiloe Laurentinah , Yang Yanling , Lyu Jianxin , Fang Hezhi , Wang Ya
Published: August 2024

Background

Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.

Methods

Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.

Results

We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.

Conclusion

Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.
Oxygenator assisted dynamic microphysiological culture elucidates the impact of hypoxia on valvular interstitial cell calcification
Authors: Dittfeld Claudia , Schmieder Florian , Behrens Stephan , Jannasch Anett , Matschke Klaus , Sonntag Frank , Tugtekin Sems-Malte
Published: August 2024

Introduction

Microphysiological systems (MPS) offer simulation of (patho)physiological parameters. Investigation includes items which lead to fibrosis and calcification in development and progress of calcific aortic valve disease, based e.g. on culturing of isolated valvular interstitial cells (VICs). Hypoxia regulated by hypoxia inducible factors impacts pathological differentiation in aortic valve (AV) disease. This is mimicked via an MPS implemented oxygenator in combination with calcification inducing medium supplementation.

Methods

Human valvular interstitial cells were isolated and dynamically cultured in MPS at hypoxic, normoxic, arterial blood oxygen concentration and cell incubator condition. Expression profile of fibrosis and calcification markers was monitored and calcification was quantified in induction and control media with and without hypoxia and in comparison to statically cultured counterparts.

Results

Hypoxic 24-hour culture of human VICs leads to HIF1α nuclear localization and induction of EGLN1, EGLN3 and LDHA mRNA expression but does not directly impact expression of fibrosis and calcification markers. Dependent on medium formulation, induction medium induces monolayer calcification and elevates RUNX2, ACTA2 and FN1 but reduces SOX9 mRNA expression in dynamic and static MPS culture. But combining hypoxic oxygen concentration leads to higher calcification potential of human VICs in calcification and standard medium formulation dynamically cultured for 96 h.

Conclusion

In hypoxic oxygen concentration an increased human VIC calcification in 2D VIC culture in an oxygenator assisted MPS was detected. Oxygen regulation therefore can be combined with calcification induction media to monitor additional effects of pathological marker expression. Validation of oxygenator dependent VIC behavior envisions future advancement and transfer to long term aortic valve tissue culture MPS.
Prehospital guidelines on in-water traumatic spinal injuries for lifeguards and prehospital emergency medical services: an international Delphi consensus study
Authors: Breindahl Niklas , Bierens Joost L. M. , Wiberg Sebastian , Barcala-Furelos Roberto , Maschmann Christian
Published: August 2024

Background

Trauma guidelines on spinal motion restriction (SMR) have changed drastically in recent years. An international group of experts explored whether consensus could be reached and if guidelines on SMR performed by trained lifeguards and prehospital EMS following in-water traumatic spinal cord injury (TSCI) should also be changed.

Methods

An international three-round Delphi process was conducted from October 2022 to November 2023. In Delphi round one, brainstorming resulted in an exhaustive list of recommendations for handling patients with suspected in-water TSCI. The list was also used to construct a preliminary flowchart for in-water SMR. In Delphi round two, three levels of agreement for each recommendation and the flowchart were established. Recommendations with strong consensus (≥ 85% agreement) underwent minor revisions and entered round three; recommendations with moderate consensus (75–85% agreement) underwent major revisions in two consecutive phases; and recommendations with weak consensus (< 75% agreement) were excluded. In Delphi round 3, the level of consensus for each of the final recommendations and each of the routes in the flowchart was tested using the same procedure as in Delphi round 2.

Results

Twenty-four experts participated in Delphi round one. The response rates for Delphi rounds two and three were 92% and 88%, respectively. The study resulted in 25 recommendations and one flowchart with four flowchart paths; 24 recommendations received strong consensus (≥ 85%), and one recommendation received moderate consensus (81%). Each of the four paths in the flowchart received strong consensus (90–95%). The integral flowchart received strong consensus (93%).

Conclusions

This study produced expert consensus on 25 recommendations and a flowchart on handling patients with suspected in-water TSCI by trained lifeguards and prehospital EMS. These results provide clear and simple guidelines on SMR, which can standardise training and guidelines on SMR performed by trained lifeguards or prehospital EMS.
MulTI-domain self-management in older People wiTh OstEoarthritis and multi-morbidities: protocol for the TIPTOE randomised controlled trial
Authors: Deere Rachel , Pallmann Philip , Shepherd Victoria , Brookes-Howell Lucy , Carson-Stevens Andrew , Davies Ffion , Dunphy Emma , Gupta Preeti , Hickson Mary , Hill Val , Ingarfield Kate , Ivins Nicola , Jones Fiona , Letchford Robert , Lowe Rachel , Nash Sarah , Otter Paula , Prout Hayley , Randell Elizabeth , Sewell Bernadette , Smith Debs , Trubey Robert , Wainwright Tom , Busse Monica , Button Kate
Published: August 2024

Background

Four out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone.

Methods

TIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded ‘Study Within A Project’ (SWAP) will explore and address barriers to the inclusion of under-served patient groups (e.g. oldest old, low socioeconomic groups, ethnic groups).

Discussion

TIPTOE will evaluate the clinical and cost-effectiveness of a co-designed, living well personalised self-management support intervention for older individuals with knee and/or hip OA and MLTCs. The trial has been designed to maximise inclusivity and access.

Trial registration

ISRCTN 16024745. Registered on October 16, 2023.
Associations of physical activity and physical education enjoyment with self-concept domains among Hungarian adolescents
Authors: Berki Tamás , Csányi Tamás , Tóth László
Published: August 2024

Background

Sport enjoyment is one of the most important factors in physical activity (PA) and physical education (PE) domains. It is not only beneficial for regular participation but also has a positive effect on mental health. Due to these benefits, this study aims to understand the relationships between PA, two forms of enjoyment, and the dimension of self-concept.

Methods

The sample consisted of 315 students (Mage=12.63). The Self-Description Questionnaire-I was used to measure the domains of self-concept. Enjoyment was measured with two scales. The Physical Activity Enjoyment Scale reflects extracurricular PA enjoyment, and the Factors Influencing Enjoyment of Physical Education Questionnaire reflects school PE enjoyment. The International Physical Activity Questionnaire was used to assess vigorous, moderate, and walking types of extracurricular PA enjoyment.

Results

Hierarchical multivariate regression analysis revealed that vigorous PA predicted physical ability (β = 0.19) and physical appearance (β = 0.15). PA enjoyment was a significant predictor of general self-concept (β = 0.29), physical ability (β = 0.28), physical appearance (β = 0.16), peer relation (β = 0.16), and parental relations (β = 0.14). PE enjoyment significantly predicted general school (β = 0.17), physical ability (β = 0.27), peer relations (β = 0.21) and parental relations (β = 0.22). Furthermore, boys scored at a higher level on most of self-concept domains.

Conclusions

The present study suggested that enjoyment plays a more important role in self-concept than PA. PE enjoyment mainly strengthens boys’ self-concept, but PA enjoyment is an important predictor of general self-concept in both genders. It is concluded that extracurricular PA enjoyment is beneficial, but increasing enjoyment of physical education could increase girls’ self-concepts as well.
Inverse analysis of seismic activity rate changes for severely incomplete sequences: comparison of aftershock activity patterns immediately following the 2023 M6.5 and 2024 M7.6 Noto Peninsula earthquakes
Authors: Ogata Yosihiko , Kumazawa Takao
Published: August 2024

We estimate the true aftershock activity rate from the detected initial aftershocks of the M7.6 Noto Peninsula earthquake on January 1, 2024, in addition to the preceding M6.5 Noto Peninsula earthquake on May 5, 2023. Estimating the initial aftershock activity rates has the serious problem of missing data, but in itself contains important clues to the physical structure associated with aftershocks and other external factors. We first estimate the detection rate models of the two aftershock sequences assuming the Gutenberg–Richter frequency laws, and we have found the contrasting time evolution of b-values immediately after the mainshocks, in addition to the contrasting detection rate evolutions. Furthermore, by applying the compensated nonstationary ETAS (epidemic-type aftershock sequence) model, we have revealed the contrasting time evolution of the background intensity rates, which characterizes the external factor of the original ETAS model besides the static triggering seismic activity. We discuss the implications of these differences of the analyzed outputs.

Graphical Abstract
Antidiabetic effects of aqueous leaf extract of Vernonia amygdalina on serum liver markers in streptozotocin-induced diabetic albino Rats: a new data to support its Anti-diabetic effect
Authors: Adekemi Falae Esther , Folake Jayesinmi Kikelomo , Omowumi Falae Philips
Published: August 2024

Background

Numerous plants have been explored for their potential antidiabetic properties, and Vernonia amygdalina (VA) stands among them. This study aims to investigate the antidiabetic activities of VA and validate its efficacy.

Methods

An aqueous extract of Vernonia amygdalina leaves was obtained through maceration. The antidiabetic effects of this plant extract were evaluated in vivo using diabetic model rats. Albino Wistar rats were induced into a diabetic state through intraperitoneal injection of streptozocin and subsequently treated with an optimal dose of 250 mg/kg aqueous extract of VA over a 21-day period. Parameters such as body weight, blood glucose levels, and serum marker enzymes were measured.

Results

The results demonstrated a significant reduction (p < 0.05) in the glucose levels of streptozocin-induced diabetic rats following treatment with VA extract, highlighting its potential as an antidiabetic agent that performed comparably to the reference drug, glimepiride. Additionally, a significant increase (p < 0.05) in the body weight of the treated diabetic rats was observed. Aqueous extracts also significantly (p < 0.05) altered the serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a manner similar to the glimepiride-treated group.

Conclusion

This study affirms the anti-diabetic effects of the aqueous extract of Vernonia amygdalina in streptozotocin-induced diabetic rats and suggests that the extract holds promise as an important phytomedicine for the development of more effective treatments for diabetes.
Large macular hole and autologous retinal transplantation: a systematic review and meta-analysis
Authors: Hanai Mário , Amaral Dillan Cunha , Jacometti Raiza , Aguiar Eduardo Henrique Cassins , Gomes Fernando Cotrim , Cyrino Laura Goldfarb , Alves Milton Ruiz , Monteiro Mário Luiz Ribeiro , Fuganti Raphaela Masetto , Casella Antonio Marcelo Barbante , Louzada Ricardo Noguera
Published: August 2024

Introduction

Macular holes are breaks in the retinal tissue at the center of the macula, affecting central vision. The standard treatment involves vitrectomy with membrane peeling and gas tamponade. However, for larger or chronic holes, alternative techniques like autologous retinal graft have emerged. This meta-analysis evaluates the efficacy and safety of retinal transplantation in managing large macular holes.

Methods

We conducted a systematic review and meta-analysis following PRISMA guidelines. The study was prospectively registered in PROSPERO (CRD42024504801). We searched PubMed, Web of Science, Cochrane, and Embase databases for observational studies including individuals with large macular holes with or without retinal detachments and retinal transplantation as the main therapy. We used a random-effects model to compute the mean difference with 95% confidence intervals and performed statistical analysis using R software.

Results

We conducted a comprehensive analysis of 19 studies involving 322 patients diagnosed with various types of macular holes (MHs). These included cohorts with refractory MH, high myopia associated with MH, primary MH, and MH with retinal detachment (RD). The findings were promising, revealing an overall closure rate of 94% of cases (95% CI 88–98, I2 = 20%). Moreover, there was a significant improvement in postoperative visual acuity across all subgroups, averaging 0.45 (95% CI 0.33–0.58 ; I2 = 72%; p < 0.01) overall. However, complications occurred with an overall incidence rate of 15% (95% CI 7–25; I2 = 59%).

Conclusion

ART for large MH shows promising results, including significant improvements in visual acuity and a high rate of MH closure with low complication risks overall and for subgroups.
Complementary use of cardiac magnetic resonance and 18 F-FDG positron emission tomography imaging in suspected immune checkpoint inhibitor myocarditis
Authors: Tong Jieli , Vogiatzakis Nikolaos , Andres Maria Sol , Senechal Isabelle , Badr Ahmed , Ramalingam Sivatharshini , Rosen Stuart D. , Lyon Alexander R. , Nazir Muhummad Sohaib
Published: August 2024

Background

Immune checkpoint inhibitor (ICI) myocarditis is an uncommon but potentially fatal complication of immunotherapy. Cardiac imaging is essential to make timely diagnoses as there are critical downstream implications for patients.

Objective

To determine the agreement of cardiac magnetic resonance (CMR) and 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in patients with suspected ICI myocarditis.

Methods

Patients with suspected ICI myocarditis, who underwent CMR and 18 F-FDG-PET imaging at a single cardio-oncology service from 2017 to 2023, were enrolled. CMR was performed according to recommended guidelines for assessment of myocarditis. 18 F-FDG-PET imaging was performed following 18 h carbohydrate-free fast. Imaging was analysed by independent reviewers to determine the presence or absence of ICI myocarditis.

Results

Twelve patients (mean age 60 ± 15 years old, 7 [58%] male) underwent both CMR and 18 F-FDG-PET imaging. Three (25%) met the 2018 Lake Louise Criteria for CMR diagnosis of myocarditis; 4 (33%) had evidence of myocardial inflammation as determined by 18 F-FDG-PET. Amongst those with positive 18 F-FDG-PET, mean standard uptake value (SUV) was 3.5 ± 1.7. There was agreement between CMR and PET in 7 cases (CMR and PET positive (n = 1), CMR and PET negative (n = 6)) and discordance in 5 cases (CMR positive and PET negative (n = 2), CMR negative and PET positive (n = 3)).

Conclusion

Both CMR and PET provide complementary clinical information in diagnostic of ICI myocarditis. CMR informs on myocardial oedema, whilst 18 F-FDG-PET provides information on glucose metabolism reflecting monocyte and lymphocytic activity. Future studies should investigate the role of hybrid PET-CMR for the timely diagnosis of ICI myocarditis.
“For them it’s not the work, it’s the life”: humanitarian leadership development in the Global South
Authors: Saha Manika , Zadeh-Cummings Nazanin , McGlasson Mary Ana , Brockington Sonia
Published: August 2024

What are the leadership development needs of so-called ‘Global South’ humanitarian professionals? The humanitarian professionalisation agenda begun in the 1990s has evolved to include short courses and accredited programmes specifically aiming to build leadership skills. This paper explores how humanitarian professionals from the Global South understand the current context of leadership development, including its barriers of access, and potential for change to be more relevant to their lives and work. Using thematic analysis of eleven key informant interviews, the paper finds three levels of consideration: global politics and inequality, personal and professional enrichment, and practical support. The findings suggest that while humanitarian leadership training can be better tailored and made available to Global South leaders at all career stages, there is a wider, more crucial need to address systemic imbalances. This paper contributes to wider discussion on localisation and inequality in the humanitarian aid sector, and more specifically contributes to the literature on how systemic factors shape the limits of both professionalisation and expansion of humanitarian education initiatives.