bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxytocin measurements in saliva: an analytical perspective
Authors: López-Arjona Marina , Botía María , Martínez-Subiela Silvia , Cerón José Joaquín
Published: July 2023

Oxytocin has traditionally been known for its physiological effects on muscle contraction associated with birth and lactation, but in the last years is widely used as a biomarker of “positive experiences” in psychology and behavior. Different types of samples have been used for oxytocin measurements with saliva samples having the particular advantage of an easy and non-stressful collection. However, the low concentration of oxytocin in saliva can represent a limitation for its use. For this reason, sensitive assays and even a previous sample treatment in some cases are required for saliva oxytocin quantification. In addition, the lack of standardized and generally agreed-upon approach to peripheral oxytocin measurement leads to large discrepancies between different laboratories, that use different sample treatment protocols and different assays. The main objectives of this review are to describe the current status of the use of saliva for oxytocin measurement, provide details of the different sample processing techniques that can be applied and inform about the analytical techniques and assays available in different animal species, and also in humans for comparative purposes. It is expected that this information can contribute to an increase in the knowledge about the measurements of oxytocin in saliva and to its wider use in the future.
Exosomal miR-184 in the aqueous humor of patients with central serous chorioretinopathy: a potential diagnostic and prognostic biomarker
Authors: Yang Jee Myung , Kim Soo Jin , Park Seongyeol , Son Wonyung , Kim Anna , Lee Junyeop
Published: July 2023

Background

Central serous chorioretinopathy (CSC) is the fourth most prevalent retinal disease leading to age-related macular degeneration (AMD) and retinal atrophy. However, CSC's pathogenesis and therapeutic target need to be better understood.

Results

We investigated exosomal microRNA in the aqueous humor of CSC patients using next-generation sequencing (NGS) to identify potential biomarkers associated with CSC pathogenesis. Bioinformatic evaluations and NGS were performed on exosomal miRNAs obtained from AH samples of 62 eyes (42 CSC and 20 controls). For subgroup analysis, patients were divided into treatment responders (CSC-R, 17 eyes) and non-responders (CSC-NR, 25 eyes). To validate the functions of miRNA in CECs, primary cultured-human choroidal endothelial cells (hCEC) of the donor eyes were utilized for in vitro assays. NGS detected 376 miRNAs. Our results showed that patients with CSC had 12 significantly upregulated and 17 downregulated miRNAs compared to controls. miR-184 was significantly upregulated in CSC-R and CSC-NR patients compared to controls and higher in CSC-NR than CSC-R. In vitro assays using primary cultured-human choroidal endothelial cells (hCEC) demonstrated that miR-184 suppressed the proliferation and migration of hCECs. STC2 was identified as a strong candidate for the posttranscriptional down-regulated target gene of miR-184.

Conclusion

Our findings suggest that exosomal miR-184 may serve as a biomarker reflecting the angiostatic capacity of CEC in patients with CSC.
Smad7 in the hippocampus contributes to memory impairment in aged mice after anesthesia and surgery
Authors: Liu Changliang , Wu Jiahui , Li Ming , Gao Rui , Zhang Xueying , Ye-Lehmann Shixin , Song Jiangning , Zhu Tao , Chen Chan
Published: July 2023

Background

Postoperative cognitive dysfunction (POCD) is a common neurological complication following anesthesia and surgery. Increasing evidence has demonstrated that neuroinflammation caused by systemic inflammatory responses during the perioperative period is a key factor in the occurrence of POCD. In addition, SMAD family member 7 (Smad7) has been confirmed to play vital roles in the pathogenesis and treatment of inflammatory diseases, such as inflammatory bowel disease. However, whether Smad7 participates in the regulatory process of neuroinflammation and apoptosis in the development of POCD is still unknown.

Methods

In this study, a POCD mouse model was constructed by unilateral nephrectomy under anesthesia, and cognitive function was assessed using the fear conditioning test and open field test. The expression of Smad7 at the mRNA and protein levels in the hippocampus 3 days after surgery was examined by qRT-PCR, western blot and immunofluorescence assays. Furthermore, to identify whether the elevation of Smad7 in the hippocampus after unilateral nephrectomy contributes to cognitive impairment, the expression of Smad7 in the hippocampal CA1 region was downregulated by crossing Smad7fl/fl conditional mutant mice and CaMKIIα-Cre line T29-1 transgenic mice or stereotaxic injection of shRNA–Smad7. Inflammation and apoptosis in the hippocampus were assessed by measuring the mRNA levels of typical inflammatory cytokines, including TNF-α, IL-1β, IL-6, CCL2, CXCL1, and CXCL2, and the protein levels of apoptotic proteins, including Bax and Bcl2. In addition, apoptosis in the hippocampus postoperation was investigated by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining assay. Finally, western blotting was used to explore how Smad7 mediates inflammation and apoptosis postoperation.

Results

The results unequivocally revealed that elevated Smad7 in the hippocampal CA1 region significantly inhibited TGF-β signal transduction by blocking Smad2/3 phosphorylation, which enhanced neuroinflammation and apoptosis in the hippocampus and further led to learning and memory impairment after surgery.

Conclusions

Our results revealed that Smad7 contributes to cognitive impairment after surgery by enhancing neuroinflammation and apoptosis in the hippocampus and might serve as a promising therapeutic target for the treatment of memory impairment after anesthesia surgery.
Cellulose ether treatment inhibits amyloid beta aggregation, neuroinflammation and cognitive deficits in transgenic mouse model of Alzheimer’s disease
Authors: Ali Tahir , Klein Antonia N. , McDonald Keegan , Johansson Lovisa , Mukherjee Priyanka Ganguli , Hallbeck Martin , Doh-ura Katsumi , Schatzl Hermann M. , Gilch Sabine
Published: July 2023

Alzheimer’s disease (AD) is an incurable, progressive and devastating neurodegenerative disease. Pathogenesis of AD is associated with the aggregation and accumulation of amyloid beta (Aβ), a major neurotoxic mediator that triggers neuroinflammation and memory impairment. Recently, we found that cellulose ether compounds (CEs) have beneficial effects against prion diseases by inhibiting protein misfolding and replication of prions, which share their replication mechanism with Aβ. CEs are FDA-approved safe additives in foods and pharmaceuticals. Herein, for the first time we determined the therapeutic effects of the representative CE (TC-5RW) in AD using in vitro and in vivo models. Our in vitro studies showed that TC-5RW inhibits Aβ aggregation, as well as neurotoxicity and immunoreactivity in Aβ-exposed human and murine neuroblastoma cells. In in vivo studies, for the first time we observed that single and weekly TC-5RW administration, respectively, improved memory functions of transgenic 5XFAD mouse model of AD. We further demonstrate that TC-5RW treatment of 5XFAD mice significantly inhibited Aβ oligomer and plaque burden and its associated neuroinflammation via regulating astrogliosis, microgliosis and proinflammatory mediator glial maturation factor beta (GMFβ). Additionally, we determined that TC-5RW reduced lipopolysaccharide-induced activated gliosis and GMFβ in vitro. In conclusion, our results demonstrate that CEs have therapeutic effects against Aβ pathologies and cognitive impairments, and direct, potent anti-inflammatory activity to rescue neuroinflammation. Therefore, these FDA-approved compounds are effective candidates for developing therapeutics for AD and related neurodegenerative diseases associated with protein misfolding.
Circulating miR-21 as a prognostic biomarker in HCC treated by CT-guided high-dose rate brachytherapy
Authors: Stechele Matthias , Link Henrike , Hirner-Eppeneder Heidrun , Alunni-Fabbroni Marianna , Wildgruber Moritz , Salvermoser Lukas , Corradini Stefanie , Schinner Regina , Ben Khaled Najib , Rössler Daniel , Galun Eithan , Goldberg Shraga Nahum , Ricke Jens , Kazmierczak Philipp Maximilian
Published: July 2023

Background and aims

Prognostic biomarkers identifying patients with early tumor progression after local ablative therapy remain an unmet clinical need. The aim of this study was to investigate circulating miR-21 and miR-210 levels as prognostic biomarkers of HCC treated by CT-guided high-dose rate brachytherapy (HDR-BT).

Materials and Methods

24 consecutive HCC patients (BCLC A and B) treated with CT-guided HDR-BT (1 × 15 Gy) were included in this prospective IRB-approved study. RT-PCR was performed to quantify miR-21 and miR-210 levels in blood samples acquired prior to and 2 d after HDR-BT. Follow-up imaging (contrast-enhanced liver MRI and whole-body CT) was performed in 3 months follow-up intervals. Therapy response was assessed with patients classified as either responders or non-responders (12 each). Responders were defined as having no local or diffuse systemic progression within 6 months and no diffuse systemic progression exceeding 3 nodules/nodule diameter > 3 cm from 6 months to 2 years. Non-responders had recurrence within 6 months and/or tumor progression with > 3 nodules or individual lesion diameter > 3 cm or extrahepatic disease within two years, respectively. Biostatistics included parametric and non-parametric testing (Mann–Whitney-U-test), as well as Kaplan–Meier curve construction.

Results

The responder group demonstrated significantly decreasing miR-21 values 2 d post therapy compared to non-responders (median miR-21 2−ΔΔCт: responders 0.73 [IQR 0.34], non-responders 1.53 [IQR 1.48];p = 0.0102). miR-210 did not show any significant difference between responders and non-responders (median miR-210 2−ΔΔCт: responders 0.74 [IQR 0.45], non-responders 0.99 [IQR 1.13];p = 0.8399). Kaplan–Meier curves demonstrated significantly shorter time to systemic progression for increased miR-21 (p = 0.0095) but not miR-210 (p = 0.7412), with events accumulating > 1 year post therapy in non-responders (median time to systemic progression 397 days).

Conclusion

Increasing circulating miR-21 levels are associated with poor response and shorter time to systemic progression in HDR-BT-treated HCC. This proof-of-concept study provides a basis for further investigation of miR-21 as a prognostic biomarker and potential stratifier in future clinical trials of interventional oncology therapies.

Trial registration:In this monocentric clinical study, we analyzed prospectively acquired data of 24 patients from the “ESTIMATE” patient cohort (Studiennummer: DRKS00010587, Deutsches Register Klinischer Studien). Ethical approval was provided by the ethics committee “Ethikkommission bei der LMU München” (reference number “17-346”) on June 20, 2017 and August 26, 2020.
Tongbi Huoluo Decoction alleviates cartilage degeneration in knee osteoarthritis by inhibiting degradation of extracellular matrix
Authors: Chen Weijian , Liu Weinian , Jiang Tao , Liu Lingyun , He Qi , Lin Tianye , Zhang Jiayuan , Huo Liwei , Xu Xuemeng , Wang Haibin , Liang Du , Liu Wengang
Published: July 2023

Background

Knee osteoarthritis (KOA) is an age-related degenerative disease characterized by abrasion of articular cartilage. Tongbi Huoluo Decoction (TBHLD) has been transformed from the famous traditional Chinese medicine Duhuo Jisheng Decoction, which can effectively alleviate pain symptoms in KOA. However, the active components and mechanisms of TBHLD in treating KOA have not yet been elucidated. The purpose of the study was to demonstrate the molecular mechanism of TBHLD in treating KOA.

Methods

The components and targets of TBHLD and KOA were collected from multiple databases, and the protein to protein interaction (PPI) network was constructed. Next, we performed topological calculation and enrichment analysis. Besides, we performed virtual screening for molecular docking and molecular dynamics simulation (MDS). Furthermore, the vitro and vivo experiments were performed to evaluate the validity and mechanism of TBHLD.

Results

206 active components and 187 potential targets were screened from Tongbi Huoluo Decoction. A total of 50 intersecting genes were identified between TBHLD and KOA, 20 core targets were calculated by network topology analysis. The core targets were enriched in the ECM interaction pathways. The results of virtual screening for molecular docking and MDS showed that the active components of TBHLD had steady binding conformations with core genes. Moreover, we identified 32 differential serum components in TBHLD-containing serum using LC–MS, including 22 upregulated and 10 downregulated serum components. TBHLD improved the proliferation activity of OA chondrocytes, decreased the expression of Col1a1, Col1a2, Mmp2, Mmp13 in OA chondrocytes, ameliorated the cartilage lesions and restored the cartilage abrasion.

Conclusion

TBHLD inhibited degradation of cartilage ECM by regulating the expression of type I collagens and Mmps to ameliorate cartilage degeneration in KOA.
Super-enhancers complexes zoom in transcription in cancer
Authors: Wang MengTing , Chen QingYang , Wang ShuJie , Xie Han , Liu Jun , Huang RuiXiang , Xiang YuFei , Jiang YanYi , Tian DaSheng , Bian ErBao
Published: July 2023

Super-enhancers (SEs) consist of multiple typical enhancers enriched at high density with transcription factors, histone-modifying enzymes and cofactors. Oncogenic SEs promote tumorigenesis and malignancy by altering protein-coding gene expression and noncoding regulatory element function. Therefore, they play central roles in the treatment of cancer. Here, we review the structural characteristics, organization, identification, and functions of SEs and the underlying molecular mechanism by which SEs drive oncogenic transcription in tumor cells. We then summarize abnormal SE complexes, SE-driven coding genes, and noncoding RNAs involved in tumor development. In summary, we believe that SEs show great potential as biomarkers and therapeutic targets.
Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells
Authors: Cui Yanfen , Liu Hui , Wang Zhaosong , Zhang He , Tian Jianfei , Wang Zhiyong , Song Weijie , Guo Hui , Liu Liming , Tian Ruinan , Zuo Xiaoyan , Ren Sixin , Zhang Fei , Niu Ruifang
Published: July 2023

Background

Fructose is a very common sugar found in natural foods, while current studies demonstrate that high fructose intake is significantly associated with increased risk of multiple cancers and more aggressive tumor behavior, but the relevant mechanisms are not fully understood.

Methods

Tumor-grafting experiments and in vitro angiogenesis assays were conducted to detect the effect of fructose and the conditioned medium of fructose-cultured tumor cells on biological function of vascular endothelial cells (VECs) and angiogenesis. 448 colorectal cancer specimens were utilized to analyze the relationship between Glut5 expression levels in VECs and tumor cells and microvascular density (MVD).

Results

We found that fructose can be metabolized by VECs and activate the Akt and Src signaling pathways, thereby enhancing the proliferation, migration, and tube-forming abilities of VECs and thereby promoting angiogenesis. Moreover, fructose can also improve the expression of vascular endothelial growth factor (VEGF) by upregulating the production of reactive oxygen species (ROS) in colorectal cancer cells, thus indirectly enhancing the biological function of VECs. Furthermore, this pro-angiogenic effect of fructose metabolism has also been well validated in clinical colorectal cancer tissues and mouse models. Fructose contributes to angiogenesis in mouse subcutaneous tumor grafts, and MVD is positively correlated with Glut5 expression levels of both endothelial cells and tumor cells of human colorectal cancer specimens.

Conclusions

These findings establish the direct role and mechanism by which fructose promotes tumor progression through increased angiogenesis, and provide reliable evidence for a better understanding of tumor metabolic reprogramming.
Simultaneous venous–arterial Doppler during preload augmentation: illustrating the Doppler Starling curve
Authors: Kenny Jon-Émile S. , Gibbs Stanley O. , Eibl Joseph K. , Eibl Andrew M. , Yang Zhen , Johnston Delaney , Munding Chelsea E. , Elfarnawany Mai , Lau Vivian C. , Kemp Benjamin O. , Nalla Bhanu , Atoui Rony
Published: July 2023

Providing intravenous (IV) fluids to a patient with signs or symptoms of hypoperfusion is common. However, evaluating the IV fluid ‘dose–response’ curve of the heart is elusive. Two patients were studied in the emergency department with a wireless, wearable Doppler ultrasound system. Change in the common carotid arterial and internal jugular Doppler spectrograms were simultaneously obtained as surrogates of left ventricular stroke volume (SV) and central venous pressure (CVP), respectively. Both patients initially had low CVP jugular venous Doppler spectrograms. With preload augmentation, only one patient had arterial Doppler measures indicative of significant SV augmentation (i.e., ‘fluid responsive’). The other patient manifested diminishing arterial response, suggesting depressed SV (i.e., ‘fluid unresponsive’) with evidence of ventricular asynchrony. In this short communication, we describe how a wireless, wearable Doppler ultrasound simultaneously tracks surrogates of cardiac preload and output within a ‘Doppler Starling curve’ framework; implications for IV fluid dosing are discussed.
Personalized estimates of brain cortical structural variability in individuals with Autism spectrum disorder: the predictor of brain age and neurobiology relevance
Authors: Xie Yingying , Sun Jie , Man Weiqi , Zhang Zhang , Zhang Ningnannan
Published: July 2023

Background

Autism spectrum disorder (ASD) is a heritable condition related to brain development that affects a person’s perception and socialization with others. Here, we examined variability in the brain morphology in ASD children and adolescent individuals at the level of brain cortical structural profiles and the level of each brain regional measure.

Methods

We selected brain structural MRI data in 600 ASDs and 729 normal controls (NCs) from Autism Brain Imaging Data Exchange (ABIDE). The personalized estimate of similarity between gray matter volume (GMV) profiles of an individual to that of others in the same group was assessed by using the person-based similarity index (PBSI). Regional contributions to PBSI score were utilized for brain age gap estimation (BrainAGE) prediction model establishment, including support vector regression (SVR), relevance vector regression (RVR), and Gaussian process regression (GPR). The association between BrainAGE prediction in ASD and clinical performance was investigated. We further explored the related inter‐regional profiles of gene expression from the Allen Human Brain Atlas with variability differences in the brain morphology between groups.

Results

The PBSI score of GMV was negatively related to age regardless of the sample group, and the PBSI score was significantly lower in ASDs than in NCs. The regional contributions to the PBSI score of 126 brain regions in ASDs showed significant differences compared to NCs. RVR model achieved the best performance for predicting brain age. Higher inter-individual brain morphology variability was related to increased brain age, specific to communication symptoms. A total of 430 genes belonging to various pathways were identified as associated with brain cortical morphometric variation. The pathways, including short-term memory, regulation of system process, and regulation of nervous system process, were dominated mainly by gene sets for manno midbrain neurotypes.

Limitations

There is a sample mismatch between the gene expression data and brain imaging data from ABIDE. A larger sample size can contribute to the model training of BrainAGE and the validation of the results.

Conclusions

ASD has personalized heterogeneity brain morphology. The brain age gap estimation and transcription-neuroimaging associations derived from this trait are replenished in an additional direction to boost the understanding of the ASD brain.
Difficult diagnosis in the clinical evaluation of a patient with squamous cell carcinoma of the sigmoid colon: a case report
Authors: Garro-Mendiola Alonso , Guevara-Lazo David , Samanez Willian Pinto , Lizarzaburu-Robles Juan Carlos
Published: July 2023

Background

Squamous cell carcinoma (SCC) of the sigmoid colon is an exceedingly rare subtype of colorectal cancer (CRC) associated with chronic inflammatory conditions. Due to its variable clinical presentation ranging from subclinical to fully symptomatic and limited available information, it poses a diagnostic challenge. We aim to provide a review of the current literature and raise awareness about the importance of a thorough clinical analysis for an early diagnosis.

Case presentation

We describe the case of a 59-year-old Peruvian woman with a medical history of diverticular disease and irritable bowel syndrome. The patient presented with nonspecific symptoms such as abdominal discomfort, constipation, and bloating. Diagnostic tests and biopsy revealed a rare case of squamous cell carcinoma of the sigmoid colon. The patient underwent surgical resection and adjuvant chemotherapy.

Conclusion

Despite the rarity of this type of cancer in the colon, the patient's clinical course highlights the importance of considering it as a potential diagnosis in patients with nonspecific symptoms and a history of gastrointestinal disorders. Surgical treatment followed by radiotherapy is the preferred management. Factors such as lack of postoperative complications and the stage of the neoplasia can augur a positive. prognosis. A prompt diagnosis is crucial, as detecting a neoplasia in its early stages can make surgery more effective.
hESC-derived striatal progenitors grafted into a Huntington’s disease rat model support long-term functional motor recovery by differentiating, self-organizing and connecting into the lesioned striatum
Authors: Schellino Roberta , Besusso Dario , Parolisi Roberta , Gómez-González Gabriela B. , Dallere Sveva , Scaramuzza Linda , Ribodino Marta , Campus Ilaria , Conforti Paola , Parmar Malin , Boido Marina , Cattaneo Elena , Buffo Annalisa
Published: July 2023

Background

Huntington’s disease (HD) is a motor and cognitive neurodegenerative disorder due to prominent loss of striatal medium spiny neurons (MSNs). Cell replacement using human embryonic stem cells (hESCs) derivatives may offer new therapeutic opportunities to replace degenerated neurons and repair damaged circuits.

Methods

With the aim to develop effective cell replacement for HD, we assessed the long-term therapeutic value of hESC-derived striatal progenitors by grafting the cells into the striatum of a preclinical model of HD [i.e., adult immunodeficient rats in which the striatum was lesioned by monolateral injection of quinolinic acid (QA)]. We examined the survival, maturation, self-organization and integration of the graft as well as its impact on lesion-dependent motor alterations up to 6 months post-graft. Moreover, we tested whether exposing a cohort of QA-lesioned animals to environmental enrichment (EE) could improve graft integration and function.

Results

Human striatal progenitors survived up to 6 months after transplantation and showed morphological and neurochemical features typical of human MSNs. Donor-derived interneurons were also detected. Grafts wired in both local and long-range striatal circuits, formed domains suggestive of distinct ganglionic eminence territories and displayed emerging striosome features. Moreover, over time grafts improved complex motor performances affected by QA. EE selectively increased cell differentiation into MSN phenotype and promoted host-to-graft connectivity. However, when combined to the graft, the EE paradigm used in this study was insufficient to produce an additive effect on task execution.

Conclusions

The data support the long-term therapeutic potential of ESC-derived human striatal progenitor grafts for the replacement of degenerated striatal neurons in HD and suggest that EE can effectively accelerate the maturation and promote the integration of human striatal cells.
Vertical nanoscale strain-induced electronic localization in epitaxial La2/3Sr1/3MnO3 films with ZrO2 nanopillar inclusions
Authors: Gao Yuze , Roldan Manuel A. , Qiao Liang , Mandrus David , Shen Xuechu , Chisholm Matthew F. , Singh David J. , Cao Guixin
Published: July 2023

Unusual electrical transport properties associated with weak or strong localization are sometimes found in disordered electronic materials. Here, we report experimental observation of a crossover of electronic behavior from weak localization to enhanced weak localization due to the spatial influence of disorder induced by ZrO2 nanopillars in (La2/3Sr1/3MnO3)1−x:(ZrO2)x (x = 0, 0.2, and 0.3) nanocomposite films. The spatial strain regions, identified by scanning transmission electron microscopy and high-resolution x-ray diffraction, induce a coexistence of two-dimentional (2D) and three-dimentional (3D) localization and switches to typical 2D localization with increasing density of ZrO2 pillars due to length scale confinement, which interestingly accords with enhancing vertically interfacial strain. Based on the excellent agreement of our experimental results with one-parameter scaling theory of localization, the enhanced weak localization exists in metal range close to the fixed point. These films provide a tunable experimental model for studying localization in particular the transition regime by appropriate choice of the second epitaxial phase.

Graphical Abstract
“It’s research, our input can grow”: identifying health research priorities with Aboriginal and Torres Strait Islander communities—study protocol
Authors: Massi Luciana , Weatherall Loretta , Nielsen Christine , Toombs Maree , Fredericks Bronwyn , Rae Kym M.
Published: July 2023

Background

In Australia, Aboriginal and Torres Strait Islander (Indigenous) families have strong, cohesive, and nurturing cultural practices that contribute to effective family functioning and child rearing. These practices can lead to positive effects on children and communities, and include kinship relations, traditional knowledge systems, collective community focus, respect for Elders contributions, and spirituality. However, poor health and wellbeing outcomes exist across the lifespan for Indigenous Australians. Health programs, services and research that support Indigenous women, babies and their families are a critical investment to improve birthing and health outcomes and impact the life trajectories of Indigenous Australians.

Aim

The Indigenous Health Research Priorities study aims to identify the research priorities for families during the perinatal and early childhood period through a co-designed and collaborative process. This has been led by communities to determine the priorities identified with and for local Indigenous families in Queensland. This paper aims to report on engagement and involvement with Indigenous communities to identity health research priorities for families and presents preliminary findings of the research process including participants’ demographic information and feedback on the yarning sessions, as part of the study protocol.

Methods

The study protocol showcases the Participatory Action Research approach, yarning sessions with clients and staff of three community-controlled health services to date, and Delphi workshop methods to prioritise the health issues identified during the yarns with corresponding communities. The study will undertake qualitative data collection and analysis to identify and report on community and health service research priorities for Indigenous families in Queensland. A short survey was conducted to collect participants’ demographic information. A feedback form with five open-ended questions was also administered to collect data on participants’ views and satisfaction with the research process.

Preliminary results

This protocol paper reports on the participant demographic information and feedback on the research process and reactions to participating in the yarning sessions. There have been 12 yarning sessions in Far North Queensland to date. The qualitative analysis of these will be reported on in future, with South East Queensland and further sites to follow. Feedback from 61 community members and health professionals has highlighted they valued sharing stories, being heard, and feeling hopeful. Preliminary findings will be reported.

Discussion

Identification of health research priorities will allow each organisation and region of Queensland to develop research initiatives and the translational outcomes that are a focus for their community members.
Emergency team competencies: scoping review for the development of a tool to support the briefing and debriefing activities of emergency healthcare providers
Authors: Lorenzini Gabriele , Zamboni Alberto , Gelati Luca , Di Martino Alberto , Pellacani Alberto , Barbieri Nicolò , Baraldi Marcello
Published: July 2023

Globally, at least one adverse event occurs in 10% of patients using emergency, inpatient, outpatient, surgical and primary care services. Particularly in emergency health care, this problem is exacerbated by additional variables such as patient criticality, high-risk diagnostic and therapeutic interventions and varying levels of healthcare provider training. In relation to the last point, briefing and debriefing activities during an emergency reinforce staff training and support them in managing work resources, planning interventions and improving future performance. The aim of the scoping review is to explore the state of the art in human factors applied to emergency situations and to develop a new tool to support healthcare professionals in conducting evidence-based briefings and debriefings. This review was developed using a search strategy based on the Arksey and O’Malley’s six-step framework for scoping reviews. The literature analysed and the data identified, which are heterogeneous due to different study methodologies, objectives and types of interventions, suggest that human factors applied to emergency situations are still under-researched. At the end of the data extraction, analysis process, authors’ reviews, discussion rounds and comparison with the multidisciplinary team of healthcare providers, 42 behaviours, 33 elements and 8 domains were considered relevant and included in the Emergency Team Comptencies (ETC) briefing and debriefing tool, ranked in order of priority as follows: communication, decision-making, clinical skills, situational awareness, leadership, task management, collaboration and stress and fatigue management. Further research is needed to investigate human factors applied to emergency situations and to generate new evidence to improve clinical practice and reduce the risk of error. In the near future, further studies will be conducted by the authors to test the validity of the Emergency Team Competencies tool in objectively measuring the performance of professionals and multidisciplinary teams.
Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial
Authors: Ascierto Paolo A. , Dummer Reinhard , Gogas Helen J. , Arance Ana , Mandala Mario , Liszkay Gabriella , Garbe Claus , Schadendorf Dirk , Krajsova Ivana , Gutzmer Ralf , Chiarion-Sileni Vanna , Dutriaux Caroline , de Groot Jan Willem B. , Yamazaki Naoya , Loquai Carmen , Robert Caroline , Flaherty Keith T.
Published: July 2023

PURPOSE

In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms.

METHODS

In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety.

RESULTS

Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2  months (7.4 to 11.1) for ENCO300 (parts 1  and  2) and 7.4  months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1  and  2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1  and  2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300.

CONCLUSION

COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.
Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients
Authors: Stein John P. , Lieskovsky Gary , Cote Richard , Groshen Susan , Feng An-Chen , Boyd Stuart , Skinner Eila , Bochner Bernard , Thangathurai Duriayai , Mikhail Maged , Raghavan Derek , Skinner DonaldG.
Published: July 2023

PURPOSE: To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes.

PATIENTS AND METHODS: All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients.

RESULTS: A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node–negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node–negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node–negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers ( P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement ( P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence.

CONCLUSION: These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.
ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma
Authors: Zinzani Pier Luigi , Mayer Jiří , Flowers Christopher R. , Bijou Fontanet , De Oliveira Ana C. , Song Yuqin , Zhang Qingyuan , Merli Michele , Bouabdallah Krimo , Ganly Peter , Zhang Huilai , Johnson Roderick , Martín García-Sancho Alejandro , Provencio Pulla Mariano , Trněný Marek , Yuen Sam , Tilly Herve , Kingsley Edwin , Tumyan Gayane , Assouline Sarit E. , Auer Rebecca , Ivanova Elena , Kim Pil , Huang Sha , Delarue Richard , Trotman Judith
Published: July 2023

Deep and durable responses with zanubrutinib plus obinutuzumab in patients with R/R FL.
Transposable elements in normal and malignant hematopoiesis
Authors: Lemerle Eline , Trompouki Eirini
Published: July 2023

Transposable elements (TEs) are dispersed repetitive DNA sequences that can move within a genome. Even though hundreds of years of evolution have led to the accumulation of mutations that render most TEs unable to transpose, they still exert multiple important functions. They play a role in hematopoiesis, especially during periods of high cellular plasticity, such as development, regeneration and aging. This is because TEs can populate functional elements, such as enhancers. Furthermore, TE RNA can be sensed by innate immune sensors that play a role in inflammation and inflammaging. TEs also play an important role in different aspects of leukemia and lymphoma, leading to either beneficial or detrimental outcomes. Further studies into the function of TEs in healthy or diseased hematopoietic systems are necessary to manipulate them for therapeutic benefit.
Economic foresight & scenario thinking as a planning tool for addressing China’s uncertain environment
Authors: Χριστοφιλόπουλος Επαμεινώνδας
Published: July 2023

Η Κίνα είναι ένας κορυφαίος παγκόσμιος παράγοντας, ο οποίος γίνεται αντιληπτός τόσο ως απειλή όσο και ως ευκαιρία από εταιρείες, ακαδημαϊκά ιδρύματα και κυβερνήσεις. Για παράδειγμα, η κινεζική αγορά αποτελεί μεγάλη ευκαιρία για τις ευρωπαϊκές βιομηχανίες, αλλά ταυτόχρονα η διαδικασία εισόδου στην κινεζική αγορά ενέχει αρκετούς κινδύνους και απαιτεί τεράστια επένδυση σε πόρους και προσεκτικό σχεδιασμό. Επιπλέον, στο ταχέως μεταβαλλόμενο παγκόσμιο περιβάλλον, η Κίνα αποτελεί βασικό μοχλό αλλαγής, επηρεάζοντας έντονα και με διάφορους τρόπους τον υπόλοιπο κόσμο. Η μεταπολεμική εποχή υπήρξε μάρτυρας των οικονομικών θαυμάτων της Ιαπωνίας και της Νότιας Κορέας, οι οποίες κατάφεραν να γίνουν ουσιαστικοί παράγοντες στην παγκόσμια αγορά υψηλής τεχνολογίας. Ωστόσο, και οι δύο χώρες δεν είχαν τον δυναμισμό και το μέγεθος για να μετασχηματίσουν την παγκόσμια οικονομία και να ελέγξουν τους κανόνες του παιχνιδιού. Σήμερα, στις αρχές του 21ου αιώνα, δύο νέες χώρες, η Κίνα και η Ινδία, και οι δύο (ιδίως η Κίνα) έχουν τις προοπτικές ή τη δυνατότητα να αλλάξουν την ισορροπία της παγκόσμιας οικονομίας.Ο κύριος στόχος της έρευνας είναι να αποδείξει ότι, καθώς σήμερα ο ρυθμός των αλλαγών είναι ταχύτερος από ποτέ, είναι σημαντικό για τους οργανισμούς να χρησιμοποιούν μεθοδολογικά εργαλεία που θα τους βοηθήσουν να κατανοήσουν την πολυπλοκότητα αυτών των αλλαγών και θα τους επιτρέψουν να επιτύχουν μακροπρόθεσμη ανθεκτικότητα. Το αντικείμενο της παρούσας διδακτορικής διατριβής πρόκειται να αποδείξει την εγκυρότητα της χρήσης σεναρίων για την αντιμετώπιση των αβεβαιοτήτων σχετικά με τη μελλοντική εξέλιξη του πολύπλοκου περιβάλλοντος καινοτομίας και οικονομίας στην Κίνα. Η παρούσα διατριβή εξετάζει όλα τα προαναφερθέντα ζητήματα και προτείνει μια μεθοδολογία για την αντιμετώπιση των αβεβαιοτήτων του μέλλοντος της Κίνας.
PASS: A scoring system to evaluate persistent kidney injury in critically ill ICU adult patients
Authors: Prabhu Dattatray , Prabhu Sonali Dattatray , Mahabala Chakrapani , Prabhu Mayoor V
Published: July 2023

Background: We evaluated if the course of recovery from sepsis-induced acute kidney injury (AKI) can be predicted using variables collected at admission.

Methods: A total of 63 patients admitted for sepsis-induced AKI in our Mangalore ICU were evaluated and baseline demographic and clinical/laboratory parameters, including serum creatinine (SCr), base excess (BE), Plethysmographic Variability Index (PVI), Caval Index, R wave variability index (RVI), mean arterial pressure (MAP) and renal resistivity index (RI) using renal doppler and need for inotropes were assessed on admission. Patients were managed as per standard protocol. After six hours of fluid resuscitation, patients were classified as volume responders or non-responders. Re-assessment was done at 24 hours and 72 hours after admission. Primary outcome was persistent AKI after 72 hours. Secondary outcome was initiation of dialysis or death within 15 days of admission.

Results: A total of 34 subjects recovered from AKI, of whom 32 patients were volume responders and 31 were non-responders. Response to fluid, MAP at admission and six hours, BE at admission, inotrope requirement, and PVI at admission did not correlate with recovery. Multiple logistic regression showed that SCr < 2.36 mg%, RVI > 14.45 and RI < 0.8 on admission correlated with recovery and they were evaluated further to model AKI recovery and develop PASS. PASS score = (SCr points × 5.4) + (RVI points × 4.0) + (RI points × 6.2).  One point each was allotted if SCr was < 2.36, RVI was > 14.45 and RI was <0.8, and 0 otherwise. A score > 7.8 predicted recovery with a sensitivity of 79.4%, specificity of 72.4%, PPV 81.8%, NPV 76.7% and AuROC of 0.85.

Conclusions: The PASS score can be used to identify salvageable cases of sepsis-AKI, guiding fluid resuscitation and aiding early referral from rural to tertiary care centers for better management.
Association study of melatonin receptor 1 A with litter size in sheep: A review
Authors: Abuzahra Mutasem , Wijayanti Dwi , Effendi Mustofa Helmi , Mustofa Imam , Lamid Mirni
Published: July 2023

Sheep are a valuable livestock species worldwide, providing meat, milk, and various dairy products. This article aims to review the latest literature on the melatonin receptor 1A (MTNR1A) gene as a potential candidate gene associated with reproductive traits, particularly the litter size trait in sheep, by searching various databases for available literature. Studies have shown that different parts of the MTNR1A gene play various roles in sheep. By identifying marker genes associated with reproductive traits in MTNR1A polymorphisms linked to the litter size trait, breeders can achieve a faster selection response in sheep breeding by recognizing the genomic region where these genes are located and understanding their physiological functions. Therefore, highlighting the literature on these functions and their association with reproductive traits may contribute to improving the genetic makeup during sheep breeding.
How Learning Strategies and Academic Parameters Predict Medical Student Success.
Authors: O'Connell Michael T. , Badia Rohit R. , Tellez Juan C. , Cook Grayden S. , Sachs Arlene
Published: July 2023

Background

Student scores on the Learning and Study Strategies Inventory (LASSI), an assessment of academic skills, have been shown in previous studies to be significantly different between U.S. medical students based on their scores in various examinations during the pre-clerkship curriculum. This study aimed to evaluate LASSI and other early academic performance markers for predicting the likelihood of shelf exam underperformance in third-year medical students.

Methods

A retrospective analysis of student-specific demographic information and medical school exam performance from 220 medical students from the University of Texas Southwestern was performed. Students were then categorized based on underperformance (score in <25th percentile) on each NBME shelf exam and statistical analysis was performed to identify predictors of shelf underperformance.

Results

For predicting Surgery shelf underperformance, pre-clerkship final exam average (PCA), STEP 1, and LASSI Time Management (TMT) were statistically significant in univariate analysis. Internal Medicine: PCA, STEP 1, LASSI Attitude (ATT), Test Strategies (TST), and TMT. Pediatrics: PCA and STEP 1 quartile. Obstetrics-Gynecology: PCA, STEP 1, and LASSI Anxiety (ANX), with ANX an independent predictor on multivariate analysis. Neurology: PCA, STEP 1, LASSI ANX, Information Processing (INP), TST, and average LASSI, with PCA, LASSI Concentration (CON), TMT, and ANX independent predictors on multivariate analysis. Family Medicine: PCA, STEP 1, LASSI ANX, TST, and Using Academic Resources (UAR), with PCA an independent predictor on multivariate analysis. Psychiatry: only STEP 1 was significant.

Conclusion

In contrast to previous studies, no single LASSI scale was significantly associated with underperformance on all 7 NBME shelf exams. Univariate analysis identified several LASSI scales that correlated with NBME underperformance, but the drastic inter-clerkship heterogeneity makes use of these scales in early academic intervention impractical. Conversely, PCA was found to be strongly associated with shelf exam underperformance.
The Cost of Clearing Fragmentation
Authors: Benos Evangelos , Huang Wenqian , Menkveld Albert , Vasios Michalis
Published: July 2023

Fragmenting clearing across multiple central counterparties (CCPs) is costly because global dealers cannot net positions across CCPs. They have to collateralize both the short position in one CCP and an offsetting long position in another CCP. This, coupled with a structural net order imbalance across CCPs, can cause prices to persistently differ across them (“the CCP basis”). Tests based on unique CCP data for interest-rate derivatives (IRDs) yield broad empirical support for this intuition and suggest that the clearing friction costs sellers clearing in LCH, the largest European CCP for IRDs, $80 million daily.

This paper was accepted by Victoria Ivashina, finance.

Funding: This work was supported by the Netherlands Organization for Scientific Research (NWO). A. Menkveld gratefully acknowledges the support of NWO Vici grant.

Supplemental Material: The data files are available at https://doi.org/10.1287/mnsc.2023.4867 .