bluuebunny/crossref_metadata_2025 huggingface dataset:
Perturbation-based balance training of older adults and effects on physiological, cognitive and sociopsychological factors: a secondary analysis from a randomised controlled trial with 12-month follow-up
Authors: Nørgaard Jens Eg , Andersen Stig , Ryg Jesper , Andreasen Jane , Oliveira Anderson de Souza Castelo , Stevenson Andrew James Thomas , Danielsen Mathias Brix Brix , Jorgensen Martin Gronbech
Published: August 2024

Background

Perturbation-based balance training (PBT) has shown promising, although diverging, fall-preventive effects; however, the effects on important physical, cognitive and sociopsychological factors are currently unknown. The study aimed to evaluate these effects on PBT at three different time points (post-training, 6-months and 12-months) in community-dwelling older adults compared with regular treadmill walking.

Methods

This was a preplanned secondary analysis from a randomised, controlled trial performed in Aalborg, Denmark, between March 2021 and November 2022. Community-dwelling older adults aged ≥65 were randomly assigned to participate in four sessions (lasting 20 min each) of either PBT (intervention) or regular treadmill walking (control). All participants were assigned to four testing sessions: pretraining, post-training, 6-month follow-up and 12-month follow-up. At these sessions, physical, cognitive and sociopsychological measures were assessed.

Results

In total, 140 participants were randomly allocated to either the PBT or control group. Short-term (pretraining to post-training) between-group differences were seen for choice stepping reaction time (−49 ms, 95% CI −80 to −18), dual-task gait speed (0.05 m/s, 95% CI 0.01 to 0.09) favouring the PBT group. However, these improvements were not sustained at the 6-month and 12-month follow-up. No significant between-group differences were found in other physical, cognitive or sociopsychological factors.

Conclusions

This study showed that PBT, in the short term, improved choice stepping reaction time and dual-task gait speed among community-dwelling older adults. Yet, these improvements were not retained for 6- or 12-months. The healthy state of the study’s population may have imposed a ceiling effect limiting the ability to show any clinically relevant effects of PBT.

Trial registration number

NCT04733222.
IOL decentration sensitivity according to spatial frequencies
Authors: Pieh Stefan , Artmayr Cornelia , Schartmüller Daniel , Kriechbaum Katharina
Published: August 2024

Background/aims

Investigation of the decentration sensitivity of monofocal intraocular implants with a focus on different aberration corrections depending on different spatial frequencies.

Methods

Using an optical bench, the decentration sensitivities of an intraocular lens (IOL) with a high spherical aberration correction of −0.27 µm (ZCB00 Johnson & Johnson), an IOL with an aberration correction of −0.20 µm (Primus HD OphthalmoPro) and an IOL with an aberration neutral design (CT Asphina 409MP Carl Zeiss Meditec) were evaluated for Strehl ratio values and for 25, 50 and 100 lp/mm. Two different corneas with +0.13 µm and +0.28 µm were used. The lenses were tested in the best centration and up to a decentration of 0.5 mm.

Results

Decentration sensitivity affects high spatial frequencies more than lower ones. The possible decentration sensitivity is determined by the amount of spherical aberration of the cornea. The effective decentration sensitivity is determined by the extent to which these spherical aberrations are compensated. If these are not compensated, there is hardly any decentration sensitivity.

Conclusion

High spatial frequencies are more affected by decentration sensitivity. The decentration sensitivity of an IOL is determined by the extent to which the spherical aberration of the cornea is corrected.
Exploring factors associated with failure of totally implanted vascular access devices in a regional and rural health service: a retrospective case–control study
Authors: Meredith Carolyn , Mander Gordon TW , Thompson Murray , Elliott Jessica , Reynolds Lorraine , Ng Linda
Published: August 2024

Background

The assessment and management of totally implanted vascular access devices (TIVAD) prior to the administration of medications/fluids are vital to ensuring the risk of harm is mitigated. While numerous guidelines exist for the insertion and management of TIVAD, the level of evidence and external validity to support these guidelines is lacking.

Objectives

The purpose of this study was to identify factors associated with suboptimal TIVAD placement and with failure of TIVAD.

Methods

A retrospective case–control study (n=80) was conducted at a regional hospital and health service in Australia. Binomial logistic regression analysis was performed using a backward selection approach to establish variables associated suboptimal TIVAD placement and with TIVAD failure.

Findings

Significant associations were identified between the patient’s primary diagnosis and suboptimal TIVAD insertion. Specifically, a prior diagnosis of breast cancer was associated with a decreased probability of optimal TIVAD tip placement (OR=0.236 (95% CI 0.058 to 0.960), p=0.044). A statistically significant association between TIVAD failure and the log of the heparinised saline flush rate and rate of undocumented flushes was also established. Further research is needed to identify and assess whether modification of these variables improves initial totally implantable venous access ports placement and risk of subsequent failure.
Creating a postgraduate syllabus for a team care diploma examination: a Delphi study
Authors: Iqbal Adil , Zhao Zhi , van Klaveren William , Elbashir Mohammed , Moxon Adam , Houghton Jonathan , Kerss Jim , Jones Natasha , Marino Katherine Rose , Power Jonathan , Roberts Huw , Cooke Rosalyn , Astill Sarah , Nykjaer Camilla , Vishnubala Dane
Published: August 2024

Objectives

There is no agreed standard assessment of the minimum knowledge and skills that are required to provide healthcare to participants in individual or team sports. This study aims to develop a syllabus for the Faculty of Sport and Exercise Medicine (FSEM) Team Care Diploma examination. This will provide a recognised assessment of the minimum required skills and knowledge for healthcare professionals providing care in an individual and team sport environment.

Methods

A modified Delphi approach was used. A syllabus was developed by a purposeful selection of members of the FSEM, all of whom have significant team care experience. This was then reviewed by the Delphi expert panel who were team care practitioners with at least 5 years of experience. A two-round Delphi approach was used to develop a consensus.

Results

The expert panel consisted of 50 individuals, with 46 (92%) completing both rounds. Of the 447 learning objectives (LOs) proposed; 430 (96%) were accepted outright, 17 (4%) were rejected and four new LOs were introduced based on expert panel feedback. The final syllabus contained 434 LOs across 6 modules (clinical governance, safe and effective practice, interdisciplinary teamwork, specific athlete groups, specific health conditions and duties of the medical team).

Conclusion

This standardised syllabus will be used as the basis for the new FSEM Team Care Diploma examination which will aim to provide world-leading standardised assessment of the minimum skills and knowledge required for healthcare professionals across the multidisciplinary team providing care in individual and team sport.
Evaluation of the effects of a gamified, fully immersive and stroke-specific virtual reality intervention for improving disability and quality of life in patients with stroke in the subacute phase: study protocol of the RESET randomised trial
Authors: Hernández-Martínez Alba , Fernandez-Escabias Manuel , Amaya-Pascasio Laura , Carrilho-Candeias Sofia , Ramos-Teodoro Máriam , Gil-Rodríguez Mercedes , Orellana-Jaen Andrea , Martínez-Rosales Elena , Ruiz-González David , Esteban-Simón Alba , Castro-Ropero Belén , del-Olmo-Iruela Laura , López-López María Isabel , Ramos-Herrera Ana Isabel , Fajardo-Rodríguez Manuel F. , Gómez-García Silvia , Rodríguez-Camacho Marta , Conde-Negri Elena , Rodríguez-Pérez Mónica , Marcos-Pardo Pablo Jorge , Ruiz Jonatan R , Villegas-Rodríguez Inmaculada , Amaro-Gahete Francisco J , Martínez-Sánchez Patricia , Soriano-Maldonado Alberto
Published: August 2024

Stroke is the leading cause of disability and the second cause of death worldwide. The increasing burden of stroke underscores the importance of optimising rehabilitation protocols. Virtual reality (VR) can improve poststroke prognosis. A VR software combining gamification, full immersion and stroke specificity (ie, the Development and validation of a novel viRtual rEality software for improving diSability and quality of lifE in patients with sTroke (RESET) software) might substantially improve disability and quality of life (QoL). However, this technology is still very scarce. The RESET trial aims to assess the effects of an early 10-week gamified, fully immersive and stroke-specific VR intervention (ie, starting at week 3 poststroke) on disability and QoL in people with stroke in the subacute phase. People with ischaemic or haemorrhagic stroke (n=94) aged ≥18 years will be randomised to receive (1) usual care (UC), (2) commercial VR or (3) gamified, fully immersive and stroke-specific VR (RESET). The three groups will receive UC (ie, three sessions/week of 90 min of standard rehabilitation). The VR groups will additionally receive three VR sessions of 20 min per week. The outcome measures will be assessed at baseline (week 2 from stroke occurrence), week 13 (approximately 90 days from the event) and week 26 (approximately 6 months from the event). The primary outcome is disability measured with the Barthel Index. Secondary outcomes include QoL, upper-extremity and lower-extremity motor function, gross manual dexterity, handgrip strength and cognitive function. This study will unravel the effects of a gamified, fully immersive and stroke-specific VR software on disability and QoL in patients with stroke in the early subacute phase.

NCT06132399.
Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial
Authors: Bertrand Delphine , Joly Johan , Neerinckx Barbara , Durez Patrick , Lenaerts Jan , Joos Rik , Thevissen Kristof , Zwaenepoel Tom , Vanhoof Johan , Di Romana Silvana , Taelman Veerle , Van Essche Els , Corluy Luk , Ribbens Clio , Vanden Berghe Marc , Devinck Mieke , Ajeganova Sofia , Durnez Anne , Boutsen Yves , Margaux Joëlle , Peene Isabelle , Van Offel Jan , Doumen Michaël , Pazmino Sofia , De Meyst Elias , Kulyk Myroslava , Creten Nelly , Westhovens René , Verschueren Patrick
Published: August 2024

Objectives

To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt.

Methods

CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score – C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups.

Results

Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=−0.204, (95% CI –0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%).

Conclusion

Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104.

Trial registration number

NCT03649061.

CTR pilot approval Belgium

S59474, EudraCT number: 2017-004054-41.
Variability of cardiopulmonary exercise testing in patients with atrial fibrillation and determination of exercise responders to high-intensity interval training and moderate-to-vigorous intensity continuous training
Authors: Terada Tasuku , Keir Daniel A. , Murias Juan M. , Vidal-Almela Sol , Buckley John , Reed Jennifer L.
Published: August 2024

Disabling atrial fibrillation (AF)-related symptoms and different testing settings may influence day-to-day cardiopulmonary exercise testing (CPET) measurements, which can affect exercise prescription for high-intensity interval training (HIIT) and moderate-to-vigorous intensity continuous training (M-VICT) and their outcomes. This study examined the reliability of CPET in patients with AF and assessed the proportion of participants achieving minimal detectable changes (MDC) in peak oxygen consumption (V̇O2peak) following HIIT and M-VICT. Participants were randomized into HIIT or M-VICT after completing two baseline CPETs: one with cardiac stress technologists (CPETdiag) and the other with a research team of exercise specialists (CPETresearch). Additional CPET was completed following 12 weeks of twice-weekly training. The reliability of CPETdiag and CPETresearch was assessed by intraclass correlation coefficient (ICC) and dependent t tests. The MDC score was calculated for V̇O2peak using a reliable change index. The proportion of participants achieving MDC was compared between HIIT and M-VICT using chi-square analysis. Eighteen participants (69 ± 7 years, 33% females) completed two baseline CPETs. The ICCs were significant for all measured variables. However, peak power output (POpeak: 124 ± 40 vs. 148 ± 40 watts, p < 0.001) and HR (HRpeak: 136 ± 22 vs. 148 ± 30 bpm, p = 0.023) were significantly greater in CPETresearch than CPETdiag. Few participants achieved MDC in V̇O2peak (5.6 mL/kg/min) with no difference between HIIT (0%) and M-VICT (10.0%, p = 0.244). POpeak and HRpeak differed significantly in patients with AF when CPETs were repeated under different settings. Caution must be practised when prescribing exercise intensity based on these measures as under-prescription may increase the number of exercise non-responders.
Alberta’s 2023 wildfires: context, factors, and futures
Authors: Beverly Jennifer L. , Schroeder Dave
Published: August 2024

Wildfires burned an estimated 2.2 million hectares in Alberta in 2023. We describe key attributes of the fires relative to historical fires and fire seasons and offer a perspective on potentially influential factors. Thirty-six large fires ≥10 000 ha generated 95% of annual area burned. Individually, these fires exhibited sizes, fire weather, and behaviour consistent with historical fires; there were simply far more of them in 2023. Thirteen fires reported in early May were ignited by lightning and reached final sizes ≥10 000 ha, revealing a previously unrecognized threat. Historically, large lightning-ignited fires reported before mid-May occur just once per decade on average. Collectively, 18 large fires reported in early May coincided with drier conditions compared with 18 large fires reported after mid-May. Early May fire weather was also warmer and drier than historical weather. The early May fire group was a temporally concentrated outbreak in west-central Alberta and coincided with extreme potential rate of fire spread. Large fires reported after mid-May were intermittent through to September, concentrated in northern regions and coincided with extreme potential for fuel consumption. Individually, these two spatiotemporal modes of fire season severity (outbreak, intermittent) produced annual burned areas on par with historical extremes. Together, the 2023 multi-modal pattern of fire season severity amplified area burned far above anything previously recorded. Potential contributing factors include climate warming, hemispheric teleconnections, phenology and exhaustion of suppression resources. Implications for future fire seasons, research and management are discussed.
Geodesic structure of test particles in different regular black holes
Authors: Xi Zihan , Wu Chen , Guo Wenjun
Published: August 2024

This paper investigates the metrics of existing regular black hole space–times and calculates their effective potentials, plotting the corresponding curves. By analyzing these curves, it identifies all types of geodesic structures for test particles in various regular black hole space–times. Using dynamical equations near black holes, it determines two distinct bound orbits for fixed energy levels in different space–times and identifies stable and unstable circular orbits as the energy approaches critical values. Additionally, it provides escape orbits for fixed energy levels across different space–times. Comparative analysis reveals the fastest and slowest periapsis precession rates, identifies space–times with counterclockwise periapsis precession, and highlights those with the most intricate escape orbits for fixed energy levels.
Advancing Ethics in the Games Industry: A Round Table
Authors: Blumberg Fran C.
Published: August 2024

How can we institute good ethical practice in the games industry, safeguarding the welfare of players and employees alike? Inspired by the code of ethics drafted by the Ethical Games Initiative, this roundtable convenes industry regulators and leaders from Minecraft to Sesame Workshop to discuss these questions. They highlight the importance and difficulty of finding common ground in cultural diversity; the leverage in laws and regulations, positive aspirations, making a business case, and groundswell employee demands; and the need to align scalable systems with contextual player experiences and behavior.
CNN-Based Models for Emotion and Sentiment Analysis Using Speech Data
Authors: Madan Anjum , Kumar Devender
Published: August 2024

The study aims to present an in-depth Sentiment Analysis (SA) grounded by the presence of emotions in the speech signals. Nowadays, all kinds of web-based applications ranging from social media platforms and video-sharing sites to e-commerce applications provide support for Human–Computer Interfaces (HCIs). These media applications allow users to share their experiences in all forms such as text, audio, video, GIF, and so on. The most natural and fundamental form of expressing oneself is through speech. Speech-Based Sentiment Analysis (SBSA) is the task of gaining insights into speech signals. It aims to classify the statement as neutral, negative, or positive. On the other hand, Speech Emotion Recognition (SER) categorizes speech signals into the following emotions: disgust, fear, sadness, anger, happiness, and neutral. It is necessary to recognize the sentiments along with the profoundness of the emotions in the speech signals. To cater to the above idea, a methodology is proposed defining a text-oriented SA model using the combination of CNN and Bi-LSTM techniques along with an embedding layer, applied to the text obtained from speech signals; achieving an accuracy of 84.49%. Also, the proposed methodology suggests an Emotion Analysis (EA) model based on the CNN technique highlighting the type of emotion present in the speech signal with an accuracy measure of 95.12%. The presented architecture can also be applied to different other domains like product review systems, video recommendation systems, education, health, security, and so on.
Mechanical Strain‐Modulated Multifunctional Pr‐Doped BaTiO3 Thin Film for Luminescence Sensing and Piezoelectric Energy‐Harvesting Applications
Authors: Chabungbam Akendra Singh , Kim Dong-eun , Kim Geonwoo , Kim Minjae , Lee Hong-Sub , Kim Sang-Woo , Park Hyung-Ho
Published: August 2024

Piezoelectric materials with tunable photoluminescence have gained widespread attention for their application in optical communications and optoelectronic sensing devices. This has provided new opportunities to explore the possibility of developing flexible piezoelectric devices with both piezoelectricity and photoluminescence for multifunctional applications. In this study, we prepared a crystalline Pr‐doped perovskite BaTiO3 (BPTO) film on a flexible mica substrate using the radio‐frequency (RF) sputtering technique. The photoluminescence intensity remarkably increased by about 210% when external mechanical stress was applied to the film. This remarkable increase in photoluminescence is attributed to lattice distortion and a decrease in crystal symmetry. The BPTO film also exhibited reversible and high‐endurance behavior even after 103 fatigue bending cycles. Moreover, the BPTO film was utilized as a piezoelectric nanogenerator device, which demonstrated a maximum output voltage of about 2.68 V when external stress was applied through palm tapping. The nanogenerator device yielded an instantaneous output power of 1.80 μW with an external load resistance of 0.8 MΩ. These versatile and robust properties of the BPTO film demonstrate its potential for future development of lead‐free self‐powered optoelectronic sensing applications, such as artificial intelligence and biomedical devices.
Impact of Nursing Professional Values on Depression, Stress, and Anxiety among Nurses during the COVID‐19 Pandemic
Authors: Lana Alberto , Sánchez-García Beatriz , González-García María , Fernández-Feito Ana , González-Pando David
Published: August 2024

Aim. The aim was to explore the association between nursing professional values (NPV) and mental health among registered nurses (RN) in Spain. Background. Nursing is a profession rooted in strong professional values, which guide and shape clinical practice and occupational behaviors. NPV should serve as a source of support in situations of great uncertainty. Methods. A cross‐sectional study was conducted during the remission phase of the second wave of the COVID‐19 pandemic (December 2020‐January 2021) among a sample of Spanish RN (n = 420). NPV were assessed using the Nursing Professional Values Scale (NPVS‐R), comprising 26 items grouped into five factors: caring, activism, trust, professionalism, and justice. Perceived stress, anxiety, and depression were measured by the Perceived Stress Scale (PSS‐14) and the Hospital Anxiety and Depression Scale (HADS). Adjusted linear regressions were used to estimate b coefficients for the associations between NPV scores and the three mental health indicators. Results. The fully‐adjusted analysis, including sociodemographic and occupational variables, revealed that higher activism scores were associated with higher scores of stress (b coefficient: 0.46; 95% confidence interval: 0.03–0.88; p value: 0.035), anxiety (0.24; 0.05–0.43; 0.014), and depression (0.19; 0.01–0.36; 0.035). No other NPV was associated with mental health. Conclusion. Organizational policies and programs should be established to protect the most activist RNs and to mitigate the potential detrimental effect of activism on mental health at times and/or circumstances of high workloads and personal stress.
The Spatial Structure of the Tumor Immune Microenvironment Can Explain and Predict Patient Response in High-Grade Serous Carcinoma
Authors: Van Kleunen Lucy B. , Ahmadian Mansooreh , Post Miriam D. , Wolsky Rebecca J. , Rickert Christian , Jordan Kimberly R. , Hu Junxiao , Richer Jennifer K. , Brubaker Lindsay W. , Marjon Nicole , Behbakht Kian , Sikora Matthew J. , Bitler Benjamin G. , Clauset Aaron
Published: August 2024

Ovarian cancer is the deadliest gynecologic malignancy, and therapeutic options and mortality rates over the last three decades have largely not changed. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes. To improve spatial understanding of the TIME, we performed multiplexed ion beam imaging on 83 human high-grade serous carcinoma tumor samples, identifying approximately 160,000 cells across 23 cell types. From the 77 of these samples that met inclusion criteria, we generated composition features based on cell type proportions, spatial features based on the distances between cell types, and spatial network features representing cell interactions and cell clustering patterns, which we linked to traditional clinical and IHC variables and patient overall survival (OS) and progression-free survival (PFS) outcomes. Among these features, we found several significant univariate correlations, including B-cell contact with M1 macrophages (OS HR = 0.696; P = 0.011; PFS HR = 0.734; P = 0.039). We then used high-dimensional random forest models to evaluate out-of-sample predictive performance for OS and PFS outcomes and to derive relative feature importance scores for each feature. The top model for predicting low or high PFS used TIME composition and spatial features and achieved an average AUC score of 0.71. The results demonstrate the importance of spatial structure in understanding how the TIME contributes to treatment outcomes. Furthermore, the present study provides a generalizable roadmap for spatial analyses of the TIME in ovarian cancer research.
Table S2 from Estrogen Receptor Blockade Potentiates Immunotherapy for Liver Metastases by Altering the Liver Immunosuppressive Microenvironment
Authors: Benslimane Yasmine , Amalfi Kevin , Lapin Sara , Perrino Stephanie , Brodt Pnina
Published: August 2024

Flow cytometry antibodies.
Figure 2 from Estrogen Receptor Blockade Potentiates Immunotherapy for Liver Metastases by Altering the Liver Immunosuppressive Microenvironment
Authors: Benslimane Yasmine , Amalfi Kevin , Lapin Sara , Perrino Stephanie , Brodt Pnina
Published: August 2024

Estrogen depletion alters the cytokines/chemokines repertoire of the liver and increases expression of CCR5 and CCL5 in NKT and CD8+ T cells. A, Cytokine array analysis was conducted on whole liver protein lysates (four livers/group) derived from MC-38 tumor-bearing mice. Data were normalized to SHAM-operated values. In B–E are FC results for the indicated cell populations (n = 4). In F (left)—representative RNAscope images of frozen liver sections probed with CCL5 and NK1.1, followed by CD3 staining, and in F (right) image analysis results based on 15 fields per group (n = 3). Yellow arrows denote NK1.1+CCL5+CD3+ cells, and green arrows denote NK1.1+CD3+ cells with high CCL5 density. Experimental LM were generated by intrasplenic/portal injection of 105 MC-38 cells. Intraperitoneal Mvc or vehicle injections began the following day and continued for 6 days. Mice were sacrificed and LM enumerated on day 18 post-inoculation. Results shown are of a representative experiment of two performed. The number of metastases per liver are shown in G (n = 4–7; bars indicate medians) and representative livers are shown in H. *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001, Student t test (FC) and Mann–Whitney test (LM).
Figure 1 from Estrogen Receptor Blockade Potentiates Immunotherapy for Liver Metastases by Altering the Liver Immunosuppressive Microenvironment
Authors: Benslimane Yasmine , Amalfi Kevin , Lapin Sara , Perrino Stephanie , Brodt Pnina
Published: August 2024

Estrogen depletion increases NKT cytotoxicity in the liver TME. FC was performed on hepatic immune cells isolated following injection of 5 × 105 MC-38 cells and immunolabeled with the indicated antibodies. Shown in A are flow cytometric contour plots and the respective bar graphs (n = 4). Shown in B (top) is the workflow of the NKT cytotoxicity assay, in B (bottom-left) representative images of green fluorescent (dead) MC-38 cells after co-culture with NKT cells for 30 hours and in B (bottom right) quantification of dead MC-38 cells as measured over time, normalized to time 0 hour (n = 2–3). ****, P ≤ 0.0001; Two-way ANOVA. (Created with BioRender.com.)
Table S4 from The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors
Authors: Dravillas Caroline E. , Coleman Samuel S. , Hoyd Rebecca , Caryotakis Griffin , Denko Louis , Chan Carlos H.F. , Churchman Michelle L. , Denko Nicholas , Dodd Rebecca D. , Eljilany Islam , Hardikar Sheetal , Husain Marium , Ikeguchi Alexandra P. , Jin Ning , Ma Qin , McCarter Martin D. , Osman Afaf E.G. , Robinson Lary A. , Singer Eric A. , Tinoco Gabriel , Ulrich Cornelia M. , Zakharia Yousef , Spakowicz Daniel , Tarhini Ahmad A. , Tan Aik Choon
Published: August 2024

Modeling results for the microbes enriched in the tumors responsive or not-responsive to immunotherapy
Figure S5 from The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors
Authors: Dravillas Caroline E. , Coleman Samuel S. , Hoyd Rebecca , Caryotakis Griffin , Denko Louis , Chan Carlos H.F. , Churchman Michelle L. , Denko Nicholas , Dodd Rebecca D. , Eljilany Islam , Hardikar Sheetal , Husain Marium , Ikeguchi Alexandra P. , Jin Ning , Ma Qin , McCarter Martin D. , Osman Afaf E.G. , Robinson Lary A. , Singer Eric A. , Tinoco Gabriel , Ulrich Cornelia M. , Zakharia Yousef , Spakowicz Daniel , Tarhini Ahmad A. , Tan Aik Choon
Published: August 2024

Comparison of alternate machine learning methods
Figure S3 from The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors
Authors: Dravillas Caroline E. , Coleman Samuel S. , Hoyd Rebecca , Caryotakis Griffin , Denko Louis , Chan Carlos H.F. , Churchman Michelle L. , Denko Nicholas , Dodd Rebecca D. , Eljilany Islam , Hardikar Sheetal , Husain Marium , Ikeguchi Alexandra P. , Jin Ning , Ma Qin , McCarter Martin D. , Osman Afaf E.G. , Robinson Lary A. , Singer Eric A. , Tinoco Gabriel , Ulrich Cornelia M. , Zakharia Yousef , Spakowicz Daniel , Tarhini Ahmad A. , Tan Aik Choon
Published: August 2024

Predictive values (AUROC) of the 16 gene signatures in the ORIEN cohort (IO_NOVA_Mel) and 22 other melanoma cohorts
Figure S1 from The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors
Authors: Dravillas Caroline E. , Coleman Samuel S. , Hoyd Rebecca , Caryotakis Griffin , Denko Louis , Chan Carlos H.F. , Churchman Michelle L. , Denko Nicholas , Dodd Rebecca D. , Eljilany Islam , Hardikar Sheetal , Husain Marium , Ikeguchi Alexandra P. , Jin Ning , Ma Qin , McCarter Martin D. , Osman Afaf E.G. , Robinson Lary A. , Singer Eric A. , Tinoco Gabriel , Ulrich Cornelia M. , Zakharia Yousef , Spakowicz Daniel , Tarhini Ahmad A. , Tan Aik Choon
Published: August 2024

Association of CIBERSORT cell types with the response to ICIs
Figure 3 from The Tumor Microbiome as a Predictor of Outcomes in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors
Authors: Dravillas Caroline E. , Coleman Samuel S. , Hoyd Rebecca , Caryotakis Griffin , Denko Louis , Chan Carlos H.F. , Churchman Michelle L. , Denko Nicholas , Dodd Rebecca D. , Eljilany Islam , Hardikar Sheetal , Husain Marium , Ikeguchi Alexandra P. , Jin Ning , Ma Qin , McCarter Martin D. , Osman Afaf E.G. , Robinson Lary A. , Singer Eric A. , Tinoco Gabriel , Ulrich Cornelia M. , Zakharia Yousef , Spakowicz Daniel , Tarhini Ahmad A. , Tan Aik Choon
Published: August 2024

Melanoma tumors that respond to ICIs have a distinct tumor microbiome. A, The relative abundances of the tumor microbiome at the phylum level showed wide intersample variation in the abundances of Proteobacteria (blue) and viruses [Uroviricota (maroon)], without gross differences between nonresponders (NR) and responders (R). B, Differential abundance analysis of taxa found within tumor RNA-seq data. Colored points represent significantly (P value <0.05) enriched taxa with a high (>1.00) fold difference in abundance between responders and nonresponders to ICIs. C, The diversity of the tumor microbiome between responders and nonresponders shows no significant differences. D, The diversity of the microbiome is a poor predictor of outcomes.
MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine Prostate Cancer
Authors: German Beatriz , Alaiwi Sarah A. , Ho Kun-Lin , Nanda Jagpreet S. , Fonseca Marcos A. , Burkhart Deborah L. , Sheahan Anjali V. , Bergom Hannah E. , Morel Katherine L. , Beltran Himisha , Hwang Justin H. , Freedman Matthew L. , Lawrenson Kate , Ellis Leigh
Published: August 2024

Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in patients with prostate cancer. Although underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in prostate cancer, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYB proto-oncogene like 2 (MYBL2) as a significantly enriched transcription factor in prostate cancer exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine prostate cancer cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in prostate cancer. Furthermore, high MYBL2 activity identifies prostate cancer that would be responsive to CDK2 inhibition.

Significance:

Prostate cancers that escape therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic prostate cancer and implicates CDK2 inhibition as a novel therapeutic target for this most lethal subtype of prostate cancer.
Fallbericht über das Sjögren-Syndrom mit Autoimmunhepatitis
Authors: Caretti Rachael , Wojtas Caroline , Baniasadi Mojdeh , Milis Liana , Scott Randy
Published: August 2024

Das Sjögren-Syndrom (SS) ist das Ergebnis einer abnormalen Immunreaktion des Körpers, die zur Zerstörung exokriner Drüsen führt, insbesondere der Augen- und Speicheldrüsen, was Xerophthalmie und Xerostomie zur Folge hat. Wir beschreiben den Fall einer 55-jährigen Frau, die sich mit auffälligen Leberfunktionswerten in der Klinik vorstellte. Nach umfangreichen Untersuchungen wurden bei der Patientin eine Autoimmunhepatitis (AIH) und ein SS diagnostiziert. Eine AIH tritt bei einer kleinen Anzahl von Patienten mit primärem SS auf, und es gibt nur wenige Studien über eine mögliche Überschneidung dieser beiden Autoimmunerkrankungen. In diesem Bericht werden einige der Herausforderungen bei der Diagnose einer AIH und der Identifizierung von SS als zugrunde liegender Diagnose dargestellt. Die Diagnose der AIH kann aufgrund des unklaren klinischen Bildes schwierig sein, insbesondere bei begleitenden Autoimmunerkrankungen.
Ingestion of the Non-Nutritive Sweetener Erythritol, but Not Glucose, Enhances Platelet Reactivity and Thrombosis Potential in Healthy Volunteers—Brief Report
Authors: Witkowski Marco , Wilcox Jennifer , Province Valesha , Wang Zeneng , Nemet Ina , Tang W.H. Wilson , Hazen Stanley L.
Published: August 2024

BACKGROUND:

Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease–relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined.

METHODS:

Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released.

RESULTS:

Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930–7300] versus 3.75 [3.35–3.87] μmol/L;
P
<0.0001) and exhibited acute enhancement of stimulus-dependent aggregation responses in all subjects, agonists, and doses examined. Erythritol ingestion also enhanced stimulus-dependent release of the platelet dense granule marker serotonin (
P
<0.0001 for TRAP6 [thrombin activator peptide 6] and
P
=0.004 for ADP) and the platelet α-granule marker CXCL4 (C-X-C motif ligand-4;
P
<0.0001 for TRAP6 and
P
=0.06 for ADP). In contrast, glucose ingestion triggered no significant increases in stimulus-dependent release of either serotonin or CXCL4.

CONCLUSIONS:

Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04731363.
Abstract 5: A New Miniaturized Chest Compressor
Authors: Wang Hao , Ristagno Giuseppe , Huang Ler , Sun Shijie , Tang Wanchun , Weil Max H
Published: August 2024

Introduction. After prolonged cardiac arrest, uninterrupted chest compression with restoration of myocardial blood flow facilitates defibrillation (2005 AHA Guidelines for CPR,

Circulation

2005
;
112
:
24

). We recognized that such may best be accomplished with a mechanical device and especially so during transport. We therefore sought a lightweight, portable chest compressor which may be carried on the belt of the first response rescuer. This device contrasts with currently available large devices with high energy requirements.

Hypothesis. A Miniaturized Pneumatic Chest Compressor (MCC) weighing less than 2 kg will be as effective as the standard “Thumper” for restoring circulation during CPR.

Methods. In 10 domestic male pigs weighing 40 ± 2 kg, ventricular fibrillation (VF) was electrically induced and untreated for 5 minutes. Animals were randomized to receive chest compressions with either the MCC or a Thumper
R
(Model 1000, Michigan Instruments, Grand Rapids, MI) after 5 minutes of untreated cardiac arrest. After 5 minutes of mechanical chest compression, defibrillation was attempted with a 150 J biphasic precordial shock. Coronary perfusion pressure (CPP) and ETCO
2
were measured by conventional techniques together with right carotid artery blood flow (CBF) utilizing an ultransonic flowprobe.

Results. Each animal compressed with the MCC and 4 of 5 animals compressed with Thumper
R
were successfully resuscitated. No significant differences in CPP or ETCO
2
were observed between groups (Table

).

Conclusions. The Miniaturized Chest Compressor of small dimension and weight is as effective as the conventional Thumper for maintaining forward blood flow during CPR. (Patent in favour of the Weil Institute is pending)
Abstract 719: Effectiveness of Therapeutic RNA Interference is Dependent on Genomic Target Selection and Emergence of Escape Mutants: Implications for Enteroviral Heart Disease
Authors: Merl Sabine , Michaelis Cornelia , Wessely Rainer
Published: August 2024

Background: We have shown previously that therapeutic RNA interference with short interfering RNA (siRNA) may limit coxsackieviral (CVB) heart disease (

Circulation

2005
;
111
:
1583
–92

). Aim of this study was the identification of major factors that limit early efficacy of antiviral siRNA therapy.

Methods and results: To assess therapeutic efficacy of siRNA depending on genomic target selection, siRNA were designed against distinct regions representing the entire CVB genome (5′UTR, VP1, VP2, 2A, 3C, 3D) and examined for their antiviral effectiveness in permissive human HeLa cells (Fig.A

). siRNA targeting the 3CD region were particularly protective for cell survival and inhibition of viral replication. Early effectiveness of single siRNA application was hampered by the emergence of viral escape mutants. Sequencing of siRNA resistant viral genomes revealed the occurrence of 1 or 2 point mutations at the siRNA binding site. Yet, mutated viruses remained fully susceptible to siRNA targeting different genomic regions. Thus, simultaneous administration of dual siRNA decreased the emergence of viral escape mutants. Delivery of a siRNA cocktail with 3 different siRNA almost completely suppressed the emergence of viral escape and further improved therapeutic effectiveness (Fig.B

).

Conclusion: The early effect of antiviral RNA interference is highly dependent on genomic target selection and impeded by the occurrence of viral escape mutations containing single or dual mutations at the siRNA binding site. Administration of at least three siRNA molecules targeting different regions is sufficient to significantly suppress viral escape, thus leading to improved outcome.
Abstract 1023: Proprotein Convertase Subtilisin Kexin type 9 is repressed by the Peroxisome Proliferator Activated Receptor alpha ligand fenofibric acid.
Authors: Costet Philippe , Kourimate Sanae , Pineau Thierry , Krempf Michel
Published: August 2024

Familial autosomal dominant hypercholesterolemia is characterized by high levels of cholesterol associated to LDL (LDLc), secondary to mutations in the LDL receptor, its ligand the apolipoprotein B or the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9). PCSK9 is a natural inhibitor of the LDLr and its absence reduces the risk for cardiovascular disease and increases sensitivity to statins. We recently showed that PCSK9’s expression is upregulated by insulin and the Liver X Receptor ligand T0901317, via SREBP-1c, and that it is downregulated by fasting. Here we show that the SREBP-1c response element we isolated in PCSK9 proximal promoter is also a sterol responsive element and mediates a large part of the promoter’s activation by statins. The decrease observed in PCSK9 expression during fasting couldn’t be entirely attributed to variations in SREBPs. New investigations show that this down regulation also involves an active repression by PPARalpha. Indeed PCSK9 mRNA is 4 fold (p = 0.01) more abundant in wild type mice than in PPARalpha -/- mice, after a 24h-long fasting, although fed mice present similar mRNA and protein levels. In vitro, in human immortalized hepatocytes, the PPARalpha agonist fenofibric acid (250 μM) diminished PCSK9 mRNA content by 75% (p = 0.002), its protein content by 65 % (p = 0.006), and its autocatalytic activity by −30%, (p = 0.02), as reflected by the cleavage of a peptide corresponding to the autocatalytic cleavage site (

Naureckiene S. et al.
2003

Arch. Biochem. Biophys.

420
:
55
–67.

). Fenofibric acid also prevented the Liver X Receptor-mediated activation of PCSK9 by T0901317. Among several PPAR agonist (ciprofibrate, clofibrate, gemfibrozil), fenofibric acid was the most efficient in reducing PCSK9 autocatalytic activity. These results suggest that fenofibric acid, or the next generation of PPARalpha agonists, might constitute good repressors of PCSK9 in humans.
Abstract 2115: Relationship Between Stature and the Prevalence of Atrial Fibrillation and Cardiovascular Mortality
Authors: Tan Swee Y , Myers Jonathan , Froelicher Victor F
Published: August 2024

Background:
A recent study (

JACC

Apr
2006
;
47
:
1683
–1688

) suggested that atrial fibrillation was more prevalent in patients of tall stature (AF) . However, the impact that this association has on survival is unknown.

Aims:
To validate the previous findings regarding height and to investigate how height and atrial fibrillation effect survival.

Methods:
Computerized 12 lead resting ECGs on 45,855 consecutive male veterans obtained by physician discretion at the Palo Alto Veterans Affairs Medical Center from 1987 to 2000 were analyzed. After excluding inpatients, patients with WPW, paced rhythms and inpatients, 29,587 patients remained. After a mean follow up of 7.5 ± 3.8years, there were 2,616 cardiovascular (CV) deaths (8.8%). Age and heart rate adjusted proportional hazard analyses were performed. Tall patients were considered those in the 75th percentile (71 inches and above).

Results:
There were 2468 patients with atrial fibrillation. Mean height of people with AF was 69.4 ± 3.6 inches while those without AF was 68.6 ± 3.7 (p<0.001). Prevalence of AF in tall people was 3.2% whilst it was 2.6 % in shorter individuals (Chi-Square 11.4 p<0.001). Being of tall stature and having AF were associated both univariately and multivariately with cardiovascular mortality. Kaplan-Meier curves show significant differences between patients who were tall with AF and who were short with AF.

Conclusion:
This study confirms the recent observation that tall individuals have a higher prevalence of AF. Tall stature protects from cardiovascular mortality even in patients with AF.