bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of immediate and distant health consequences: different types of health warning messages on sweets affect the purchase probability
Authors: Mehlhose Clara , Risius Antje
Published: September 2023

Background

Several health control policies have been discussed as a regulatory approach to tackle the increasing prevalence of obesity and other health risks related to sugar consumption. Health warnings, like the ones used in tobacco control worldwide, are one of the most promising approaches. However, in the case of health warning messages for food products, it is much more complicated and involves much more consumer involvement than tobacco guidance. Therefore, it is important to better understand the efficacy, evaluation, and reactance of health warning labels in the food sector regarding consumers’ behavior, persuasion, and perceptions. The aim of this study was to examine how different types (design and message) of health warning messages in combination with graphical applications affect consumer behavior.

Methods

In a 3 × 3 × 3 symmetrical design, 1,040 German participants completed an online discrete choice experiment including various text-only and image-and-text health warning labels on sweets. An accompanying questionnaire assessed socio-demographic variables as well as psychometric scales to understand the relationship between fear, control, reactance, and shocking/inhibiting/mediating health-related warnings.

Results

Our results suggest that especially emotional graphical images combined with text health warning labels might be more influential. The health effects of immediate (caries) and more distant health consequences (diabetes/obesity) differ in their impact. Further, results show that especially when consumers engage in a danger control process for overweight, warning messages have a negative impact on their choices.

Conclusion

Hence, warning labels on sweets can potentially be a decisive factor when communicating health threats related to excessive sugar consumption. In the context of a targeted health policy, we see the need for further research, especially concerning the perception and understanding of noncommunicable diseases (NCDs) in the population.
The fus test: a promising tool for evaluating fundamental motor skills in children and adolescents
Authors: Makaruk Hubert , Porter Jared M. , Webster E. Kipling , Makaruk Beata , Bodasińska Anna , Zieliński Janusz , Tomaszewski Paweł , Nogal Marta , Szyszka Paulina , Starzak Marcin , Śliwa Marcin , Banaś Michał , Biegajło Michał , Chaliburda Agata , Gierczuk Dariusz , Suchecki Bogusz , Molik Bartosz , Sadowski Jerzy
Published: October 2023

Fundamental motor skills (FMS) are essential for enjoyable, confident and skillful participation in physical activity across the lifespan. Due to the alarming low level of FMS proficiency in children and adolescents worldwide, the development of motor competency is an urgent issue for physical education. The promotion and implementation of a systematic process of teaching and learning FMS should be a physical education priority. Accordingly, effective assessment tools for evaluating FMS should be adopted or developed. Because FMS assessment for both children and adolescents need further effective solutions, the primary aim of this study was to develop the new age-related test of FMS (Fundamental Motor Skills in Sport test, in Polish: Test Fundamentalnych Umiejętności Ruchowych w Sporcie, FUS). The secondary aim of this study was to establish validity and inter-rater, intra-rater, test-retest reliabilities and internal consistency of the FUS test. The FUS test involves six sport skill-based tasks: hurdling, jumping rope, forward roll, ball bouncing, throwing and catching a ball, and kicking and stopping a ball. Two hundred sixty-four Polish students in grades 1–3 (7–9 yrs; n = 81), 4–6 (10–12 yrs; n = 89) and 7–8 (13–14 yrs; n = 94), including 139 girls and 125 boys completed the FUS test. The content validity index for all items was notably high. Both inter-rater and intra-rater reliability showed substantial to almost perfect agreement, with observed agreements for FUS skills between 78.5 and 93.1%. Ball bouncing had a moderate correlation with the forward roll and throwing and catching, while other correlations were low or insignificant. ICC values, ranging from 0.95 to 0.97, confirmed excellent test-retest reliability. The results of our study provide evidence that the FUS test is valid, reliable, and feasible to administer in school settings. Therefore, this tool test has the potential to support deliberate practice and improve motor competence by providing a standardized and structured approach to measuring FMS among school-aged children and adolescents.
High-dose methylprednisolone pulse therapy during refractory COVID-19 acute respiratory distress syndrome: a retrospective observational study
Authors: Zeiner Carsten , Schröder Malte , Metzner Selina , Herrmann Johannes , Notz Quirin , Hottenrott Sebastian , Röder Daniel , Meybohm Patrick , Lepper Philipp M. , Lotz Christopher
Published: October 2023

Background

Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO).

Methods

This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT.

Results

Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support.

Conclusions

Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS.
Trends in congenital clubfoot prevalence and co-occurring anomalies during 1994–2021 in Denmark: a nationwide register-based study
Authors: Hedley Paula L. , Lausten-Thomsen Ulrik , Conway Kristin M. , Hindsø Klaus , Romitti Paul A. , Christiansen Michael
Published: October 2023

Background

Congenital talipes equinovarus (clubfoot) is a common musculoskeletal anomaly, with a suspected multifactorial etiopathogenesis. Herein, we used publicly available data to ascertain liveborn infants with clubfoot delivered in Denmark during 1994–2021, and to classify co-occurring congenital anomalies, estimate annual prevalence, and compare clubfoot occurrence with maternal smoking rates, a commonly reported risk factor. Characterizing this nationwide, liveborn cohort provides a population-based resource for etiopathogenic investigations and life course surveillance.

Methods

This case-cohort study used data from the Danish National Patient Register and Danish Civil Registration System, accessed through the publicly available Danish Biobank Register, to identify 1,315,282 liveborn infants delivered during 1994–2021 in Denmark to Danish parents. Among these, 2,358 infants (65.1% male) were ascertained with clubfoot and classified as syndromic (co-occurring chromosomal, genetic, or teratogenic syndromes) and nonsyndromic (isolated or co-occurring multiple congenital anomalies [MCA]). Annual prevalence estimates and corresponding 95% confidence intervals (CIs) for children with nonsyndromic clubfoot were estimated using Poisson regression and compared with population-based, maternal annual smoking rates obtained from publicly available resources.

Results

Infants most often presented with nonsyndromic clubfoot (isolated = 88.6%; MCA = 11.4%); limb and heart anomalies were the most frequently identified MCAs. Prevalence (per 1,000 liveborn infants) was 1.52 (CI 1.45–1.58) for isolated and 0.19 (CI 0.17–0.22) for MCA clubfoot. Prevalence estimates for both isolated and MCA clubfoot remained relatively stable during the study period, despite marked decreases in population-based maternal smoking rates.

Conclusions

From 1994 to 2021, prevalence of nonsyndromic clubfoot in Denmark was relatively stable. Reduction in population-level maternal smoking rates did not seem to impact prevalence estimates, providing some support for the suspected multifactorial etiopathogenesis of this anomaly. This nationwide, liveborn cohort, ascertained and clinically characterized using publicly available data from the Danish Biobank Register, provides a population-based clinical and biological resource for future etiopathogenic investigations and life course surveillance.
Effects of DJK-5 and chlorhexidine on exopolysaccharide volume and pH in oral biofilms
Authors: Chen Binwen , Liu He , Wang Zhejun , Ma Jingzhi , Shen Ya
Published: September 2023

Background

Exopolysaccharides (EPS) are essential constituents of the extracellular matrix within oral biofilms and are significantly influenced by the local microenvironment. This study aimed to investigate the impact of two distinct antimicrobial agents, DJK-5 and chlorhexidine (CHX), on the EPS volume and pH levels in oral biofilms.

Methods

Oral biofilms obtained from two donors were cultured on hydroxyapatite discs for durations of 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. Subsequently, these biofilms were subjected to treatment with 10 µg/mL DJK-5 or 2% CHX for 3 min. The impact of these antimicrobial treatments on factors such as the proportion of dead bacterial, in situ pH, and EPS volume within the biofilms was assessed using corresponding fluorescent probes. The examination was carried out utilizing confocal laser scanning microscopy, and the resulting images were analyzed with a focus on the upper and lower layers of the biofilm, respectively.

Results

DJK-5 exhibited a more potent bactericidal effect compared to CHX across the 3-day to 4-week duration of the biofilm (P < 0.05). The biofilms were acidic, with the upper layer being less acidic than the lower layer (P < 0.05). Both antimicrobial agents increased the pH, but DJK-5 had a greater effect than CHX (P < 0.05). The volume of EPS was significantly lower in DJK-5 treated biofilms compared to that of CHX, regardless of age or layer (P < 0.05).

Conclusion

DJK-5 exhibited superior effectiveness in reducing viable bacteria and EPS volume, as well as in raising extracellular pH, as compared to chlorhexidine.
Nickel ion release and surface analyses on instrument fragments fractured beyond the apex: a laboratory investigation
Authors: Toker Sıdıka Mine , Orhan Ekim Onur , Beklen Arzu
Published: September 2023

Background

To analyse the changes in surface and nickel ion release characteristics of fractured root canal shaping instruments in a simulated body fluid environment.

Methods

A total of 54 new instruments were studied. The instrument groups consisted of five different NiTi alloys and a stainless-steel alloy. To standardize instrument fracture, a torsional type of failure was created on each instrument. The fractured specimens of each instrument group were randomly divided into three static immersion subgroups of 1 h, 7-day, and 30-day (n = 3). Simulated body fluid (SBF) was prepared to mimic human blood plasma by Kokubo&Takadama protocol for ex situ static immersions at 37ºC. The surfaces were examined via scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy. To determine the quantitative ion release, the retrieved SBFs were analyzed using inductively coupled plasma mass spectrometry. Two-way ANOVA and Tukey post hoc tests sought the statistical significance of the nickel ion values(p < 0.05).

Results

In 1 h of immersion, the newly formed structures, exhibiting mostly oxygen signals, were widespread and evident on NiTi surfaces. In contrast, fewer structures were detected on the SS surface in that subgroup. In 7 days of immersion, a tendency for a decrease in the density of the new structures was revealed in NiTi groups. The oxygen signals on NiTi group surfaces significantly increased, contrary to their decrease in SS. Signals of sodium, chlorine, and calcium were detected, indicating salt precipitates in groups. In 30 days of immersion, salt precipitates continued to form. The Ni-ion release values in all instrument groups presented significant differences in comparison to the SBF control in all immersion periods(p < 0.001). No significant differences were observed in immersion time periods or instrument groups(p > 0.05).

Conclusions

Within the limitations of the presented study, it was concluded that the fractured SS and NiTi root canal instruments release Ni ions in contact with body fluid. However, the Ni ion release values determined during the observation periods are lower than the critical toxic or allergic thresholds defined for the human body. This was due to the ionic dissolution cycle reaching a stable state from 1-hour to 30-day exposure to the body fluid of fractured instruments.
Development of a machine learning-based acuity score prediction model for virtual care settings
Authors: Hall Justin N. , Galaev Ron , Gavrilov Marina , Mondoux Shawn
Published: October 2023

Objective

Healthcare is increasingly digitized, yet remote and automated machine learning (ML) triage prediction systems for virtual urgent care use remain limited. The Canadian Triage and Acuity Scale (CTAS) is the gold standard triage tool for in-person care in Canada. The current work describes the development of a ML-based acuity score modelled after the CTAS system.

Methods

The ML-based acuity score model was developed using 2,460,109 de-identified patient-level encounter records from three large healthcare organizations (Ontario, Canada). Data included presenting complaint, clinical modifiers, age, sex, and self-reported pain. 2,041,987 records were high acuity (CTAS 1–3) and 416,870 records were low acuity (CTAS 4–5). Five models were trained: decision tree, k-nearest neighbors, random forest, gradient boosting regressor, and neural net. The outcome variable of interest was the acuity score predicted by the ML system compared to the CTAS score assigned by the triage nurse.

Results

Gradient boosting regressor demonstrated the greatest prediction accuracy. This final model was tuned toward up triaging to minimize patient risk if adopted into the clinical context. The algorithm predicted the same score in 47.4% of cases, and the same or more acute score in 95.0% of cases.

Conclusions

The ML algorithm shows reasonable predictive accuracy and high predictive safety and was developed using the largest dataset of its kind to date. Future work will involve conducting a pilot study to validate and prospectively assess reliability of the ML algorithm to assign acuity scores remotely.
Room for resilience: a qualitative study about accountability mechanisms in the relation between work-as-done (WAD) and work-as-imagined (WAI) in hospitals
Authors: Weenink Jan-Willem , Tresfon Jaco , van de Voort Iris , van Muijden Teyler , Hamming Jaap , Bal Roland
Published: September 2023

Background

Central to Safety-II is promoting resilience of healthcare practices. In the “Room for Resilience” research project we focus on the role of horizontal and vertical accountability in healthcare teams and aim to discover how the relation between the two impacts team reflections and discussions. In this article, we report on an explorative study at the start of the project which aimed to assess the structures and dynamics of horizontal and vertical accountability.

Methods

A qualitative study in six teams in three hospitals in the Netherlands. For the project, each team selected a specific clinical process to work on (e.g. pain assessment). We interviewed healthcare professionals, managers, and quality advisors about these processes, how they are discussed in practice and how teams need to account for them. Additionally, we observed the processes and how teams discuss them in practice. In total, we conducted 35 interviews and 67.5 h of observation. Transcripts and field notes were analyzed using thematic analysis.

Results

Professionals at times varied in what they considered the right approach in the clinical process, with differing views on the importance of certain actions. When processes were discussed, this mostly was done during clinical work, and it often concerned reflections about the care for a specific patient instead of reflecting on the team’s general approach of the clinical process. Organized reflections on the processes were sparse. How processes were conducted in practice deviated from guidelines, mainly due to staff shortages, a perceived lack of value of a guideline, equipment issues, and collaboration issues. For most processes, accountability to hierarchical layers consisted of quality indicator scores. Professionals were tasked with registering indicator data but did not find this meaningful for their work.

Conclusions

The observed different perspectives within teams on what good quality care is show the importance of having team reflections about these processes. How vertical accountability was organized at times impacted the conditions for teams to discuss resilient performance. Following these findings, we recommend that reflection on resilient practice and the role of accountability processes is organized on all levels in (and outside) the organization.
Role of non-canonical post-translational modifications in gastrointestinal tumors
Authors: Liu Yihong , Liu Jingwei , Peng Na , Hai Shuangshuang , Zhang Shen , Zhao Haibo , Liu Weixin
Published: September 2023

Post-translational modifications (PTMs) of proteins contribute to the occurrence and development of tumors. Previous studies have suggested that canonical PTMs such as ubiquitination, glycosylation, and phosphorylation are closely implicated in different aspects of gastrointestinal tumors. Recently, emerging evidence showed that non-canonical PTMs play an essential role in the carcinogenesis, metastasis and treatment of gastrointestinal tumors. Therefore, we summarized recent advances in sumoylation, neddylation, isoprenylation, succinylation and other non-canonical PTMs in gastrointestinal tumors, which comprehensively describe the mechanisms and functions of non-classical PTMs in gastrointestinal tumors. It is anticipated that targeting specific PTMs could benefit the treatment as well as improve the prognosis of gastrointestinal tumors.
miRNAs derived from cobra venom exosomes contribute to the cobra envenomation
Authors: Liao Tianci , Gan Mailin , Qiu Yanhao , Lei Yuhang , Chen Qiuyang , Wang Xingyu , Yang Yiting , Chen Lei , Zhao Ye , Niu Lili , Wang Yan , Zhang Shunhua , Zhu Li , Shen Linyuan
Published: September 2023

Currently, there is an increasing amount of evidence indicating that exosomes and the miRNAs they contain are crucial players in various biological processes. However, the role of exosomes and miRNAs in snake venom during the envenomation process remains largely unknown. In this study, fresh venom from Naja atra of different ages (2-month-old, 1-year-old, and 5-year-old) was collected, and exosomes were isolated through ultracentrifugation. The study found that exosomes with inactivated proteins and enzymes can still cause symptoms similar to cobra envenomation, indicating that substances other than proteins and enzymes in exosomes may also play an essential role in cobra envenomation. Furthermore, the expression profiles of isolated exosome miRNAs were analyzed. The study showed that a large number of miRNAs were co-expressed and abundant in cobra venom exosomes (CV-exosomes) of different ages, including miR-2904, which had high expression abundance and specific sequences. The specific miR-2094 derived from CV-exosomes (CV-exo-miR-2904) was overexpressed both in vitro and in vivo. As a result, CV-exo-miR-2904 induced symptoms similar to cobra envenomation in mice and caused liver damage, demonstrating that it plays a crucial role in cobra envenomation. These results reveal that CV-exosomes and the miRNAs they contain play a significant regulatory role in cobra envenomation. Our findings provide new insights for the treatment of cobra bites and the development of snake venom-based medicines.

Graphic abstract
Cost-effectiveness thresholds or decision-making threshold: a novel perspective
Authors: Sun Lihua , Peng Xiaochen , Li Shiqi , Huang Zhe
Published: October 2023

The use of multiple cost-effectiveness thresholds in pharmacoeconomic evaluation is a hotly debated topic in the international academic community. This study analyzed and discussed thresholds in the context of pharmacoeconomic evaluation and reimbursement decision-making. We suggest that the thresholds inferred from reimbursement decisions should be distinguished from cost-effectiveness threshold in pharmacoeconomic evaluation. Pharmacoeconomic evaluations should adopt a fixed threshold, which should not vary with the subjects evaluated. This would help avoid the invitation of numerous cost-effectiveness thresholds for a specific drug, an exceptional disease, a type of innovation, or a certain level of malignancy, which misleads economic evaluation adopting restless changing standards and making pharmacoeconomic evaluation and decision-making more complex and contradictory.
Identification of novel SCD1 inhibitor alleviates nonalcoholic fatty liver disease: critical role of liver-adipose axis
Authors: Wang Wei , Kong Yulin , Wang Xia , Wang Zhe , Tang Chunlei , Li Jinyou , Yang Qin , Chen Yong Q. , Zhu Shenglong
Published: September 2023

Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 μM). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis.
Ethnobotanical study on edible flowers in Xishuangbanna, China
Authors: Zhang Qing , Cheng Zhuo , Fan Yanxiao , Zhang Dezheng , Wang Miaomiao , Zhang Jihai , Sommano Sarana , Wu Xianjin , Long Chunlin
Published: September 2023

Background

Edible flowers (EFs) represent valuable sources of both food and medicinal resources, holding the promise to enhance human well-being. Unfortunately, their significance is often overlooked. Ethnobotanical studies on the EFs are lacking in comparison with their botanical and phytochemical research. The practice of consuming flowers as food has a rich culture and long history in China, especially among different linguistic groups in Xishuangbanna, Yunnan. However, economic activities have led to a decline of this tradition. Consequently, preserving the traditional knowledge and culture tied to the EFs in Xishuangbanna becomes both essential and pressing.

Methods

The field ethnobotanical survey was conducted in Xishuangbanna during five visits in April 2021 and May 2023, covering 48 villages and 19 local markets of all three county-level areas and 9 different linguistic groups. By conducting a comprehensive literature review and on-site field surveys, relevant information regarding the EFs of Xishuangbanna was systematically collected and documented. Additionally, the relative frequency of citation (RFC) values were calculated from the survey data.

Results

A total of 212 taxa (including species and varieties) of EFs from 58 families and 141 genera were documented in the study area. The edible parts of flowers were classified into 13 categories including peduncle, petal, flower buds, inflorescence as a whole, and etc. They were consumed in 21 ways and as 8 types of food. The inflorescence was the most commonly consumed category, accounting for 85 species (40.1%) of the total categories. They always eat flowers as vegetables (184 species, 86.8%). The preparing form of stir-frying was the preferred food preparation method (138, 65.1%). The Xishuangbanna locals had profound knowledge of which EFs required specific processing to remove their toxicity or bitterness. The dishes can be made from either exclusively from the flowers themselves or by incorporating them alongside other plant parts like stems and leaves. Some EFs with high RFC value, such as Musa acuminata and Bauhinia variegata var. candida, showed significant cultural meanings. These edible flowers occupy specific positions in local traditional culture.

Conclusion

Traditional knowledge regarding edible flowers holds substantial significance and serves as a representative element of the flower-eating culture in Xishuangbanna. Nevertheless, this knowledge and cultural practice are currently decreasing. Serving as a bridge between tradition and modernity, the flower-eating culture, which derives from local people’s practical experience, shows the potential of EFs and can be applied to the conservation of biocultural diversity, healthy food systems, and sustainable development.
The influence of diabetes and age-related degeneration on body balance control during static standing: a study based on plantar center-of-pressure trajectories and principal component analysis
Authors: Hu Xing-xi , Yang Xiong-gang , Wang Xu , Ma Xin , Geng Xiang
Published: September 2023

Background

Aging and diabetes can impair the balance function of the elderly and diabetic patients and increase their fall risk. This study aimed to assess the shaking amplitude of the center-of-pressure (CoP) during static standing, to analyze the effects of aging and diabetes on the balance control.

Materials and methods

This cross-sectional observational study, compared the balance performance of 20 healthy younger adults (27.65 ± 5.60 years), 16 healthy older adults (58.88 ± 3.54 years) and 15 diabetic patients (58.33 ± 5.33 years) in four static standing conditions on a force plate: horizontal, anteroposterior (AP), left and right slope planes (5° angles on AP, left and right directions, respectively). The trajectory coordinates of the CoP over time were recorded and analyzed by principal components analysis to obtain the 95% confidence ellipse and its parameters: angle, major and minor axes lengths, and area. The balance indicators were compared among the three groups using one-way analysis of variance (ANOVA), Brown–Forsythe test or Kruskal–Wallis H test, depending on the normality and homogeneity of variance assumptions.

Results

The diabetic group had a significantly larger confidence ellipse area than the healthy younger adults on the horizontal plane (P = 0.032) and than the healthy older adults on the horizontal (P = 0.036), AP slope (P = 0.023), and right ML slope (P = 0.037) planes. There were no significant differences in the major axis length of the confidence ellipse among the three groups. The diabetic group had a significantly longer minor axis length than the healthy younger adults on the AP slope (P = 0.039), left ML slope (P = 0.045) and right ML slope (P = 0.016) planes and than the healthy older adults on the AP slope (P = 0.007), left ML slope (P = 0.035) and right ML slope (P = 0.012) planes.

Conclusions

The balance control of diabetic patients is decreased compared with healthy younger and older people, and the body swing amplitude increases mainly in the direction of minor axis of confidence ellipse during static standing, while the swing amplitude in the direction of the major axis has no significant change. Evaluating the balance function of diabetic patients can help clinicians identify people with fall risk early and intervene early, thereby reducing the occurrence of fall events in this population.
TDP-43 pathology is associated with increased tau burdens and seeding
Authors: Tomé Sandra O. , Tsaka Grigoria , Ronisz Alicja , Ospitalieri Simona , Gawor Klara , Gomes Luis Aragão , Otto Markus , von Arnim Christine A. F. , Van Damme Philip , Van Den Bosch Ludo , Ghebremedhin Estifanos , Laureyssen Celeste , Sleegers Kristel , Vandenberghe Rik , Rousseau Frederic , Schymkowitz Joost , Thal Dietmar Rudolf
Published: September 2023

Background

Most Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43: AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD.

Methods

In this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches: histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice.

Results

We found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed.

Conclusions

Our findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients.
Clinical research stakeholders’ experiences of clinical research during COVID-19: a qualitative study
Authors: FitzGerald Christine , Vaughan-Witts Aoife , Barry Louise , Corey Gillian , Leahy Fiona , Egan Siobhán , Conway Elaine , O’Connor Margaret , Galvin Rose
Published: September 2023

Background

The COVID-19 pandemic created a complex high-risk clinical research environment with clinical research activities significantly impacted. Clinical research stakeholders adapted rapidly to new clinical practices; PPE, infection control policies, all while engaging with a more unwell patient demographic. The aim of this study is to explore the experiences of conducting clinical research during COVID-19 with clinical research stakeholders.

Methods

This qualitative study of semi-structured interviews conducted with clinical research stakeholders in an acute Hospital setting across a variety of disciplines; Consultant Geriatrician, Clinical Research Nurse, Occupational Therapy, Physiotherapy. Interviews were fully transcribed prior to reflexive thematic analysis. NVivo software was used to support data management and analysis.

Results

Three main themes were produced; (1) The challenging COVID-19 clinical research landscape, (2) COVID-19 clinical research communication barriers, and (3) Adaptations and learnings from clinical research during COVID-19.

Conclusions

This study explored the experiences of conducting clinical research during COVID-19 with clinical research stakeholders examining challenges faced and adaptations required. The findings inform, equip and support clinical research stakeholders in the event of future adverse public health events.
Evaluation of the clinical and quantitative performance of a practical HPLC-UV platform for in-hospital routine therapeutic drug monitoring of multiple drugs
Authors: Morikawa Go , Fukami Kazuto , Moriiwa Yukiko , Okazawa Katsuko , Yanagida Akio
Published: September 2023

Background

In-hospital therapeutic drug monitoring (TDM) requires a suitable quantification method for target drugs from the viewpoint of precision, throughput, and testing costs. We previously developed a practical HPLC-UV platform for quantification of serum levels of various drugs. In this report, the platform was effectively applied to the quantification of patient serum levels of five different drugs by clinical professionals in our hospital during their daily work.

Methods

The residual sera of patients receiving carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), vancomycin (VCM), or voriconazole (VRCZ) were used in the present clinical study. The quantification method for each drug consisted of rapid solid-phase extraction (SPE) of each drug in the patient serum, followed by optimized HPLC-UV analysis of the drug in the SPE eluate. Furthermore, patient serum levels of PHT, CBZ, and VCM were also measured by ligand-binding assay using a cobas® analyzer in our hospital, and those of LTG and VRCZ were measured by HPLC-MS/MS at an outsourced provider. Passing–Bablok regression analysis and Bland–Altman analysis were employed to analyze the agreement of drug levels in patient sera, which was separately quantified using two different methods—our HPLC-UV platform and the cobas analyzer, or HPLC-UV and HPLC-MS/MS.

Results

All analytical conditions of the present method using our HPLC-UV platform were well optimized for each target drug quantification in the patient’s serum, and the quantification method for each drug was fully validated for accuracy, precision and reproducibility. Furthermore, Passing–Bablok regression analysis and Bland–Altman analysis revealed that patient serum levels of PHT, CBZ, and VCM quantified by our HPLC-UV platform were closely correlated with those quantified by the cobas® analyzer, and the levels of LTG and VRCZ quantified by our HPLC-UV platform were also correlated with those quantified by HPLC-MS/MS.

Conclusions

Our HPLC-UV platform can be performed without requiring special analytical techniques. This platform is expected to be used for the measurement of blood levels of multiple drugs for in-hospital routine TDM.
Primary intra-axial Ewing sarcoma of the central nervous system: report of a rare case with literature review
Authors: Dirilenoğlu Fikret , George Moyo Mthabisi Talent , Kahraman Aslı
Published: October 2023

Background

Primary intra-axial Ewing sarcoma (EWS) is extremely rare and a highly aggressive small blue round cell tumor in the central nervous system (CNS). We reported a case of primary intra-axial CNS-EWS in a 30-year-old male and presented an extensive literature review of CNS-EWS cases.

Case presentation

A 30-year-old male had been diagnosed with a grade 2 astrocytoma in the left frontal lobe a year ago and had received chemotherapy and radiotherapy. He presented with a right-sided mass, which was revealed to be a 6 cm contrast-enhancing lesion with heterogeneous hemorrhagic areas in the right frontal lobe. The patient underwent emergent craniotomy for surgical excision. Histologically, the tumor was composed of high-grade, small, blue, round cells forming trabecular islands and rosettes which were separated by fibrovascular tissues. In immunohistochemical (IHC) examination, the tumor cells were positive for CD99 and FLI-1. Fluorescence in situ hybridization analysis revealed the presence of EWSR1 gene rearrangement. The histopathological, IHC, and molecular findings were consistent with a diagnosis of EWS. Further imaging did not show evidence of another primary site. The patient was followed up without further therapy and succumbed to the disease three months after the diagnosis.

Conclusion

EWS is very rare but an aggressive neoplasm in the CNS. Chemoradiotherapy may promote secondary cancers but it is unclear whether the development of EWS was associated with chemoradiotherapy that our case had received for astrocytoma. EWS should be considered when diagnosing a CNS tumor that shows small, blue, round cell tumor morphology. A combination of IHC and molecular tests is required for accurate diagnosis to ensure that all patients receive the most appropriate treatment to optimize outcomes.
Modelling of slab track systems for design purposes
Authors: Aly Mohamed Hafez Fahmy , El-Naga Islam Mahmoud Abou , Soliman Ahmed Abdul Hay , Diab Muhammad Ahmad
Published: October 2023

Slab track is a recent technology used to cope up with the train high axle loads and speed, it has replaced the ballast material in classical ballasted track with either reinforced concrete slab or asphalt layer in order to increase both stability and durability of the railway lines. This paper aims to propose a new slab track design model which can be used to design/analyze any slab track systems under vertical loads using AREMA and EN specifications for high-speed systems (300 kmph). This model has been validated through experimental work held in Heriot-Watt University then applied to the most common slab track systems (BÖGL, Shinkansen, and RHEDA 2000) in the world. The standard section of RHEDA 2000 slab track has shown the best structural performance and efficiency compared with BÖGL and Shinkansen standard sections regarding the rail deflection, stresses of rails, and stress of replacement soil layer and subgrade soil. This paper has concluded the rail deflection is the most critical factor for the slab track design regarding EN specifications while the subgrade stresses is the vital criterion concerning AREMA specifications. Furthermore, EN-Specifications are found to be more conservative than AREMA specifications for the design or analysis of all the slab track types.
International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy
Authors: El Sissy Carine , Kirilovsky Amos , Lagorce Pagès Christine , Marliot Florence , Custers Petra A. , Dizdarevic Edina , Sroussi Marine , Castillo-Martin Mireia , Haicheur Nacilla , Dermani Mohamed , Loche Nicolas , Buttard Bénedicte , Musina Ana Maria , Anitei Maria Gabriela , van den Berg José G. , Broeks Annegien , Iseas Soledad , Coraglio Mariana , Loria Fernando Sanchez , Romero Alfredo , Laurent-Puig Pierre , de Reyniès Aurélien , Fernandez Laura M. , Karoui Mehdi , Tougeron David , Vaccaro Carlos A. , Santino Juan P. , Poulsen Laurids Østergaard , Lindebjerg Jan , O'Connor Juan Manuel , Scripcariu Viorel , Dimofte Mihail-Gabriel , Gérard Jean-Pierre , Chalabi Myriam , Figueiredo Nuno , Perez Rodrigo O. , Habr-Gama Angelita , Galon Jérôme , Hansen Torben Frøstrup , Jensen Lars Henrik , Beets Geerard , Zeitoun Guy , Pagès Franck
Published: October 2023

PURPOSE

No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study.

METHODS

This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence.

RESULTS

Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR.

CONCLUSION

The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.
Canakinumab as Adjuvant Therapy in Patients With Completely Resected Non–Small-Cell Lung Cancer: Results From the CANOPY-A Double-Blind, Randomized Clinical Trial
Authors: Garon Edward B. , Lu Shun , Goto Yasushi , De Marchi Pedro , Paz-Ares Luis , Spigel David R. , Thomas Michael , Yang James Chih-Hsin , Ardizzoni Andrea , Barlesi Fabrice , Orlov Sergey , Yoshioka Hiroshige , Mountzios Giannis , Khanna Sadhvi , Bossen Claudia , Carbini Mariana , Turri Sabine , Myers Andrea , Cho Byoung Chul
Published: October 2023

Adjuvant canakinumab did not increase disease-free survival in resected non–small-cell lung cancer.
Metformin Improves the Prerequisites for FGF21 Signaling in Patients With Type 2 Diabetes
Authors: Pedersen Anne Kathrine Nissen , Gormsen Lars Christian , Nielsen Søren , Jessen Niels , Bjerre Mette
Published: September 2023

Context

Fibroblast growth factor (FGF) 21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21 signaling requires binding to surface receptors, FGFR1c and β-klotho. FGF21 resistance is observed in metabolic diseases and FGF21 signaling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown.

Objective

To investigate how 12 weeks of treatment with metformin affects the FGF21 signaling pathway in patients with type 2 diabetes (T2D).

Methods

Randomized, placebo-controlled study in patients with T2D (n = 24) receiving either metformin (1000 mg twice daily) or placebo. A control group of body mass index- and age-matched healthy individuals (n = 12) received a similar dose of metformin. Blood samples and muscle and fat biopsies were collected at study entry and after 12 weeks.

Methods

Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21 signaling pathway.

Results

Circulating FAP activity decreased after metformin treatment compared with placebo (P = .006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of β-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue.

Conclusion

Our findings suggest that metformin suppresses the circulating FAP activity and upregulates the expression of FGFR1c and β-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity.
The Neuroendocrine Impact of Acute Stress on Synaptic Plasticity
Authors: dos-Santos Raoni Conceição , Sweeten Brook L W , Stelly Claire E , Tasker Jeffrey G
Published: October 2023

Stress induces changes in nervous system function on different signaling levels, from molecular signaling to synaptic transmission to neural circuits to behavior—and on different time scales, from rapid onset and transient to delayed and long-lasting. The principal effectors of stress plasticity are glucocorticoids, steroid hormones that act with a broad range of signaling competency due to the expression of multiple nuclear and membrane receptor subtypes in virtually every tissue of the organism. Glucocorticoid and mineralocorticoid receptors are localized to each of the cellular compartments of the receptor-expressing cells—the membrane, cytosol, and nucleus. In this review, we cover the neuroendocrine effects of stress, focusing mainly on the rapid actions of acute stress–induced glucocorticoids that effect changes in synaptic transmission and neuronal excitability by modulating synaptic and intrinsic neuronal properties via activation of presumed membrane glucocorticoid and mineralocorticoid receptors. We describe the synaptic plasticity that occurs in 4 stress-associated brain structures, the hypothalamus, hippocampus, amygdala, and prefrontal cortex, in response to single or short-term stress exposure. The rapid transformative impact of glucocorticoids makes this stress signal a particularly potent effector of acute neuronal plasticity.