bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia
Authors: Marthin June K. , Holgersen Mathias G. , Nielsen Kim G. , Mortensen Jann
Published: October 2023

Background

Pulmonary radioaerosol mucociliary clearance (PRMC) is a reliable method for assessingin vivowhole lung mucociliary clearance and has been used at the Danish PCD Centre as a supplementary diagnostic test for primary ciliary dyskinesia (PCD) for more than two decades. This study aimed to investigate genotype-specific differences in PRMC measures and evaluate its potential as an outcome parameter.

Material and methods

The study was based on a retrospective analysis of PRMC tests performed over a 24-year period (1999–2022) in individuals referred for PCD work-up and included patients with genetically confirmed PCD and non-PCD controls. Patients inhaled nebulised technetium-albumin-colloid before static and dynamic imaging was obtained. Three parameters were evaluated: 1-h lung retention (LR1), tracheobronchial velocity (TBV) and cough clearance.

Results

The study included 69 patients from the Danish PCD cohort, representing 26 different PCD genotypes. Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype. However, a single patient with aCCDC103mutation, preserved ciliary function and normal nasal nitric oxide levels exhibited normal LR1 and low TBV values. Voluntary cough significantly improved clearance, with a median improvement of 11% (interquartile range 4–24%).

Conclusion

Absent mucociliary clearance by PRMC should be expected in PCD regardless of genotype but residual ciliary function could result in measurable PRMC. This indicates a potential for PRMC to detect improvements in ciliary function if this can be restored. Addressing involuntary cough and peripheral deposition of radioaerosol is important if PRMC is to be used as an outcome measure in future clinical PCD trials.
New Technology of Multidirectional Loading Rotary Extrusion
Authors: Zhang Zhimin , Xue Yong , Zhang Xing , Dong Beibei , Cheng Mei , Chen Zhe
Published: October 2023

To satisfy the requirements for the precise formation of large-scale high-performance lightweight components with inner ring reinforcement, a new multidirectional loading rotary extrusion forming technology is developed to match the linear motion with the rotary motion and actively increases the strong shear force. Its principle is that the radial force and rotating torque increase when the blank is axially extruded and loaded. Through the synergistic action of axial, radial, and rotating motions, the orderly flow of metal is controlled, and the cumulative severe plastic deformation (SPD) of an “uplift-trowel” micro-area is generated. Consequently, materials are uniformly strengthened and toughened. Simultaneously, through the continuous deformation of a punch “ellipse-circle,” a high reinforcement component is grown on the cylinder wall to achieve the high-quality formation of cylindrical parts or the inner-ring-reinforcement components. Additionally, the effective strain increases with rotation speed, and the maximum intensity on the basal plane decreases as the number of revolutions increase. The punch structure also affects the axial extrusion loading and equivalent plastic strain. Thus, the proposed technology enriches the plastic forming theory and widens the application field of plastic forming. Furthermore, the formed large-scale high-performance inner-ring-stiffened magnesium components have been successfully verified in aerospace equipment, thereby solving the problems of integral forming and severe deformation strengthening and toughening. The developed technology has good prospects for mass production and application.
Adaptations for remote research work: a modified web-push strategy compared to a mail-only strategy for administering a survey of healthcare experiences
Authors: Vimalananda Varsha G. , Wormwood Jolie B. , Sitter Kailyn E. , Fincke B. Graeme , Qian Shirley , Tait Maya N. , Meterko Mark
Published: October 2023

Background

The COVID-19 pandemic required that our research team change our mail-only (MO) strategy for a research survey to a strategy more manageable by staff working remotely. We used a modified web-push approach (MWP), in which patients were mailed a request to respond online and invited to call if they preferred the questionnaire by mail or phone. We also changed from a pre-completion gift to a post-completion gift card incentive. Our objective is to compare response patterns between modes for a survey that used an MO strategy pre-pandemic followed by an MWP strategy peri-pandemic for data collection.

Methods

Observational study using data from a national multi-scale survey about patients’ experience of specialty care coordination administered via MO in 2019 and MWP from 2020 to 2021 to Veterans receiving primary care and specialty care within the Veterans Health Administration (VA). We compared response rates, respondent characteristics and responses about care coordination between MO and MWP, applying propensity weights to account for differences in the underlying samples.

Results

The response rate was lower for MWP vs. MO (13.4% vs. 36.6%), OR = 0.27, 95% CI = 0.25–0.30, P < .001). Respondent characteristics were similar across MO and MWP. Coordination scale scores tended to be slightly higher for MWP, but the effect sizes for these differences between modes were small for 9 out of 10 scales.

Conclusions

While the logistics of MWP survey data collection are well-suited to the remote research work environment, response rates were lower than those for the MO method. Future studies should examine addition of multi-mode contacts and/or pre-completion incentives to increase response rates for MWP.
Ototoxicity associated with extended dalbavancin treatment for a shoulder prosthetic joint infection
Authors: Lange Anna , Thunberg Ulrica , Söderquist Bo
Published: October 2023

Background

Dalbavancin is a lipoglycopeptide antibiotic approved for treatment of skin and soft tissue infections, administered as a single or two-dose treatment. The extended half-life, good penetration into bone and synovial fluid, and bactericidal activity against gram-positive bacteria, including those in biofilm, make dalbavancin an appealing choice for treatment of bone and joint infections in outpatient settings. However, we present a rare case of ototoxicity associated with off-label extended dalbavancin treatment of a prosthetic joint infection.

Case presentation

A 55-year-old man with a prosthetic joint infection of the shoulder underwent off-label extended dalbavancin treatment, receiving a cumulative dose of 2500 mg. The patient experienced a gradual onset of hearing loss following the first dose, leading to a diagnosis of bilateral sensorineural hearing loss that persisted 1 year after dalbavancin was discontinued.

Conclusions

This case report highlights the importance of exercising caution when administering dalbavancin beyond approved dosing guidelines, and emphasizes the need for vigilance regarding the potential for ototoxicity.
Prolonged facemask wearing among hospital workers and dry eye – a mixed-methods study
Authors: Li Tianjing , McCann Paul M. , Wilting Sarah , McNamara Steve , Gregory Darren G. , Hauswirth Scott G. , Ifantides Cristos , Benning Lorie , Sequeira Tamara A. , Qureshi Riaz , Liu Su-Hsun , Clark Melissa A. , Saldanha Ian J. , Abraham Alison G.
Published: October 2023

Background

Prolonged facemask wearing may have negatively affected essential workers with dry eye. We conducted a mixed-methods study to examine and understand the associations of the ocular surface, periocular environment, and dry eye-related symptoms among hospital workers across the job spectrum with prolonged facemask use.

Methods

We recruited clinical and non-clinical hospital workers with self-reported symptoms of dry eye and prolonged facemask use. We measured symptoms using the 5-item Dry Eye Questionnaire and the Ocular Surface Disease Index (OSDI). Objective ocular signs included corneal and conjunctival staining, fluorescein tear break up time (TBUT), meibography, tear film interferometry, and periocular humidity. We compared symptoms and signs across levels of periocular humidity, dry eye severity, facemask type, and job type. Participants with moderate or severe dry eye symptoms (OSDI > = 23) were invited for a semi-structured, one-on-one interview.

Results

We enrolled 20 clinical and 21 non-clinical hospital workers: 27% were 40 years or older, 76% were female, 29% reported a race other than White, and 20% were Hispanic. Seventeen individuals participated in the semi-structured interviews. From the quantitative analyses, we found that 90% of participants reported worsened severity of dry eye at work due to facemasks. Although wearing facemasks resulted in higher periocular humidity levels compared with not wearing facemasks, 66% participants reported increased airflow over their eyes. Findings from the qualitative interviews supported the finding that use of facemasks worsened dry eye symptoms, especially when facemasks were not fitted around the nose. The data did not suggest that non-clinical hospital workers experienced a greater impact of dry eye than clinical workers.

Conclusions

Healthcare providers and patients with dry eye should be educated about the discomfort and the ocular surface health risks associated with inadequately fitted facemasks. Wearing a fitted facemask with a pliable nose wire appears to mitigate the upward airflow.
Psychosocial determinants associated with healthcare workers’ self-reported compliance with infection prevention and control during the COVID-19 pandemic: a cross-sectional study in Dutch residential care facilities for people with intellectual and developmental disabilities
Authors: Houben Famke , Heijer Casper DJ den , Dukers-Muijrers Nicole HTM , Smeets-Peels Claudia , Hoebe Christian JPA
Published: October 2023

Background

Healthcare workers’ (HCWs) compliance with infection prevention and control (IPC) is crucial to reduce the infection transmission risk. However, HCWs’ compliance with IPC in residential care facilities (RCFs) for people with intellectual and developmental disabilities (IDDs) is known to be suboptimal. Therefore, this study examined sociodemographic and psychosocial determinants associated with IPC non-compliance in this setting, to inform IPC policy and promotion programmes for adequate IPC behaviour.

Methods

An online questionnaire was administered to 285 HCWs from 16 RCFs between March 2021 and March 2022. Determinants associated with IPC non-compliance were assessed using logistic regression analyses.

Results

Being a woman (OR: 3.57; 1.73–7.37), and being a non-medical professional were associated with increased odds of non-compliance (social workers, OR: 2.83; 1.65–4.85; behavioural specialists, OR: 6.09; 1.98–18.72). Perceived inadequate education/training (aOR: 1.62; 1.15–2.27) and perceived time constraints/competing priorities (aOR: 1.43; 1.03–1.98) were also associated with increased odds of non-compliance, independent of sociodemographic variables. In contrast, the belief that the supervisor complies with IPC (descriptive norm supervisor) was associated with decreased odds of non-compliance (aOR: 0.60; 0.41–0.88).

Conclusions

To improve IPC in disability care settings, the implementation of tailored and structural IPC education and training programmes (e.g., on-the-job training) is recommended to increase HCWs’ capabilities and bridge the IPC compliance gap between medical and non-medical professionals. In addition, role models, particularly supervisors, are crucial for promoting IPC behaviour. Facilities should create a culture of IPC compliance by norm setting, acting on, and modelling IPC behaviours at all levels of the organisation (management, medical, and non-medical staff).
Using an adaptive network-based fuzzy inference system for prediction of successful aging: a comparison with common machine learning algorithms
Authors: Yazdani Azita , Shanbehzadeh Mostafa , Kazemi-Arpanahi Hadi
Published: October 2023

Introduction

The global society is currently facing a rise in the elderly population. The concept of successful aging (SA) appeared in the gerontological literature to overcome the challenges and problems of population aging. SA is a subjective and multidimensional concept with many ambiguities regarding its meaning or measuring. This study aimed to propose an intelligent predictive model to predict SA.

Methods

In this retrospective study, the data of 784 elderly people were used to develop and validate machine learning (ML) methods. Data pre-processing was first performed. First, an adaptive neuro-fuzzy inference system (ANFIS) was proposed to predict SA. Then, the predictive performance of the proposed model was compared with three ML algorithms, including multilayer perceptron (MLP) neural network, support vector machine (SVM), and random forest (RF) based on accuracy, sensitivity, precision, and F-score metrics.

Results

The findings indicated that the ANFIS model with gauss2mf built-in membership function (MF) outperformed the other models with accuracy, sensitivity, precision, and F-score of 91.57%, 95.18%, 92.31%, and 92.94%, respectively.

Conclusions

The predictive performance of ANFIS is more efficient than the other ML models in SA prediction. The development of a decision support system (DSS) using our prediction model can provide healthcare administrators and policymakers with a reliable and responsive tool to improve elderly outcomes.
Escape to the future – a qualitative study of physicians’ views on the work environment, education, and support in a digital context
Authors: Hägglund Maria , Ekwall Anna Kristensson , Davoody Nadia , Farrokhnia Nasim
Published: October 2023

Background

The use of remote services such as video consultations (VCs) has increased significantly in the wake of the COVID-19 pandemic. In Sweden, private healthcare providers offering VCs have grown substantially since 2016 and have been controversial. Few studies have focused on physicians’ experiences providing care in this context. Our aim was to study physicians’ experiences of VCs, focusing on the work environment, quality of care, and educational needs.

Methods

Twenty-two semi-structured interviews were performed with physicians working with VCs in Sweden, and analyzed through inductive content analysis.

Results

We identified five categories; flexibility, social work environment, impact on care and society, continuous learning and career development, and organizational support. Flexibility and accessibility were considered positive features of working digitally by giving physicians control over their time and workplace and increasing patients’ timely access to healthcare. Regarding collegial contact and social activities in a digital context, the majority of the participants did not experience any significant difference compared to the physical context. Access to technical support services, educational support, and collegial support in decision-making, guidance, and consultations were described as well-functioning. Satisfied patients positively impacted the work environment, and participants felt that VCs have a positive socio-economic effect. Continuity of care was considered supported, but patients did not always prioritize this. Privacy risks were considered a challenge, as were poor development of clinical skills due to the low variation of patient cases. Working for an online healthcare provider was contributing to career advancements for junior clinicians.

Conclusions

Physicians appreciate the flexibility of the digital context and seem satisfied with a work environment where they have a high level of control, but few consider this a full-time career option. The pandemic year 2020 has led to a significant increase in the implementation of VCs in traditional care systems. How this affects the work environment and continuous education needs and career development remains to be seen.
Opportunities to strengthen resilience of health care workers regarding patient safety
Authors: Pacutova Veronika , Geckova Andrea Madarasova , de Winter Andrea F. , Reijneveld Sijmen A.
Published: October 2023

Background

The COVID-19 pandemic endangered the quality of health care and the safety of patients and health care workers (HCWs). This provided challenges for HCWs’ resilience and for hospital management and probably increased risks for patient safety incidents (PSI). HCWs may also have experienced psychological consequences as second victims of PSI, but evidence on this is lacking. Therefore, we mapped HCWs’ experiences with PSI during the second wave of COVID-19, the associations of these experiences with the hospital management of patient safety culture and HCWs’ interests in receiving further training.

Methods

We obtained data from 193 HCWs working at the COVID-related departments of one large hospital in eastern Slovakia via a questionnaire developed in direct collaboration with them. We measured PSI experiences as various HCWs’ experiences with near miss and adverse events and the hospital management of patient safety culture using indicators such as risk of recurrence, open disclosure and second victim experiences. For analysis, we used logistic regression models adjusted for age and gender of the HCWs.

Results

One-third of the hospital HCWs had experienced PSI; these were more likely to expect adverse events to recur (odds ratio, OR = 2.7–3.5). Regarding the hospital management of patient safety culture, the HCWs’ experiencing openly disclosed PSI was associated with one negative outcome, i.e. conflicts among colleagues (OR = 2.8), and one positive outcome, i.e. patients’ acceptance of their explanation and apologies (OR = 2.3). We found no associations for any other essential domains after disclosure. PSI experiences were strongly associated with psychological indicators of second victimhood, such as sadness, irritability, anxiety and depression (OR = 2.2–4.3), while providing support was not. The majority of the HCWs would like to participate in the suggested trainings (83.4%).

Conclusion

HCWs with PSI experiences reported poor hospital management of the patient safety culture, which might reflect they missed the opportunities to strengthen their resilience, especially during the COVID-19 pandemic.
Factors affecting T2DM patients’ behaviors associated with integrated treatment and prevention services in China
Authors: Zhao Ran , Zhang Xia , Wang Sizhe , Zhao Nan , Li Dianjiang , Fan Hong
Published: October 2023

Objective

To explore the relationship between type 2 diabetes mellitus (T2DM) patients’ attitude, subjective norms (SN), perceived behavioral control (PBC), behavioral intention (BI) and behavior associated with integrated treatment and preventive (ITP) services.

Methods

A convenient sampling method was employed at a community health center in Nanjing, China between January and July 2022. The collected data were processed using Epidata 3.1, SPSS 26.0, and AMOS 24.0. Descriptive statistics and a structural equation model based on the theory of planned behavior (TPB) were used to explore the correlation between the study variables.

Results

430 participants were eventually included, with a response rate of 98.6%. The mean age was 72.50 ± 5.69 years. The TPB model proved to be suitable and explained 41% of the variance in the BI. Attitude (β = 0.289, P < 0.001), SN (β = 0.314, P < 0.001) and PBC (β = 0.261, P < 0.001) were the main predictors of BI, and the SN was the strongest. BI (β = 0.452, P < 0.001) and PBC (β = 0.452, P < 0.001) had similar direct effects on patients’ behavior.

Conclusion

The TPB model explained the behavioral variations associated with ITP services and provided a framework for developing targeted interventions and improving community-based ITP services for T2DM. To encourage patients to engage in desirable behaviors, interventions should focus on modifying patients’ SN towards behavior associated with ITP services by promoting peer pressure and increasing the family’s emphasis on health.
Insulin-induced gene 2 protects against hepatic ischemia–reperfusion injury via metabolic remodeling
Authors: Wu Yichao , Li Changbiao , Khan Abid Ali , Chen Kangchen , Su Renyi , Xu Shengjun , Sun Yiyang , Gao Fengqiang , Wang Kai , Wang Xiaodong , Lian Zhengxing , Wang Shuo , Yu Mengyuan , Hu Xin , Yang Fan , Zheng Shusen , Qiu Nasha , Liu Zhikun , Xu Xiao
Published: October 2023

Background

Hepatic ischemia–reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous.

Methods

Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2.

Results

Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate).

Conclusions

Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.
Targeting RPA promotes autophagic flux and the antitumor response to radiation in nasopharyngeal carcinoma
Authors: Feng Yanchun , Jiang Yingming , Liu Jun , Liu Jiaqi , Shi Mengchen , Chen Junxiong , Zhang Jingdan , Tian Yu , Yang Xiangling , Liu Huanliang
Published: October 2023

Background

Autophagy is involved in nasopharyngeal carcinoma (NPC) radioresistance. Replication protein A 1 (RPA1) and RPA3, substrates of the RPA complex, are potential therapeutic targets for reversing NPC radioresistance. Nevertheless, the role of RPA in autophagy is not adequately understood. This investigation was performed to reveal the cytotoxic mechanism of a pharmacologic RPA inhibitor (RPAi) in NPC cells and the underlying mechanism by which RPAi-mediated autophagy regulates NPC radiosensitivity.

Methods and results

We characterized a potent RPAi (HAMNO) that was substantially correlated with radiosensitivity enhancement and proliferative inhibition of in vivo and in NPC cell lines in vitro. We show that the RPAi induced autophagy at multiple levels by inducing autophagic flux, AMPK/mTOR pathway activation, and autophagy-related gene transcription by decreasing glycolytic function. We hypothesized that RPA inhibition impaired glycolysis and increased NPC dependence on autophagy. We further demonstrated that combining autophagy inhibition with chloroquine (CQ) treatment or genetic inhibition of the autophagy regulator ATG5 and RPAi treatment was more effective than either approach alone in enhancing the antitumor response of NPC to radiation.

Conclusions

Our study suggests that HAMNO is a potent RPAi that enhances radiosensitivity and induces autophagy in NPC cell lines by decreasing glycolytic function and activating autophagy-related genes. We suggest a novel treatment strategy in which pharmacological inhibitors that simultaneously disrupt RPA and autophagic processes improve NPC responsiveness to radiation.
Proteomic interrogation of the meninges reveals the molecular identities of structural components and regional distinctions along the CNS axis
Authors: Santorella Elise , Balsbaugh Jeremy L. , Ge Shujun , Saboori Parisa , Baker David , Pachter Joel S.
Published: October 2023

The meninges surround the brain and spinal cord, affording physical protection while also serving as a niche of neuroimmune activity. Though possessing stromal qualities, its complex cellular and extracellular makeup has yet to be elaborated, and it remains unclear whether the meninges vary along the neuroaxis. Hence, studies were carried-out to elucidate the protein composition and structural organization of brain and spinal cord meninges in normal, adult Biozzi ABH mice. First, shotgun, bottom-up proteomics was carried-out. Prominent proteins at both brain and spinal levels included Type II collagen and Type II keratins, representing extracellular matrix (ECM) and cytoskeletal categories, respectively. While the vast majority of total proteins detected was shared between both meningeal locales, more were uniquely detected in brain than in spine. This pattern was also seen when total proteins were subdivided by cellular compartment, except in the case of the ECM category where brain and spinal meninges each had near equal number of unique proteins, and Type V and type III collagen registered exclusively in the spine. Quantitative analysis revealed differential expression of several collagens and cytoskeletal proteins between brain and spinal meninges. High-resolution immunofluorescence and immunogold-scanning electronmicroscopy on sections from whole brain and spinal cord – still encased within bone –identified major proteins detected by proteomics, and highlighted their association with cellular and extracellular elements of variously shaped arachnoid trabeculae. Western blotting aligned with the proteomic and immunohistological analyses, reinforcing differential appearance of proteins in brain vs spinal meninges. Results could reflect regional distinctions in meninges that govern protective and/or neuroimmune functions.
Ethnoprimatology of the Shipibo of the upper Ucayali River, Perú
Authors: Anca Evelyn , Shanee Sam , Svensson Magdalena S.
Published: October 2023

In the Anthropocene, primate conservation can only take place when considering human culture, perspectives, and needs. Such approaches are increasingly important under the growing impact of anthropogenic activities and increasing number of threatened primates. The Amazon rainforest, rich in cultural and biological diversity, where indigenous people play a crucial role in primate conservation, provides ample opportunity to study human–primate interactions and the sociocultural context in which they occur. Human activities threaten the Amazon’s fragile ecosystems and its primates, which play a key role in its maintenance and regeneration. This study focuses on one of the largest indigenous groups in the Peruvian Amazon: the Shipibo. Interviews and participant observation were used to investigate local perceptions of animal presence and depletion, food preferences, and how primates are incorporated into daily life and culture. Since time immemorial and still today, primates remain important in Shipibo culture, mythology, and subsistence. Local Shipibo participants consistently identified the presence of 13 species of primate. Primates were among the preferred species for consumption, pet keeping, and held a fundamental role in mythology, traditional knowledge, and storytelling. Large-bodied primates were often mentioned as being locally extinct, with reports and observations suggesting increasing consumption of smaller-bodied primates. Commonly perceived reasons for primate depletion include noise disturbance, hunting, and population growth, often in parallel. This study sheds light on the cultural context of an area rich in biodiversity, where primates, essential for ecological balance and integral to Shipibo lives and identity, are being depleted. We highlight the need for an inclusive ethnoprimatological approach to conserving primates and preserving indigenous heritage while improving local livelihoods.
Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms
Authors: Xie Manling , Pallegar Praveen N. , Parusel Sebastian , Nguyen Aivi T. , Wu Long-Jun
Published: October 2023

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.
The role of endotoxin in septic shock
Authors: Kellum John A. , Ronco Claudio
Published: October 2023

Septic shock can be caused by a variety of mechanisms including direct effects of bacterial toxins such as endotoxin. Annually, approximately 5–7 million patients worldwide develop sepsis with very high endotoxin activity in the blood and more than half die. The term endotoxic septic shock has been used for these patients but it is important to emphasize that endotoxin may be a factor in all forms of septic shock including non-bacterial etiologies like COVID-19 since translocation of bacterial products is a common feature of septic shock. A pattern of organ failure including hepatic dysfunction, acute kidney injury and various forms of endothelial dysfunction ranging from disseminated intravascular coagulation to thrombotic microangiopathy characterize endotoxic septic shock. However, while characteristic, the clinical phenotype is not unique to patients with high endotoxin, and the diagnosis relies on the measurement of endotoxin activity in addition to clinical assessment. Therapies for endotoxic septic shock are limited with immune modulating therapies under investigation and extracorporeal blood purification still controversial in many parts of the world.
Metabolomic biomarkers of habitual B vitamin intakes unveil novel differentially methylated positions in the human epigenome
Authors: Costeira Ricardo , Evangelista Laila , Wilson Rory , Yan Xinyu , Hellbach Fabian , Sinke Lucy , Christiansen Colette , Villicaña Sergio , Masachs Olatz M. , Tsai Pei-Chien , Mangino Massimo , Menni Cristina , Berry Sarah E. , Beekman Marian , van Heemst Diana , Slagboom P. Eline , Heijmans Bastiaan T. , Suhre Karsten , Kastenmüller Gabi , Gieger Christian , Peters Annette , Small Kerrin S. , Linseisen Jakob , Waldenberger Melanie , Bell Jordana T.
Published: October 2023

Background

B vitamins such as folate (B9), B6, and B12 are key in one carbon metabolism, which generates methyl donors for DNA methylation. Several studies have linked differential methylation to self-reported intakes of folate and B12, but these estimates can be imprecise, while metabolomic biomarkers can offer an objective assessment of dietary intakes. We explored blood metabolomic biomarkers of folate and vitamins B6 and B12, to carry out epigenome-wide analyses across up to three European cohorts. Associations between self-reported habitual daily B vitamin intakes and 756 metabolites (Metabolon Inc.) were assessed in serum samples from 1064 UK participants from the TwinsUK cohort. The identified B vitamin metabolomic biomarkers were then used in epigenome-wide association tests with fasting blood DNA methylation levels at 430,768 sites from the Infinium HumanMethylation450 BeadChip in blood samples from 2182 European participants from the TwinsUK and KORA cohorts. Candidate signals were explored for metabolite associations with gene expression levels in a subset of the TwinsUK sample (n = 297). Metabolomic biomarker epigenetic associations were also compared with epigenetic associations of self-reported habitual B vitamin intakes in samples from 2294 European participants.

Results

Eighteen metabolites were associated with B vitamin intakes after correction for multiple testing (Bonferroni-adj. p < 0.05), of which 7 metabolites were available in both cohorts and tested for epigenome-wide association. Three metabolites — pipecolate (metabolomic biomarker of B6 and folate intakes), pyridoxate (marker of B6 and folate) and docosahexaenoate (DHA, marker of B6) — were associated with 10, 3 and 1 differentially methylated positions (DMPs), respectively. The strongest association was observed between DHA and DMP cg03440556 in the SCD gene (effect = 0.093 ± 0.016, p = 4.07E−09). Pyridoxate, a catabolic product of vitamin B6, was inversely associated with CpG methylation near the SLC1A5 gene promoter region (cg02711608 and cg22304262) and with SLC7A11 (cg06690548), but not with corresponding changes in gene expression levels. The self-reported intake of folate and vitamin B6 had consistent but non-significant associations with the epigenetic signals.

Conclusion

Metabolomic biomarkers are a valuable approach to investigate the effects of dietary B vitamin intake on the human epigenome.
Pharmacological EZH2 inhibition combined with retinoic acid treatment promotes differentiation and apoptosis in rhabdomyosarcoma cells
Authors: O’Brien Eleanor , Tse Carmen , Tracy Ian , Reddin Ian , Selfe Joanna , Gibson Jane , Tapper William , Pengelly Reuben J. , Gao Jinhui , Aladowicz Ewa , Petts Gemma , Thway Khin , Popov Sergey , Kelsey Anna , Underwood Timothy J. , Shipley Janet , Walters Zoë S.
Published: October 2023

Background

Rhabdomyosarcomas (RMS) are predominantly paediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (< 30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumours.

Results

We demonstrate combining inhibition of the epigenetic modulator EZH2 with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3-FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signalling resulting in differentiation. In both subtypes, EZH2 is significantly associated with enrichment of trimethylated lysine 27 on histone 3 (H3K27me3) in genes that are downregulated in untreated RMS cells and upregulated with EZH2 inhibitor treatment. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS.

Conclusions

The results of this study demonstrate the potential utility of combining EZH2 inhibitors with differentiation agents for the treatment of paediatric rhabdomyosarcomas. As EZH2 inhibitors are currently undergoing clinical trials for adult and paediatric solid tumours and retinoic acid differentiation agents are already in clinical use this presents a readily translatable potential therapeutic strategy. Moreover, as inhibition of EZH2 in the poor prognosis FPRMS subtype results in an inflammatory response, it is conceivable that this strategy may also synergise with immunotherapies for a more effective treatment in these patients.
Longitudinal resting-state EEG in amyloid-positive patients along the Alzheimer’s disease continuum: considerations for clinical trials
Authors: Scheijbeler Elliz P. , de Haan Willem , Stam Cornelis J. , Twisk Jos W. R. , Gouw Alida A.
Published: October 2023

Background

To enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer’s disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD.

Methods

Resting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration.

Results

Whole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures’ rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power.

Conclusions

Resting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.
Cutaneous metastasis from cervical cancer to the scalp and trunk: a case report and review of the literature
Authors: Dai Ying , Zhang Yufei , Ke Xue , Liu Yunqin , Zang Chunbao
Published: October 2023

Background

An estimated 119,300 new cases of cervical cancer occur annually in China, accounting for 372,00 deaths. Cutaneous metastasis from cervical cancer is a rare event, with an incidence of 0.1–1.3% and typically a preterminal occurrence. Scalp metastasis from cervical cancer is exceptionally anecdotal, with only a dozen examples well documented.

Case presentation

The patient is a 33-year-old Chinese woman who was diagnosed with International Federation of Gynecology and Obstetrics stage IVB cervical cancer in November 2021. From December 2021 to April 2022, the patient was enrolled in the clinical trial of sintilimab combined with chemotherapy and radiotherapy for treatment of stage IV cervical cancer and underwent six cycles of immunotherapy and chemotherapy (sintilimab plus paclitaxel liposome and cisplatin). Treatment was well tolerated and led to a partial response. The masses adjacent to the spine and iliac bone was largely reduced. Thus, radiotherapy of the metastatic residues was carried out and followed by radiotherapy to the primary tumor at the cervix uteri. However, by the time of the radiotherapy completion in October 2022, the patient noticed painless nodules at the left scapular region and the right hypochondrium. The following month, more nodules occurred on the scalp and trunk, including the left axilla, anterior abdomen, and left back, along with a lesion invading the sternum that caused acute bone pain. The cutaneous masses were white, discrete with a rubbery consistency, and fixed to the skin. Several nodules increased in size and eventually ulcerated. Fine‑needle aspiration cytology of the left back swellings revealed metastatic squamous cell carcinoma, P16 positive. No visceral or brain metastasis was observed at this point.

Conclusions

Cervical cancer metastases to the scalp are extremely uncommon. When a scalp metastasis is present, it might be the only symptomatic sign of disease progression or widespread metastatic lesions. So far, there is no clear guideline regarding skin metastases treatment. Such skin lesions warrant a thorough radiologic and pathologic workup to form a comprehensive management plan.
Context-based refinement of mappings in evolving life science ontologies
Authors: Yamamoto Victor Eiti , Destro Juliana Medeiros , dos Reis Julio Cesar
Published: October 2023

Background

Biomedical computational systems benefit from ontologies and their associated mappings. Indeed, aligned ontologies in life sciences play a central role in several semantic-enabled tasks, especially in data exchange. It is crucial to maintain up-to-date alignments according to new knowledge inserted in novel ontology releases. Refining ontology mappings in place, based on adding concepts, demands further research.

Results

This article studies the mapping refinement phenomenon by proposing techniques to refine a set of established mappings based on the evolution of biomedical ontologies. In our first analysis, we investigate ways of suggesting correspondences with the new ontology version without applying a matching operation to the whole set of ontology entities. In the second analysis, the refinement technique enables deriving new mappings and updating the semantic type of the mapping beyond equivalence. Our study explores the neighborhood of concepts in the alignment process to refine mapping sets.

Conclusion

Experimental evaluations with several versions of aligned biomedical ontologies were conducted. Those experiments demonstrated the usefulness of ontology evolution changes to support the process of mapping refinement. Furthermore, using context in ontological concepts was effective in our techniques.
Exploring the potential of vagus nerve stimulation in treating brain diseases: a review of immunologic benefits and neuroprotective efficacy
Authors: Jin Zeping , Dong Jing , Wang Yang , Liu Yunpeng
Published: October 2023

The vagus nerve serves as a critical connection between the central nervous system and internal organs. Originally known for its effectiveness in treating refractory epilepsy, vagus nerve stimulation (VNS) has shown potential for managing other brain diseases, including ischaemic stroke, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. However, the precise mechanisms of VNS and its benefits for brain diseases are not yet fully understood. Recent studies have found that VNS can inhibit inflammation, promote neuroprotection, help maintain the integrity of the blood-brain barrier, have multisystemic modulatory effects, and even transmit signals from the gut flora to the brain. In this article, we will review several essential studies that summarize the current theories of VNS and its immunomodulatory effects, as well as the therapeutic value of VNS for brain disorders. By doing so, we aim to provide a better understanding of how the neuroimmune network operates and inspire future research in this field.
Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
Authors: Holt Amy K. , Najumudeen Arafath K. , Collard Tracey J. , Li Hao , Millett Laura M. , Hoskin Ashley J. , Legge Danny N. , Mortensson Eleanor M. H. , Flanagan Dustin J. , Jones Nicholas , Kollareddy Madhu , Timms Penny , Hitchings Matthew D. , Cronin James , Sansom Owen J. , Williams Ann C. , Vincent Emma E.
Published: October 2023

Background

To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.

Methods

We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.

Results

We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.

Conclusions

Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.