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Background Poor medication adherence (MA) is prevalent globally. MA assessment, often based on scales or pill count, lacks actionability. A mobile application (app), MediEasy, targeting patients on multiple daily medications, has been developed to engage their caregivers to enhance their MA. Objectives This pilot single-arm study aimed to determine the feasibility, acceptability, utility and glycaemic control of the MediEasy-app by patients with type-2 diabetes mellitus and their caregivers. Methods 20 Multi-ethnic Asian patients aged 51 to 70 years with suboptimal glycaemic control (HbA1c>7.5%) and their caregivers were recruited at a Primary care outpatient clinic in Singapore. The Medieasy app that contains the following major functionalities such as the alerts to take medications, embedded medication details, personalized dosing options (such as frequency and scheduling dosage settings) is twinned to their designated caregivers. The Caregivers can remind the patients who missed the scheduled medication intake when the paired device was alerted. Results 85% (17/20) of the participants used the app for the entire 4 weeks, reflecting feasibility; 3 dropped out due to technical glitches or failure to adhere to protocol. The app was activated with an average of 2.8 times per day showing adequate utility. The 17 participants and their caregivers agreed that the app supported medication adherence. Their mean HbA1c decreased by 0.2% after 12 weeks of app usage. Conclusions The results showed feasibility, utility and acceptability of the MediEasy-app, with improved glycaemic control after its usage.

Loranthaceae are parasitic plants whose management remains a challenge. This study aimed to record Loranthaceae species and their local names, assess their use diversity and cultural importance, identify the socio-demographic groups with the highest levels of knowledge about Loranthaceae uses, and analyze the variation of Loranthaceae utilization between and within ethnic groups. Ethnobotanical data were collected in northern Benin from March 2015 to February 2017 through semi-structured interviews and show-and-tell method with 240 informants. We assessed Loranthaceae use diversity and cultural importance using the Relative Frequency of Citations (RFC), Number of Uses (NU), Use Value (UV), Number of Use Categories (NUC), and Cultural Importance Index (CI). Poisson's regression and Jaccard's Similarity Index were used to identify the socio-demographic groups with the highest levels of knowledge about Loranthaceae uses and evaluate the similarity of Loranthaceae uses between ethnic groups. Results showed 15 local names used to designate four Loranthaceae species namely Agelanthus dodoneifolius, Tapinanthus globiferus, Phragmanthera kamerunensis, and T. ophioides. Loranthaceae were involved in 113 uses gathered in six categories namely human medicine, magic, veterinary, fodder, food, and cosmetic. Human medicine was the most important category with 0.825 as RFC, 61.10 % of the uses, and 100 % of Loranthaceae species involved. A. dodoneifolius was the most important Loranthaceae species regarding its RFC, NU, UV, and NUC of 0.938, 95, 2.296, and 6 respectively. CI showed A. dodoneifolius and T. globiferus were mainly used in human medicine with 0.729 and 0.458 respectively. Bariba, traditional healers and breeders, old people, and animists presented the highest levels of knowledge about Loranthaceae uses. Loranthaceae utilization varied according to ethnic groups and Bariba and Yom presented a similarity in Loranthaceae uses. Loranthaceae valorization in the production of improved traditional medicines, animal feed, soap, and green fertilizers will contribute to the biological control of these plants.

Architecture requires many aspects to be considered – during research, concept development, detailing, construction and even postoccupancy. Not many architects nowadays see to all the aspects mentioned as it is easier and sometimes better to collaborate with architects specialised in each area. However, knowledge about each aspect (and most of all understanding the importance of each in the whole building process) is essential in order to corroborate information and thus assure the quality of the final product – the building in use. An important question arises in an architecture educational environment: which aspects must be considered as core elements to be taught? We wish to set didactic objectives of architectural technology and follow specific pedagogical methods that underline its specific role in an academic environment, but also its role of reaffirming, refining and enriching the design. Beyond its obvious constructive role, architectural technology can be regarded as a tool along the various phases of design, including post-occupancy. Its approach as such throughout the years of study has an undeniable effect upon its understanding and further application in practice. Also, how architectural technology is taught and guided can contribute to the achievement of general competences and abilities linked to the general didactic objectives of a school of architecture.

In the recent past, a comprehensive experimental program has been worked out at the Mainz Energy-Recovery Superconducting Accelerator, MESA, at the Institute of Nuclear Physics in Mainz. MESA is a high-intensity, low-energy electron accelerator presently under construction and will thereby provide great opportunities to perform a new generation of high-precision scattering experiments. The versatile MAGIX experiment will use MESA’s innovative energy recovery technique, with a science focus on the study of hadron structure and few-body systems, dark sector searches, and investigations into reactions pertinent to nuclear astrophysics. An external beam line will supply spin-polarized electrons to the P2 experiment, enabling the performance of sensitive tests of the Standard Model through parity-violating electron scattering. The DarkMESA beam dump experiment, situated behind P2, is dedicated to the search for light dark matter particles.

The OSG-operated Open Science Pool is an HTCondor-based virtual cluster that aggregates resources from compute clusters provided by several organizations. Most of the resources are not owned by OSG, so demand-based dynamic provisioning is important for maximizing usage without incurring excessive waste. OSG has long relied on GlideinWMS for most of its resource provisioning needs but is limited to resources that provide a Grid-compliant Compute Entrypoint. To work around this limitation, the OSG Software Team has developed a glidein container that resource providers could use to directly contribute to the OSPool. The problem with that approach is that it is not demand-driven, relegating it to backfill scenarios only. To address this limitation, a demand-driven direct provisioner of Kubernetes resources has been developed and successfully used on the NRP. The setup still relies on the OSG-maintained backfill container image but automates the provisioning matchmaking and successive requests. That provisioner has also been extended to support Lancium, a green computing cloud provider with a Kubernetes-like proprietary interface. The provisioner logic has been intentionally kept very simple, making this extension a low-cost project. Both NRP and Lancium resources have been provisioned exclusively using this mechanism for many months.

The IceCube experiment has substantial simulation needs and is in continuous search for the most cost-effective ways to satisfy them. The most CPU-intensive part relies on CORSIKA, a cosmic ray air shower simulation. Historically, IceCube relied exclusively on x86-based CPUs, like Intel Xeon and AMD EPYC, but recently server-class ARM-based CPUs are also becoming available, both on-prem and in the cloud. In this paper we present our experience in running a sample CORSIKA simulation on both ARM and x86 CPUs available through Google Kubernetes Engine (GKE). We used the production binaries for the x86 instances, but had to build the binaries for ARM instances from source code, which turned out to be mostly painless. Our benchmarks show that ARM-based CPUs in GKE were not only the most cost-effective but were also the fastest in absolute terms in all the tested configurations. While the advantage is not drastic, about 20% in cost-effectiveness and less than 10% in absolute terms, it is still large enough to warrant an investment in ARM support for IceCube.

The x86_64 instruction set architecture is not a single, consistent, compatible interface to execute computer programs. Since the initial release in 1999, every new generation has added new instructions, some of which were later removed. Most of these new instructions are intended to improve the performance of those programs which explicitly take advantage of them. However, running such a program on older CPUs without appropriate support, results in Linux SIGILL exception signal, which is difficult for end users to diagnose. On the other hand, compiling scientific code for the least common denominator ISA can leave significant performance on the table. High Throughput systems, containing very large number of machines, cannot require a single CPU version across hundreds of thousands of machines operating in dozens of sites. The OSG Open Science Pool alone consists of more than 20 different, subtly incompatible X86_64 implementations. In 2020, Intel, AMD and RedHat proposed new terminology and partitioned these dozens of microarchitectures into a strict hierarchy of four groups. The HTCondor Software Suite and the OSG now have first class support for these microarchitectures. This paper discusses the advantages for users and future work around microarchitecture support.

The IceCube Neutrino Observatory is a cubic kilometer neutrino telescope located at the geographic South Pole. Understanding detector systematic effects is a continuous process. This requires the Monte Carlo simulation to be updated periodically to quantify potential changes and improvements in science results with more detailed modeling of the systematic effects. IceCube’s largest systematic effect comes from the optical properties of the ice the detector is embedded in. Over the last few years there have been considerable improvements in the understanding of the ice, which require a significant processing campaign to update the simulation. IceCube normally stores the results in a central storage system at the University of Wisconsin–Madison, but it ran out of disk space in 2022. The Prototype National Research Platform (PNRP) project thus offered to provide both GPU compute and storage capacity to IceCube in support of this activity. The storage access was provided via XRootD-based OSDF Origins, a first for IceCube computing. We report on the overall experience using PNRP resources, with both successes and pain points.

Creating new materials, discovering new drugs, and simulating systems are essential processes for research and innovation and require substantial computational power. While many applications can be split into many smaller independent tasks, some cannot and may take hours or weeks to run to completion. To better manage those longer-running jobs, it would be desirable to stop them at any arbitrary point in time and later continue their computation on another compute resource; this is usually referred to as checkpointing. While some applications can manage checkpointing programmatically, it would be preferable if the batch scheduling system could do that independently. This paper evaluates the feasibility of using CRIU (Checkpoint Restore in Userspace), an open-source tool for the GNU/Linux environments, emphasizing the OSG’s OSPool HTCondor setup. CRIU allows checkpointing the process state into a disk image and can deal with both open files and established network connections seamlessly. Furthermore, it can checkpoint traditional Linux processes and containerized workloads. The functionality seems adequate for many scenarios supported in the OSPool. However, some limitations prevent it from being usable in all circumstances.

The study investigates the effect of conventional and novel extraction techniques on the protein extraction yield from bitter gourd seeds (Momordica charantia). Ultrasound assisted-extraction (UAE) treatment for 30 min at 4 °C using a 20 kHz ultrasound probe resulted in the highest extraction yield of crude proteins. After purification, 9.08 ± 0.23 g of protein with 82.69 ± 0.78% purity was obtained from 100 g of M. charantia seeds on a dry basis. Mass spectrometry identified proteins with reported antidiabetic activity. Antidiabetic assays showed significantly higher antidiabetic activity for the purified protein (81.10 ± 2.64%) compared to the crude protein (32.59 ± 2.76%). In vitro cytotoxicity analysis showed minimal cytotoxicity levels at concentrations <200 μg.mL -1 . Overall, UAE was effective to obtain crude protein from M. charantia seeds and a subsequent purification step enhanced antidiabetic activity. However, further research is required to demonstrate in-vivo antidiabetic activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest of personal relationship that could have appeared to influence the wok reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The ability to induce different potentials in different regions of a (bipolar) electrode could transform applications such as on-demand drug delivery, the electrostimulation of biological cells, the development of advanced electroceuticals, and multi-analyte detection devices where different analytes could be wirelessly detected in different regions of a single sensing surface dramatically simplifying the device design. Here, we demonstrate the use of multiple feeder electrodes to control the electric field distribution in solution thus changing the potential induced in different regions of the bipolar electrode depending on the feeder voltage, polarity and feeder electrode position. The principle is demonstrated for the deposition of films of the conducting polymer, Poly(3,4-EthyleneDiOxyThiophene) (PEDOT), without the need for a physical template to control the regions in which polymer deposits.

Active Pharmaceutical Ingredient-Ionic liquids (API-ILs) have the potential to improve the bioavailability of BCS Class IV Drugs. However, the problematic physical handling properties of room temperature API-ILs have impaired clinical and commercial exploitation to date. Lipid-based formulations (LBFs) are used to improve the absorption of drugs with limited bioavailability. Nonetheless, LBFs face limitations such as low drug loading capacity and sub-par physical stability. A platform for transforming API-ILs into solid forms at high loadings via spray encapsulation with polymers has been developed and previously demonstrated for hydrophilic API-ILs. The current work demonstrates that this platform technology can be applied to a lipophilic API-IL of the BCS Class IV API, chlorpromazine, and to multi-component solutions comprising API-IL and a LBF. Furthermore, solidification of a type IIIB, liquid LBF was achieved via spray encapsulation with cellulose- and methacrylate- based polymers for the first time. The spray-encapsulated formulations had excellent physical handling properties, and successfully eluted the API-IL in aqueous media. The chlorpromazine release profiles from the API-IL, the API-IL containing LBF, and the solidified formulations, were evaluated in vitro using phosphate buffer (pH 6.8) and fasted state simulated intestinal fluid (FaSSIF). Spray-encapsulated formulations exhibited improved release profiles compared to the liquid formulations. Overall, these findings indicate that phase-separated, polymeric, solid formulations of liquid API forms represent a promising platform technology for developing oral solid dosage forms of poorly bioavailable drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The cerebellar cognitive affective syndrome (CCAS) encompasses cognitive and affective symptoms in patients with cerebellar disorders, for which no proven treatment is available., Objectives: Our primary objective was to study the effect of cerebellar anodal transcranial direct current stimulation (tDCS) on cognitive performance in CCAS patients. Secondary effects on ataxia severity, mood, and quality of life were explored., Methods: We performed a randomized, double-blind, sham-controlled trial. Thirty-five patients with CCAS were included and received 10 sessions of 20 minutes sham (n = 17) or real (n = 18) tDCS, with a current of 2 mA. Cognitive performance was assessed using executive function subtests of the computerized Test of Attentional Performance (TAP), with the composite as primary endpoint. Secondary outcomes were ataxia severity, mood, and quality of life. Outcomes were evaluated 1, 3, 6, and 12 months post-intervention., Results: Cerebellar tDCS was well tolerated and no serious adverse events related to the intervention occurred. No significant tDCS effect was found on cognitive performance. Improvement on the TAP was observed in the sham group 1 month post-treatment (estimate = -0.248, 95% CI, -0.49 to -0.01), but not clinically relevant. A positive tDCS effect was observed for ataxia severity 1 month post-treatment (estimate = -0.985, 95% CI, -1.94 to -0.03)., Conclusions: Ten sessions of 20 minutes cerebellar anodal tDCS did not prove efficacious for CCAS-related cognitive impairment, but a significant positive effect of tDCS was found for ataxia severity, aligning with previous findings indicative of tDCS as a therapeutic neuromodulation tool in cerebellar disorders. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The Home Health Project, set on Clare Island, five kilometres off the Irish Atlantic coast, is a pilot exploration of ways in which various forms of technology can be utilised to improve healthcare for individuals living in isolated communities. The integration of digital health technologies presents enormous potential to revolutionise the accessibility of healthcare systems for those living in remote communities, allowing patient care to function outside of traditional healthcare settings. This study aims to explore the personal experiences and perspectives of participants who are using digital technologies in the delivery of their healthcare as part of the Home Health Project. Individual semi-structured interviews were conducted with nine members of the Clare Island community participating in the Home Health Project. Interviews took place in-person, in June 2023. Interviews were audio-recorded and transcribed verbatim. The data were analysed inductively using reflexive thematic analysis. To identify determinants of engagement with the Home Health Project, the data was then deductively coded to the Theoretical Domains Framework (TDF) and organised into themes. Seven of the possible 14 TDF domains were supported by the interview data as influences on engagement with the Project: Knowledge, Beliefs about capabilities, Optimism, Intentions, Environmental context and resources, Social influences and Emotion. Overall, participants evaluated the Home Health Project as being of high quality which contributed to self-reported increases in health literacy, autonomy, and feeling well supported in having their health concerns addressed. There was some apprehension related to data protection, coupled with a desire for extended training to address aspects of digital illiteracy. Future iterations can capitalise on the findings of this study by refining the technologies to reflect tailored health information, personalised to the individual user., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kearney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Protein therapeutics are essential in the treatment of various diseases, but most of them require parenteral administration. Since intravenous and subcutaneous injections are associated with discomfort and pain, other routes have been investigated including intradermal microneedle delivery. Microneedles are shorter than hypodermic needles and therefore minimize contact with pain receptors in deeper skin layers. But the differences in anatomical and physiological characteristics of dermis and subcutis can potentially result in varying protein penetration through the skin, absorption, and metabolism. This review summarizes pharmacokinetic studies that compare the administration of protein therapeutics by subcutaneous injections and different types of microneedles intradermally including hollow, dissolvable, coated, and hydrogel-forming microneedles. Across animal and human studies, hollow microneedle delivery resulted in quicker and higher peak plasma levels of proteins and comparable bioavailability to subcutaneous injections potentially due to the extensive network of lymphatic and blood vessels in the dermis. In case of dissolvable and coated microneedles, drug release kinetics depend on component materials. The dissolution of polymer excipients can slow the release and permeation of protein therapeutics at the administration site and thereby delay absorption. The understanding of drug penetration through different skin layers, its absorption into blood capillaries or lymphatics, and dermal metabolism remains limited. Additionally, the effects of these processes on the differences in pharmacokinetic profiles of proteins following intradermal microneedle administration are not well understood. Greater insights are required for the development of the next generation of intradermal microneedle biotherapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: We previously demonstrated the potential of radiomics for the prediction of severe histological placenta accreta spectrum (PAS) subtypes using T2-weighted MRI. We aim to validate our model using an additional dataset. Secondly, we explore whether the performance is improved using a new approach to develop a new multivariate radiomics model., Methods: Multi-centre retrospective analysis was conducted between 2018 and 2023. Inclusion criteria: MRI performed for suspicion of PAS from ultrasound, clinical findings of PAS at laparotomy and/or histopathological confirmation. Radiomic features were extracted from T2-weighted MRI. The previous multivariate model was validated. Secondly, a 5-radiomic feature random forest classifier was selected from a randomized feature selection scheme to predict invasive placenta increta PAS cases. Prediction performance was assessed based on several metrics including area under the curve (AUC) of the receiver operating characteristic curve (ROC), sensitivity, and specificity., Results: We present 100 women [mean age 34.6 (±3.9) with PAS], 64 of whom had placenta increta. Firstly, we validated the previous multivariate model and found that a support vector machine classifier had a sensitivity of 0.620 (95% CI: 0.068; 1.0), specificity of 0.619 (95% CI: 0.059; 1.0), an AUC of 0.671 (95% CI: 0.440; 0.922), and accuracy of 0.602 (95% CI: 0.353; 0.817) for predicting placenta increta. From the new multivariate model, the best 5-feature subset was selected via the random subset feature selection scheme comprised of 4 radiomic features and 1 clinical variable (number of previous caesareans). This clinical-radiomic model achieved an AUC of 0.713 (95% CI: 0.551; 0.854), accuracy of 0.695 (95% CI 0.563; 0.793), sensitivity of 0.843 (95% CI 0.682; 0.990), and specificity of 0.447 (95% CI 0.167; 0.667)., Conclusion: We validated our previous model and present a new multivariate radiomic model for the prediction of severe placenta increta from a well-defined, cohort of PAS cases., Advances in Knowledge: Radiomic features demonstrate good predictive potential for identifying placenta increta. This suggests radiomics may be a useful adjunct to clinicians caring for women with this high-risk pregnancy condition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Polysaccharides like hyaluronan (HA) and chondroitin sulfate (CS) are native of the brain's extracellular matrix crucial for myelination and brain maturation. Despite extensive research on HA and CS as drug delivery systems (DDS), their high water solubility limits their application as drug carriers. This study introduces an injectable DDS using aldehyde-modified hyaluronic acid (HAOX) hydrogel containing polyelectrolyte complexes (PEC) formed with calcium, gelatin, and either CS or aldehyde-modified CS (CSOX) to deliver minocycline for Multiple Sclerosis therapy. PECs with CSOX enable covalent crosslinking to HAOX, creating immobilized PECs (HAOX&#95;PECOX), while those with CS remain unbound (HAOX&#95;PECS). The in situ forming DDS can be administered via a 20 G needle, with rapid gelation preventing premature leakage. The system integrates into an implanted device for minocycline release through either Fickian or anomalous diffusion, depending on PEC immobilization. HAOX&#95;PECOX reduced burst release by 88 %, with a duration of 127 h for 50 % release. The DDS exhibited an elastic modulus of 3800 Pa and a low swelling ratio (0-1 %), enabling precise control of minocycline release kinetics. Released minocycline reduced IL-6 secretion in the Whole Blood Monocytes Activation Test, suggesting that DDS formation may not alter the biological activity of the loaded drug., Competing Interests: Declaration of competing interest Vladimír Velebný has a financial interest in the company Contipro a.s., Dolní Dobrouč, Czech Republic, the commercial producer of hyaluronic acid, Martin Pravda is employee of Contipro a.s., (Copyright © 2024 Contipro a.s. Published by Elsevier Ltd.. All rights reserved.)

In the burgeoning field of proteins, the effective analysis of intricate protein data remains a formidable challenge, necessitating advanced computational tools for data processing, feature extraction, and interpretation. This study introduces ProteinFlow, an innovative framework designed to revolutionize feature engineering in protein data analysis. ProteinFlow stands out by offering enhanced efficiency in data collection and preprocessing, along with advanced capabilities in feature extraction, directly addressing the complexities inherent in multidimensional protein data sets. Through a comparative analysis, ProteinFlow demonstrated a significant improvement over traditional methods, notably reducing data preprocessing time and expanding the scope of biologically significant features identified. The framework's parallel data processing strategy and advanced algorithms ensure not only rapid data handling but also the extraction of comprehensive, meaningful insights from protein sequences, structures, and interactions. Furthermore, ProteinFlow exhibits remarkable scalability, adeptly managing large-scale data sets without compromising performance, a crucial attribute in the era of big data., (© 2024 The Author(s). Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Upstream open reading frames (uORFs) are a class of translated regions (translons) in mRNA 5' leaders. uORFs are believed to be pervasive regulators of the translation of mammalian mRNAs. Some uORFs are highly repressive but others have little or no impact on downstream mRNA translation either due to inefficient recognition of their start codon(s) or/and due to efficient reinitiation after uORF translation. While experiments with uORF reporter constructs proved to be instrumental in the investigation of uORF-mediated mechanisms of translation control, they can have serious limitations as manipulations with uORF sequences can yield various artefacts. Here we propose a general approach for using translation complex profiling (TCP-seq) data for exploring uORF regulatory characteristics. Using several examples, we show how TCP-seq could be used to estimate both repressiveness and modes of action of individual uORFs. We demonstrate how this approach could be used to assess the mechanisms of uORF-mediated translation control in the mRNA of several human genes, including EIF5, IFRD1, MDM2, MIEF1, PPP1R15B, TAF7, and UCP2., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [P.V.B. is a co-founder and a shareholder of Eirna Bio. The remaining authors declare no competing interests.]., (Copyright © 2024. Published by Elsevier Ltd.)

Induced pluripotent stem cell (iPSC) technology, in combination with electrophysiological characterization via multielectrode array (MEA), has facilitated the utilization of iPSC-derived motor neurons (iPSC-MNs) as highly valuable models for underpinning pathogenic mechanisms and developing novel therapeutic interventions for motor neuron diseases (MNDs). However, the challenge of MN adherence to the MEA plate and the heterogeneity presented in iPSC-derived cultures raise concerns about the reproducibility of the findings obtained from these cellular models. We discovered that one novel factor modulating the electrophysiological activity of iPSC-MNs is the extracellular matrix (ECM) used in the coating to support in vitro growth, differentiation and maturation of iPSC-MNs. The current study showed that two coating conditions, namely, Poly-L-ornithine/Matrigel (POM) and Polyethyleneimine (PEI) strongly promoted attachment of iPSC-MNs on MEA culture dishes compared to three other coating conditions, and both facilitated the maturation of iPSC-MNs as characterized by the detection of extensive electrophysiological activities from the MEA plates. POM coating accelerated the maturation of the iPSC-MNs for up to 5 weeks, which suits modeling of neurodevelopmental disorders. However, the application of PEI resulted in more even distribution of the MNs on the culture dish and reduced variability of electrophysiological signals from the iPSC-MNs in 7-week cultures, which permitted the detection of enhanced excitability in iPSC-MNs from patients with amyotrophic lateral sclerosis (ALS). This study provides a comprehensive comparison of five coating conditions and offers POM and PEI as favorable coatings for in vitro modeling of neurodevelopmental and neurodegenerative disorders, respectively., (© 2024. The Author(s).)

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700s-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL-based cohort were analyzed using 5,761 Y-specific SNPs. We identified 160 distinct terminal haplogroups, the majority of which (71.4%) belong to the R1b haplogroup. When compared with global reference populations, the NL population haplogroup composition and frequencies primarily resemble those observed in English and Irish ancestral source populations. There is also evidence of genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers who frequented NL. Interestingly, the observed population structure shows geographical and religious clustering that can be associated with the settlement of the ancestral source populations from predominantly Protestant, England, and Catholic, Ireland respectively. For example, the R1b-M222 haplogroup, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplogroups in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation, and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population., (© 2024. The Author(s).)

Objectives: Diversity and inclusion in clinical trials remains an important topic, particularly for participants with disabilities such as vision impairment. With advances in smartphone and tablet technologies, and their increasing use in clinical trials, accessibility features such as "pinch-to-zoom" are now at our fingertips. However, implementing such accessibility features when collecting electronic clinical outcomes assessments (eCOA) does not come without risks and must be designed with careful consideration and scientifically tested to ensure no impact to data integrity. Therefore, the objectives of this study were to determine the measurement equivalence of an eCOA questionnaire with and without a zoom accessibility feature and test its usability., Methods: An eCOA app with a zoom accessibility feature was designed following industry standards for eCOA best design. Participants (n=53) with chronic or recent pain completed a questionnaire with standard response scales (verbal rating scale [VRS], numerical rating scale [NRS], visual analog scale [VAS]), with and without the zoom accessibility feature enabled, in a randomized crossover design. Intraclass Correlation Coefficients (ICCs) were determined. A subset of participants (n=10) with vision impairment participated in a usability testing interview., Results: The ICC analysis showed high agreement (0.894-0.982) between zoomed and non-zoomed completions of the VRS, NRS and VAS. Participant usability testing showed good ease of use, ability to read the screen, and usefulness of the zoom feature, especially when not wearing corrective measures for vision impairment., Conclusions: These findings support the use of a specially designed eCOA zoom accessibility feature for use in clinical trials., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: Sepsis results from a dysregulated host immune response to infection and is responsible for ~11 million deaths each year. In the laboratory, many aspects of sepsis can be replicated using a cecal ligation and puncture (CLP) model, which is considered the most clinically relevant rodent model of sepsis. In the present study, histological and biomarker multiplex analyses revealed that the CLP model initiated a large-scale inflammatory response in mice by 24 h, with evidence of acute organ damage by 48-72 h. While many typical pro-inflammatory cytokine/chemokines were systemically elevated, a specific array including IL-10, eotaxin, MIP-1α, MIP-1β, MCP-1 and RANTES noticeably increased just prior to animals reaching the humane endpoint. Treatment of mice with 10 μg of a synthetic 68-amino acid peptide derived from an immunomodulatory molecule secreted by a parasitic worm of humans and livestock, Fasciola hepatica, termed Fasciola hepatica helminth defence molecule (FhHDM), potently suppressed the systemic inflammatory profile, protected mice against acute kidney injury, and improved survival between 48 and 72 h post-procedure. These results suggest that the anti-inflammatory parasite-derived FhHDM peptide has potential as a bio-therapeutic treatment for sepsis., (Copyright © 2024 by the Shock Society.)

Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The number of older people with unmet health care and support needs is increasing substantially due to the challenges facing health care systems worldwide. There are potentially great benefits to using the Internet of Things coupled with artificial intelligence to support independent living and the measurement of health risks, thus improving quality of life for the older adult population. Taking a co-design approach has the potential to ensure that these technological solutions are developed to address specific user needs and requirements., Objective: The aim of this study was to investigate stakeholders' perceptions of independent living and technology solutions, identify stakeholders' suggestions on how technology could assist older adults to live independently, and explore the acceptability and usefulness of a prototype Internet of Things solution called the NEX system to support independent living for an older adult population., Methods: The development of the NEX system was carried out in 3 key phases with a strong focus on diverse stakeholder involvement. The initial predesign exploratory phase recruited 17 stakeholders, including older adults and family caregivers, using fictitious personas and scenarios to explore initial perceptions of independent living and technology solutions. The subsequent co-design and testing phase expanded this to include a comprehensive web-based survey completed by 380 stakeholders, encompassing older adults, family caregivers, health care professionals, and home care support staff. This phase also included prototype testing at home by 7 older adults to assess technology needs, requirements, and the initial acceptability of the system. Finally, in the postdesign phase, workshops were held between academic and industry partners to analyze data collected from the earlier stages and to discuss recommendations for the future development of the system., Results: The predesign phase revealed 3 broad themes: loneliness and technology, aging and technology, and adopting and using technology. The co-design phase highlighted key areas where technology could assist older adults to live independently: home security, falls and loneliness, remote monitoring by family members, and communication with clients. Prototype testing revealed that the acceptability aspects of the prototype varied across technology types. Ambient sensors and voice-activated assistants were described as the most acceptable technology by participants. Last, the postdesign analysis process highlighted that ambient sensors have the potential for automatic detection of activities of daily living, resulting in key recommendations for future developments and deployments in this area., Conclusions: This study demonstrates the significance of incorporating diverse stakeholder perspectives in developing solutions that support independent living. Additionally, it emphasizes the advantages of prototype testing in home environments, offering crucial insights into the real-world experiences of users interacting with technological solutions., (© Claire M Timon, Emma Heffernan, Sophia Kilcullen, Louise Hopper, Hyowon Lee, Pamela Gallagher, Alan F Smeaton, Kieran Moran, Pamela Hussey, Catriona Murphy. Originally published in JMIR Aging (https://aging.jmir.org).)

Epilepsy care generates multiple sources of high-dimensional data, including clinical, imaging, electroencephalographic, genomic, and neuropsychological information, that are collected routinely to establish the diagnosis and guide management. Thanks to high-performance computing, sophisticated graphics processing units, and advanced analytics, we are now on the cusp of being able to use these data to significantly improve individualized care for people with epilepsy. Despite this, many clinicians, health care providers, and people with epilepsy are apprehensive about implementing Big Data and accompanying technologies such as artificial intelligence (AI). Practical, ethical, privacy, and climate issues represent real and enduring concerns that have yet to be completely resolved. Similarly, Big Data and AI-related biases have the potential to exacerbate local and global disparities. These are highly germane concerns to the field of epilepsy, given its high burden in developing nations and areas of socioeconomic deprivation. This educational paper from the International League Against Epilepsy's (ILAE) Big Data Commission aims to help clinicians caring for people with epilepsy become familiar with how Big Data is collected and processed, how they are applied to studies using AI, and outline the immense potential positive impact Big Data can have on diagnosis and management., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In recent years, organised and competitive video gaming, esports, has gained enormous popularity in many parts of the world, contributing to the growing professionalisation of this sports branch. To become or remain a professional esports player, individuals practice video gaming for several hours a day while remaining in a sitting posture which may not only lead to a decrease in training quality in the short term (eg, due to cognitive fatigue) but also put them at a higher risk for negative health events in the long-term (eg, overuse injuries). Thus, interrupting periods of prolonged video gaming in a sitting posture with acute physical exercise is strongly recommended for esports players even though the optimal dosage of acute physical exercise breaks remains unclear. To address this gap, we propose in this viewpoint that traditional concepts of exercise prescription and dosage determination using the variables frequency, intensity, time (also referred to as duration) and type of physical exercise (ie, abbreviated with the acronym FITT) should be complemented by the variable density which characterises the timing of consecutive bouts of acute physical exercise during an esports session., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Human microbiomes are essential to health throughout the lifespan and are increasingly recognized and studied for their roles in metabolic, immunological and neurological processes. Although the full complexity of these microbial communities is not fully understood, their clinical and industrial exploitation is well advanced and expanding, needing greater oversight guided by a consensus from the research community. One of the most controversial issues in microbiome research is the definition of a 'healthy' human microbiome. This concept is complicated by the microbial variability over different spatial and temporal scales along with the challenge of applying a unified definition to the spectrum of healthy microbiome configurations. In this Perspective, we examine the progress made and the key gaps that remain to be addressed to fully harness the benefits of the human microbiome. We propose a road map to expand our knowledge of the microbiome-health relationship, incorporating epidemiological approaches informed by the unique ecological characteristics of these communities., (© 2024. Springer Nature Limited.)

Objectives: To explore the priorities and directions of athlete upper and lower limb pain assessment by facilitating shared understandings of athletes and sport physiotherapists., Design: Qualitative research using a hermeneutic phenomenological approach., Methods: We carried out focus groups comprising a deliberate criterion sample using a constructivist perspective. At the end of each focus group, we used the nominal group technique method to generate a list of consensus-based priorities for future pain assessment. Our paper follows the consolidated criteria for reporting qualitative research (COREQ) guidelines., Results: We completed five focus groups, comprising twelve athletes (female, n = 5, male, n = 7) and four sport physiotherapists (male, n = 4). Two final themes (and six subthemes) were developed; I Enhanced Communication and Pain Descriptions (describing and representing pain, better communication, the role of technology, providing direction and setting the pace), and II Integrating Sport Specific and Multidimensional Assessments (broadening the pain assessment toolkit, the role of technology). We developed a set of thirteen practical priorities for pain assessment that span the subjective, objective, and general aspects of the athlete pain assessment., Conclusions: We have presented stakeholder-generated perspectives, direction and priorities for athlete pain assessment. Athletes and physiotherapists must continue to work together to achieve a comprehensive sport-specific multidimensional pain assessment experience alongside their wider support networks to ensure optimal representation and communication. We have highlighted some available pain assessment tools and strategies and outlined how novel tools may address certain gaps. Researchers, clinicians, and athletes can consider the practical guidance we have provided to address these priorities., Competing Interests: Declaration of interest statement The authors have no competing interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Preserving the function of human tendon-derived cells (hTDCs) during cell expansion is a significant challenge in regenerative medicine. In this study, a non-genetic approach is introduced to control the differentiation of hTDCs using a newly developed tympanic bioreactor. The system mimics the functionality of the human tympanic membrane, employing a piezoelectrically tuned acoustic diaphragm made of polyvinylidene fluoride-co-trifluoroethylene and boron nitride nanotubes. The diaphragm is vibrationally actuated to deliver targeted electromechanical stimulation to hTDCs. The results demonstrate that the system effectively maintains the tendon-specific phenotype of hTDCs, even under conditions that typically induce nonspecific differentiation, such as osteogenesis. This stabilization is achieved by modulating integrin-mediated mechanosignaling via ion channel-regulated calcium activity, potentially by TREK-1 and PIEZO1, yet targeted studies are required for confirmation. Finally, the system sustains the activation of key differentiation pathways (bone morphogenetic protein, BMP) while downregulating osteogenesis-associated (mitogen-ctivated protein kinase, MAPK and wingless integrated, WNT) pathways and upregulating Focal Adhesion Kinase (FAK) signaling. This approach offers a finely tunable, dose-dependent control over hTDC differentiation, presenting significant potential for non-genetic approaches in cell therapy, tendon tissue engineering, and the regeneration of other mechanosensitive tissues., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Longgang Volcano (LGV) and Changbaishan Tianchi Volcano (CTV) share a common magmatic source at mantle depths. However, the two volcanoes have produced completely different types of eruptions. By performing 3D inversion of an MT dataset that completely covers the LGV and CTV, we have obtained high-resolution electrical resistivity images. The results reveal that the two volcanoes have distinct magmatic plumbing systems, and this is likely the reason for their different eruptive styles. Results from 3D modeling do not show a magma chamber in the shallow crust beneath LGV, interpreted as the rapid rise of the magma from the mantle is responsible for producing a series of densely distributed volcanic cones in the LGV field. In contrast, there is a magma chamber in the upper crust beneath the CTV, where the fractional crystallization and mixing of magma has occurred. This magma chamber has facilitated multiple centralized eruptions, and thereby has led to the formation of the large CTV volcanic cone. These results indicate that differences in their crustal structures may have controlled the different eruptive activities of the LGV and CTV in CVS, Northeast China., (© 2024. The Author(s).)

Rising on-farm electricity demand, coupled with surges in electricity prices, has increased costs associated with milk production. Additionally, the use of grid electricity with a high carbon footprint depreciates the environmental performance of dairy farming. We assessed the potential of photovoltaic (PV) systems installed on dairy parlours under different policy incentives to reduce electricity costs and the carbon footprint of dairy farms in Ireland. The HOMER Pro software was employed to model electricity consumption, generation and economic performance of four 15-year PV project scenarios for 11 Irish farms. Scenarios considering the targeted agricultural modernisation scheme II (TAMS) and the microgeneration support scheme are assessed. The results show that PV systems are a feasible option to power dairy farms when current energy prices and inflation rates are applied. Small systems eligible for TAMS grants presented an average discounted payback period of 5 years, making them a better option for farmers than larger projects, which had an average payback period of 8.5 years. The deployment of PV systems reduced the GHG intensity of electricity consumed at the farms by up to 29 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The cleaning of reusable medical devices involves inherent challenges that can impact on the effectiveness of the cleaning process; consequently, the subsequent safety of patients. Fluid dynamics play a critical role in determining the flow and distribution of cleaning agents where the design of the device can either facilitate or hinder this important process. Complex geometries, narrow channels, or irregular surfaces can impede effective flushing of contaminants leading to incomplete cleaning that creates a greater likelihood for patient contamination risks. Device features (n =23) were exposed to the most challenging cleaning conditions to find the point of failure in both fluid dynamics and soil retention. Experimental results obtained from the aforementioned along with associated compound risks were used to assign a risk value. Using the "hardest to clean" device feature approach as the base risk value, the total quantitative risk score was calculated for different reusable medical devices from numerical values obtained from addressing 14 questions focusing on variability in geometry, material use, types of cleaning, and intended patient use. Patient risk values for devices with different features were calculated from using Kremer's cleaning categories based on position within value ranges. Occurrences less than 18 correspond to minimal risk devices while a total risk score between the values of 18-39 are moderate and equal to or above 40 scores corresponds to the maximal category. Application of this quantitative assessment approach will facilitate appropriate mitigation of risk for cleaning reusable medical devices by informing use of targeted effective interventions. Future use of this Kremer cleaning classification will complement and augment disinfection and sterilization modalities., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Educational multimedia is a cost-effective and straightforward way to administer large-scale information interventions to patient populations in musculoskeletal health care. While an abundance of health research informs the content of these interventions, less guidance exists about optimizing their design., Objective: This study aims to identify randomized controlled trials of patient populations with musculoskeletal conditions that used multimedia-based patient educational materials (PEMs) and examine how design was reported and impacted patients' knowledge and rehabilitation outcomes. Design was evaluated using principles from the cognitive theory of multimedia learning (CTML)., Methods: PubMed, CINAHL, PsycINFO, and Embase were searched from inception to September 2023 for studies examining adult patients with musculoskeletal conditions receiving multimedia PEMs compared to any other interventions. The primary outcome was knowledge retention measured via test scores. Secondary outcomes were any patient-reported measures. Retrievability was noted, and PEMs were sourced through search, purchase, and author communication., Results: A total of 160 randomized controlled trials were eligible for inclusion: 13 (8.1%) included their educational materials and 31 (19.4%) required a web search, purchase, or direct requests for educational materials. Of these 44 (27.5%) studies, none fully optimized the design of their educational materials, particularly lacking in the CTML principles of coherence, redundancy, modality, and generative activities for the learner. Of the 160 studies, the remaining 116 (72.5%) contained interventions that could not be retrieved or appraised. Learning was evaluated in 5 (3.1%) studies., Conclusions: Musculoskeletal studies should use open science principles and provide their PEMs wherever possible. The link between providing multimedia PEMs and patient learning is largely unexamined, but engagement potential may be maximized when considering design principles such as the CTML., (©Garett Van Oirschot, Amanda Pomphrey, Caoimhe Dunne, Kate Murphy, Karina Blood, Cailbhe Doherty. Originally published in JMIR Rehabilitation and Assistive Technology (https://rehab.jmir.org), 15.10.2024.)

Ultrafine particles (UFPs; PM 0.1 ) possess intensified health risk due to their smaller size and unique spatial variability. One of major emission sources for UFPs is vehicle exhaust, which varies based on the traffic composition in each type of roadside sector. The current challenge of epidemiological UFPs study is limited characterization ability due to expensive instruments. This study assessed the UFPs particle number concentrations (UFPs PNC) exposure dose for typical healthy adults and children at three different roadside sectors, including industrial roadside (IN), residential roadside (RS), and urban background (UB). Furthermore, this study also developed and utilized machine learning (ML) algorithms that could accurately characterize the UFPs exposure dose and explain the covariates effects on the model outputs, representing the intra-urban variability of UFPs between sectors. It was found that the average inhaled UFPs dose for healthy adults and children during off-peak season (warm period) were 1.71 ± 0.19 × 10 10 ; 1.28 ± 0.22 × 10 10 ; 1.09 ± 0.18 × 10 10 #/hour and 1.33 ± 0.15 × 10 10 ; 0.99 ± 0.17 × 10 10 ; 0.86 ± 0.14 × 10 10 #/hour at IN, RS, UB. Inhaled UFPs were mainly deposited in tracheobronchial (TB) respiratory fraction for adults (67.7%) and in alveoli (ALV) fraction for children (67.5%). Among three ML algorithms implemented in this study, XGBoost possessed the highest UFPs PNC exposure dose estimation performances with R 2  = 0.965; 0.959; 0.929 & RMSE = 0.79 × 10 8 ; 0.54 × 10 8 ; 0.15 × 10 5 #/hour at IN, RS, and UB which then followed by multiple linear regression (MLR), and random forest (RF). Furthermore, SHAP analysis from the XGBoost model has successfully pointed out the spatial variability of each roadside sector by quantifying the approximated contributions of covariates to the model's output. Findings in this study highlighted the potential use of ML models as an alternative for preliminary particle exposure source apportionment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Iron (Fe)-based denitrification is a proven technology for removing nitrate from water, yet challenges such as limited pH preference range and low N 2 selectivity (reduction of nitrate to N 2 ) persist. Adding biochar (BC) can improve the pH preference range but not N 2 selectivity. This study aimed to improve nitrate reduction and N 2 selectivity in iron filling/biochar (Fe/BC) systems with a simplified approach by coupling unacclimated microbes (M) in the system. Factors such as initial pH, Fe/BC ratio, and Fe/BC dosage on nitrate removal efficiency and N 2 selectivity were evaluated. Results show that the introduction of microbes significantly enhanced nitrate removal and N 2 selectivity, achieving 100 % nitrate removal and 79 % N 2 selectivity. The Fe/BC/M system exhibited efficient nitrate reduction at pH of 2-10. Moreover, the Fe/BC/M system demonstrated an improved electrochemical active surface area (ECSA), lower electron transfer resistance and lower corrosion potential, leading to enhanced nitrate reduction. The high i 0 value in Fe/BC/M system means more H ads could be generated, thus improving the N 2 selectivity. This study provides valuable insights into a novel approach for effective nitrate removal, offering a potential solution to the environmental challenges posed by excessive nitrate in wastewater, surface water and ground water., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Minerals are supplemented routinely to dairy cows during the dry period to prevent metabolic issues postpartum. However, limited information exists on the impacts of mineral supplementation on colostrum carotenoids. This study aimed to determine the effects of prepartum supplementation with three micro-nutrients; inorganic selenium (INORG), organic selenium (ORG) or rumen-protected choline (RPC) on the carotenoid content of bovine colostrum and transition milk (TM) from pasture-based dairy cows. A total of 57 (12 primiparous and 45 multiparous) Holstein-Friesian (HF) and HF × Jersey (JEX) cows were supplemented daily for 49 ± 12.9 d before calving. Colostrum samples were collected from all cows immediately postpartum and TM one to five (TM1-TM5) were collected from a sub-set of 15 cows (five per treatment group) at each consecutive milking postpartum. Carotenoid concentration was determined using ultra-high performance liquid chromatography - diode array detection (UHPLC-DAD). With the use of transmittance, the colour index and colour parameters a *, b * and L * were used to determine colour variations over this period. Prepartum supplementation did not have a significant effect on colostrum β-carotene concentration or colour. Positive correlations between β-carotene and colour parameter b * ( R 2 = 0.671; P < 0.001) and β-carotene and colour index ( R 2 = 0.560; P < 0.001) were observed. Concentrations of β-carotene were highest in colostrum (1.34 μg/g) and decreased significantly with each milking postpartum (TM5 0.31 μg/g). Breed had a significant effect on colostrum colour with JEX animals producing a greater b * colostrum than HF animals ( P = 0.030). Primiparous animals produced colostrum with the weakest colour compared to second or ≥third parity animals ( P = 0.042). Despite statistical increases in the b * parameter in colostrum from JEX cows and multiparous cows, β-carotene concentrations did not significantly increase suggesting that other factors may influence colostrum colour. The b * parameter may be used as an indicator for estimating carotenoid concentrations in colostrum and TM, particularly when assessed via transmittance spectroscopy.

Hydrogels with low toxicity, antimicrobial potency and shear-thinning behavior are promising materials to combat the modern challenges of increased infections. Here, we report on 8-arm star block copolypeptides based on poly(L-lysine), poly(L-tyrosine) and poly(S-benzyl-L-cysteine) blocks. Three star block copolypeptides were synthesized with poly(S-benzyl-L-cysteine) always forming the outer block. The inner block comprised either two individual blocks of poly(L-lysine) and poly(L-tyrosine) or a statistical block copolypeptide from both amino acids. The star block copolypeptides were synthesized by the Ring Opening Polymerization (ROP) of the protected amino acid N-carboxyanhydrides (NCAs), keeping the overall ratio of monomers constant. All star block copolypeptides formed hydrogels and Scanning Electron Microscopy (SEM) confirmed a porous morphology. The investigation of their viscoelastic characteristics, water uptake and syringe extrudability revealed superior properties of the star polypeptide with a statistical inner block of L-lysine and L-tyrosine. Further testing of this sample confirmed no cytotoxicity and demonstrated antimicrobial activity of 1.5-log and 2.6-log reduction in colony-forming units, CFU/mL, against colony-forming reference laboratory strains of Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus , respectively. The results underline the importance of controlling structural arrangements in polypeptides to optimize their physical and biological properties.

The US FDA approval of trofinetide as the first pharmacological treatment to improve Rett syndrome's symptomatology marks a significant milestone with broad implications for various disorders. The LILAC trials demonstrate long-term safety and efficacy of trofinetide. 1 , 2 While further research is needed to fully resolve the condition, insights from trofinetide trials can inform strategies for future treatments and trials., Competing Interests: Declaration of interests D.T. is a consultant for Acadia through Trinity Consult. Possible earnings from this position is devoted to research. D.T. is one of the authors in the U.S. Patent: WGS Ref. No. M0656.70145US01 – “Treatment of Rett syndrome and other disorders.” However, D.T. has no financial benefits from this patent., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Preservation of residual kidney function (RKF) in dialysis patients has been associated with improved survival. RKF in the BISTRO trial was relatively well preserved and here we describe its association with survival during the trial and extended follow-up., Methods: RKF, measured as the average urea and creatinine clearance (GFR) or 24-hour urine volume was assessed at baseline, one, two and three months and three-monthly up to 2 years in incident haemodialysis patients. Time to event survival data or competing events (transplantation, modality change) were obtained for 50 months post enrolment via data linkage with the UK Renal Registry. Cox proportional hazards regression survival models, including those incorporating change in GFR from baseline as a time-varying variable and joint regression models for longitudinal and survival data (longitudinal models for GFR or urine volume) were used to explore the relationship of RKF preservation with survival. Analyses were adjusted for age, sex, comorbidity and ethnicity., Results: 2919 measures of RKF were made in 387 patients from 32 UK dialysis units. Higher age and comorbidity score associated with increased mortality in all models. Baseline GFR reduced the risk of death (Hazard Ratio: 0.918 95%CI: 0.844, 0.999) per ml/min/1.73m2. A greater fall in GFR and urine volume from baseline was associated with a non-significant increased risk of death as visualised on spline plots. In the joint survival models higher GFR (adjusted HR: 0.88 95%CI 0.80, 0.97) or urine volume (adjusted HR: 0.75 95%CI 0.57, 0.95 per L) at any time point associated with better survival., Conclusions: Lower RKF during the first two years of haemodialysis is associated with an increased death risk for up to 50 months following dialysis initiation. This adds to a growing body of evidence that interventions to preserve RKF should be developed and tested in clinical trials., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Azide functionalization of protein and peptide lysine residues allows selective bioorthogonal labeling to introduce new, site selective functionaltiy into proteins. Optimised diazotransfer reactions under mild conditions allow aqueous diazotransfer to occur in just 20 min at pH 8.5 on amino acid, peptide and protein targets. In addition, conditons can be modified to selectively label a single lysine residue in both protein targets investigated. Finally, we demonstrate selective modification of proteins containing a single azidolysine using copper(I)-catalyzed triazole formation.

The absence of established protocols for studying the in vitro performance of dissolvable microarray patches (MAPs) poses a significant challenge within the field. To overcome this challenge, it is essential to optimize testing methods in a way that closely mimics the skin's environment, ensuring biorelevance and enhancing the precision of assessing MAP performance. This study focuses on optimizing in vitro release testing (IVRT) and in vitro permeation testing (IVPT) methods for MAPs containing the antihistamine drugs loratadine (LOR) and chlorpheniramine maleate (CPM). Our primary objective is to investigate the impact of the composition of in vitro release media on the drug release rate, penetration through the skin, and permeation into the release medium. Artificial interstitial fluid is introduced as a biorelevant release medium and compared with commonly used media in IVRT and IVPT studies. Prior to these studies, we evaluated drug solubility in different release media and developed a method for LOR and CPM extraction from the skin using a design of experiment approach. Our findings highlight the effect of the in vitro release medium composition on both LOR and CPM release rate and their penetration through the skin. Furthermore, we identified the importance of considering the interplay between the physicochemical attributes of the drug molecules, the design of the MAP formulation, and the structural properties of the skin when designing IVRT and IVPT protocols.

Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in [Formula: see text]-band spectral power over time in the temporal region along with increased [Formula: see text]-band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS., (© 2024. The Author(s).)

Complex microbiomes are part of the food we eat and influence our own microbiome, but their diversity remains largely unexplored. Here, we generated the open access curatedFoodMetagenomicData (cFMD) resource by integrating 1,950 newly sequenced and 583 public food metagenomes. We produced 10,899 metagenome-assembled genomes spanning 1,036 prokaryotic and 108 eukaryotic species-level genome bins (SGBs), including 320 previously undescribed taxa. Food SGBs displayed significant microbial diversity within and between food categories. Extension to >20,000 human metagenomes revealed that food SGBs accounted on average for 3% of the adult gut microbiome. Strain-level analysis highlighted potential instances of food-to-gut transmission and intestinal colonization (e.g., Lacticaseibacillus paracasei) as well as SGBs with divergent genomic structures in food and humans (e.g., Streptococcus gallolyticus and Limosilactobabillus mucosae). The cFMD expands our knowledge on food microbiomes, their role in shaping the human microbiome, and supports future uses of metagenomics for food quality, safety, and authentication., Competing Interests: Declaration of interests D.O. is an employee of QIAGEN GmbH. E.S.K. is an employee of BaseClear B.V., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study aimed to develop hyaluronan (HA)-based hydrogel microparticles (MPs) loaded with hemin to address the limitations of traditional macroscale hydrogels. The objective is to design MPs such that they can modulate their physicochemical properties. Given the widespread use of ultraviolet C (UVC) light in various industries and the need for protective measures against accidental exposure, this study evaluated the potential of hemin-loaded MPs to protect human dermal fibroblasts from oxidative stress and cell death caused by UVC exposure. Multiple MP formulations were developed and analysed for size, surface charge, swelling behaviour, degradation rate, and radical scavenging capabilities, both with and without hemin loading. The most promising formulations were tested against UVC-exposed cells to assess cell viability, intracellular nitric oxide (˙NO) and reactive oxygen species levels, and protein carbonylation. The fabricated particles were in the form of microneedles, and the degree of their crosslinking and the role of hemin in the chemical crosslinking reaction were found to influence the surface charge and hydrodynamic diameter of the MPs. Increased crosslinking resulted in reduced swelling, slower degradation, and decreased hemin release rate. MPs with a higher degree of swelling were capable of releasing hemin into the culture medium, leading to enhanced bilirubin generation in dermal fibroblasts following cellular uptake. Pre-treatment with these MPs protected the cells from UVC-induced cell death, nitrosative stress, and protein carbonylation. These findings highlight the potential of the studied MPs to release hemin and to minimise the harmful effects of UVC on dermal fibroblasts.

Fish protein hydrolysates (FPHs) were obtained from different fish sources using a combination of microbial enzymes. The industrially produced FPHs from blue whiting ( Micromesistius poutassou ) and sprat ( Sprattus sprattus ) were compared to freeze-dried FPHs generated in-house from hake ( Merluccius merluccius ) and mackerel ( Scomber scombrus ) in terms of their physicochemical composition and functionality. Significant differences ( p < 0.05) were observed in the protein, moisture, and ash contents of the FPHs, with the majority having high levels of protein (73.24-89.31%). Fractions that were more extensively hydrolysed exhibited a high solubility index (74.05-98.99%) at different pHs. Blue whiting protein hydrolysate-B (BWPH-B) had the highest foaming capacity at pH 4 (146.98 ± 4.28%) and foam stability over 5 min (90-100%) at pH 4, 6, and 8. The emulsifying capacity ranged from 61.11-108.90 m 2 /g, while emulsion stability was 37.82-76.99% at 0.5% ( w / v ) concentration. In terms of peptide bioactivity, sprat protein hydrolysate (SPH) had the strongest overall reducing power. The highest Cu 2+ chelating activity was exhibited by hake protein hydrolysate (HPH) and mackerel protein hydrolysate (MPH), with IC 50 values of 0.66 and 0.78 mg protein/mL, respectively, while blue whiting protein hydrolysate-A (BWPH-A) had the highest activity against Fe 2+ (IC 50 = 1.89 mg protein/mL). SPH scavenged DPPH and ABTS radicals best with IC 50 values of 0.73 and 2.76 mg protein/mL, respectively. All FPHs displayed noteworthy scavenging activity against hydroxyl radicals, with IC 50 values ranging from 0.48-3.46 mg protein/mL. SPH and MPH showed the highest scavenging potential against superoxide radicals with IC 50 values of 1.75 and 2.53 mg protein/mL and against hydrogen peroxide with 2.22 and 3.66 mg protein/mL, respectively. While inhibition of α-glucosidase was not observed, the IC 50 values against α-amylase ranged from 8.81-18.42 mg protein/mL, with SPH displaying the highest activity. The stability of FPHs following simulated gastrointestinal digestion (SGID) showed an irregular trend. Overall, the findings suggest that marine-derived protein hydrolysates may serve as good sources of natural nutraceuticals with antioxidant and antidiabetic properties.

Technological innovation yielded opportunities to obtain mRNA expression data for prostate cancer (PCa) patients even prior to biopsy, which can be used in a precision medicine approach to treatment decision-making. This can apply in particular to predict the risk of, and time to biochemical recurrence (BCR). Most mRNA-based models currently proposed to this end are designed for risk classification and post-operative prediction. Effective pre-operative prediction would facilitate early treatment decision-making, in particular by indicating more appropriate therapeutic pathways for patient profiles who would likely not benefit from a systematic prostatectomy regime. The aim of this study is to investigate the possibility to leverage mRNA information pre-operatively for BCR-free survival prediction. To do this, we considered time-to-event machine learning (ML) methodologies, rather than classification models at a specific survival horizon. We retrospectively analysed a cohort of 135 patients with clinical follow-up data and mRNA information comprising over 26,000 features (data accessible at NCBI GEO database, accession GSE21032). The performance of ML models including random survival forest, boosted and regularised Cox models were assessed, in terms of model discrimination, calibration, and predictive accuracy for overall, 3-year and 5-year survival, aligning with common clinical endpoints. Results showed that the inclusion of mRNA information could yield a gain in performance for pre-operative BCR prediction. ML-based time-to-event models significantly outperformed reference nomograms that used only routine clinical information with respect to all metrics considered. We believe this is the first study proposing pre-operative transcriptomics models for BCR prediction in PCa. External validation of these findings, including confirmation of the mRNA variables identified as potential key predictors in this study, could pave the way for pre-operative precision nomograms to facilitate timely personalised clinical decision-making., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 O’Donnell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although routine two-dimensional (2D) cell culture techniques have advanced basic cancer research owing to their simplicity, cost-effectiveness, and reproducibility, they have limitations that necessitate the development of advanced three-dimensional (3D) tumor models that better recapitulate the tumor microenvironment. Various biomaterials have been used to establish these 3D models, enabling the study of cancer cell behavior within different matrices. Hyaluronic acid (HA), a key component of the extracellular matrix (ECM) in tumor tissues, has been widely studied and employed in the development of multiple cancer models. This review first examines the role of HA in tumors, including its function as an ECM component and regulator of signaling pathways that affect tumor progression. It then explores HA-based models for various cancers, focusing on HA as a central component of the 3D matrix and its mobilization within the matrix for targeted studies of cell behavior and drug testing. The tumor models discussed included those for breast cancer, glioblastoma, fibrosarcoma, gastric cancer, hepatocellular carcinoma, and melanoma. The review concludes with a discussion of future prospects for developing more robust and high-throughput HA-based models to more accurately mimic the tumor microenvironment and improve drug testing. Impact Statement This review underscores the transformative potential of hyaluronic acid (HA)-based hydrogels in developing advanced tumor models. By exploring HA's dual role as a critical extracellular matrix component and a regulator of cancer cell dynamics, we highlight its unique contributions to replicating the tumor microenvironment. The recent advancements in HA-based models provide new opportunities for more accurate studies of cancer cell behavior and drug responses. Looking ahead, these innovations pave the way for high-throughput, biomimetic platforms that could revolutionize drug testing and accelerate the discovery of effective cancer therapies.