bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted neural stimulation congruent with immersive reality decreases neuropathic pain – a Randomized Controlled Trial
Authors: Aurucci Giuseppe Valerio , Gozzi Noemi , Wagner Markus , Preatoni Greta , Brunello Nicola , Secerovic Natalija , Zipser Carl Moritz , Raspopovic Stanisa 
Published: December 2024

ABSTRACTBackgroundChronic neuropathic pain is a complex experience, posing a major challenge in personalizing its treatment. Present treatments consist of non-specific, standardized drugs that are often addictive, leaving many patients non-respondent and with significant side effects. Designing individualized therapies requires targeting the multidimensionality of pain and developing objective endpoints to demonstrate their effectiveness. Currently, non-pharmacological alternatives are emerging, such as neurostimulation and Virtual Reality (VR), activating pain relief via peripheral neuromodulation and attention modulation. Similarly to drugs, many neurostimulation approaches are unspecific, targeting areas near the pain site and disregarding the neural pathway of pain. Above all, neurostimulation and VR are yet to be evaluated as a combined synergistic intervention, particularly in a randomized controlled trial (RCT).Methods and FindingsTo this aim, we developed a targeted neurostimulation congruent with immersive VR platform providing a multisensory pain intervention through the synergistic application of somatotopic electro-tactile and visual stimuli. The endpoints included measuring sensory, neurophysiological (EEG), and self-reported indicators of pain. We tested the efficacy of the multisensory intervention against the control consisting of VR-only intervention on four consecutive intervention days in an RCT (N=18 neuropathic patients). The multisensory intervention resulted in a clinically significant reduction of pain (>50%), lasting up to one-week follow-up. The provided analgesic effect was statistically stronger compared to the VR-only control across treatment days and at follow-up. The clinically relevant pain decrease was accompanied with objective improvements in tactile acuity, proprioceptive measures, and changes in EEG pain biomarkers for the multisensory intervention group only.ConclusionsThe developed multisensory treatment showed a clinically significant reductions in self-reported pain, supported by improvements in objective sensory and neurophysiological measures. These results represent a significant advancement in the treatment and assessment of pain, offering a non-invasive, accessible, and cost-effective solution for neuropathic pain, a major societal burden and one of the most prevalent neurological conditions worldwide.Clinical trial registrationThe trial was registered withClinicalTrial.gov(NCT05483816).
Harnessing methods, data analysis, and near-real-time wastewater monitoring for enhanced public health response using high throughput sequencing
Authors: Ramachandran Padmini , Kayikcioglu Tunc , Walsky Tamara , Judy Kathryn , Amirzadegan Jasmine , Bias Candace Hope , Tesfaldet Bereket , Balkey Maria , EppSchmidt Dietrich , Rand Hugh , Pettengill James , Tallent Sandra , Brown Eric , Pfefer Tina , Timme Ruth , Windsor Amanda , Grim Christopher , Hoffmann Maria 
Published: December 2024

AbstractWastewater-based analysis has emerged as a pivotal method for monitoring SARS-CoV-2 (SC2). Leveraging high-throughput sequencing on wastewater samples facilitates a comprehensive, population-level assessment of circulating and emerging SC2 variants within a community. This study meticulously evaluates the detection performance, variant calling accuracy, and the time taken from sample collection to public data release for wastewater SC2 monitoring. We employed two different SC2 target enrichment panels on Illumina MiSeq and Oxford Nanopore Technologies (ONT) GridION sequencing platforms for a robust analysis. Daily collection of routine raw grab and composite samples took place at a wastewater treatment plant (WWTP) site in Maryland, USA (MD) from mid-January 2022 to the end of June 2022. Total Nucleic Acid (TNA) was extracted from samples and target enrichment was executed using QIAseq DIRECT and NEBNext VarSkip Short amplicon kits, with subsequent sequencing on MiSeq or ONT GridION platforms, respectively. Obtained sequences was analyzed using our custom CFSAN Wastewater Analysis Pipeline (C-WAP). Raw sequence data and detailed metadata were submitted to NCBI (BioProject PRJNA757291) as it became available. Our wastewater data successfully detected the onset of new variants BA.2, BA.2.12, BA.4.6, and BA.5 to the observed population. Notably, Omicron sub-variants were identified approximately a week ahead of publicly available clinical data at the MD ZIP-code level. Variation in quality metrics paralleled the rise and fall of BA waves, underscoring the impact of viral load on sequencing quality. Regular updates of estimated variant proportions were made available on the FDA-CFSAN “Wastewater Surveillance for SARS-CoV-2 Variants” website. In contrast to the median 28-day turnaround for our samples, the lead time from sample collection to public release of raw sequence data via NCBI was remarkably swift, accomplished within a mere 57 hours in this specific exercise. Our processing, sequencing, and analysis methods empowered the swift and accurate detection of SC2 trends and circulating variants within a community, offering insights for public health decision-making.
A Cohort Study of Urinary Tract Infections in People Living with Dementia: Epidemiology and Diagnostic Challenges
Authors: Jackson Raphaella , Tran Martin , Jensen Kirsten , Crone Michael A. , Webb Alexander J. , Cameron Loren P. , Nilforooshan Ramin , Wingfield David , Sharp David J. , Freemont Paul S. 
Published: December 2024

AbstractBackgroundUrinary tract infections (UTIs) are a leading cause of hospitalization in people living with dementia, making accurate detection and prompt treatment critical in this vulnerable population.MethodsThis retrospective, longitudinal cohort study evaluated the diagnostic accuracy of self-reported symptoms and urine dipstick test results for identifying UTIs in people with dementia. Participants included 78 community-dwelling individuals over the age of 50 with a confirmed dementia diagnosis. These participants were recruited from cohorts established by the Surrey and Borders Partnership NHS Foundation Trust and the Hammersmith & Fulham Partnership Primary Care Network between late 2019 and 2023.ResultsThe frequency of UTIs in people living with dementia (PLWD) is highly variable, some individuals having nearly chronic infections and others not acquiring a single UTI during their enrolment in the study. The taxonomy of the microbes associated with the urinary tract infections in this cohort were consistent with those that have been observed in other demographics. When we modelled the relationship between self-reported symptoms, dipstick results, and the presence of UTIs we found that there was no significant relationship between UTI and symptoms. However, there was a highly significant correlation between dipstick test results positive for leucocytes and nitrites with the presence of a UTI.ConclusionsUrine dipstick tests for nitrites and leucocytes should be incorporated into diagnostic protocols and should also be considered for ongoing surveillance of UTIs in people living with dementia.Study Registration NumbersResearch Ethics Committee (REC) reference: 19/LO/0102Integrated Research Application System (IRAS) project ID: 257561
Evolution of child acute malnutrition during war in the Gaza Strip, 2023-2024: retrospective estimates and scenario-based projections
Authors: Checchi Francesco , Jamaluddine Zeina 
Published: December 2024

AbstractBackgroundNutritional status has been compromised by ongoing war and restrictions on food deliveries in the Gaza Strip. We developed a mathematical model that outputs retrospective estimates and scenario-based projections of acute malnutrition prevalence among children given caloric intake and other factors. We present here the model and its application to the crisis in Gaza.MethodsWe extended an existing mechanistic model for weight change as a function of energy balance, calibrating it to represent variability in growth curves observed in pre-war Gaza. We simulated open cohorts of children exposed to time-varying caloric intake, infant exclusive breastfeeding prevalence, incidence of infectious disease and coverage of malnutrition treatment, while allowing for adult caloric sacrifice to supplement child intake in times of food scarcity.Results and conclusionsThe model accurately replicates growth standards, pre-war growth patterns and expected parameter dependencies. It suggests that a considerable increase in acute malnutrition occurred in northern Gaza during early 2024. Projections for late 2024 include a serious nutritional emergency if relatively pessimistic assumptions are made about food availability. The model may hold considerable promise for informing decisions in humanitarian response but requires further validation and development.
Unseen Yet Overcounted: The Paradox of Seizure Frequency Reporting
Authors: Wong Victoria , Hannon Timothy , Fernandes Kiran M. , Cook Mark J. , Nurse Ewan S. 
Published: December 2024

AbstractObjectiveSeizure control is often assessed using patient-reported seizure frequencies. Despite its subjectivity, self-reporting remains essential for guiding anti-seizure medication (ASM) decisions and ongoing patient investigations. Additionally, clinical trials frequently rely on self-reported seizure rates for participant selection and outcome measures. This study aims to compare patient-reported seizure frequencies with electrographic frequencies captured via ambulatory video EEG (avEEG).MethodsData from intake forms and seizure diaries were collected from patients undergoing home-based avEEG in Australia (April 2020–April 2022). Intake forms included monthly seizure frequency estimates. Only avEEG-confirmed epilepsy cases were analyzed. Univariate and multivariate analyses compared seizure frequencies reported via EEG, diaries, and surveys.ResultsOf 3,407 reports, 853 identified epilepsy cases, with 234 studies analyzed after excluding outliers. Diary-reported frequencies correlated with EEG frequency (p<0.00001), but survey-reported frequencies did not (p>0.05). Surveys significantly overestimated seizure frequency (median = 3.98 seizures/month, p<0.0001), while diaries showed substantially smaller differences (median = 0.01 seizures/month, p<0.0001). Carer presence was associated with higher diary-reported frequencies (p=0.047). Age negatively correlated with survey frequency estimation error (p=0.016). Multivariate analysis identified age and carer status as significant predictors of residuals.ConclusionsMost patients overestimate their seizure frequency, influencing therapeutic decisions and raising concerns about the reliability of self-reported data in clinical trials.SignificanceAn “over-reporting, over-prescribing” cascade may affect epilepsy treatment and highlights the issue of clinical drug trials relying on self-reported seizure rates.Key pointsSelf-reported seizure frequencies often differ from electrographic seizure frequencies captured by avEEG.Survey reports tend to overestimate seizure frequency compared to EEG, while diary reports show smaller discrepancies.Carer presence is associated with higher reported seizure frequencies in diaries.Older age is weakly negatively correlated with the overestimation of seizures in surveys.Over-reporting of seizures may influence clinical decision-making and the reliability of clinical trial outcomes using self-reported data.
Acute psychosis and the risk of motor vehicle crash
Authors: Staples John A , Daly-Grafstein Daniel , Khan Mayesha , Erdelyi Shannon , Chan Herbert , Honer William G. , Brubacher Jeffrey R 
Published: December 2024

ABSTRACTImportanceLimited empirical evidence guides fitness-to-drive decision-making following an episode of acute psychosis.ObjectiveTo evaluate the association between acute psychosis and subsequent crash risk.DesignRetrospective observational analyses using 20 years of population-based administrative health and driving data. We first assessed the association between psychosis and collisions using a case-crossover design, which controls for relatively fixed individual characteristics like personality, driving experience and routine driving habits. Next, we conducted a responsibility analysis which accounts for the changes in road exposure (miles of driving per month) that might occur after recent hospitalization.SettingBritish Columbia, Canada.ParticipantsDrivers with a police-attended motor vehicle crash, 2000-2016.ExposureA hospital stay for acute psychosis ending in the 6-week interval prior to crash.Main Outcomes and MeasuresThe case-crossover analysis examined crash involvement as a driver. The responsibility analysis examined driver responsibility for contributing to their crash. We used logistic regression with adjustment for potential confounders to evaluate associations between outcomes and recent acute psychosis.ResultsAmong 9842 crashes in the case-crossover analysis, a hospital stay for acute psychosis ended in 199 pre-crash intervals and in 147 control intervals, suggesting acute psychosis was temporally associated with subsequent crash (2.0% vs 1.5% of intervals; adjusted odds ratio (aOR), 1.32; 95%CI, 1.05-1.66; p=0.02). Among 819,348 drivers with a police-attended crash and determinate crash responsibility, 178 of 235 drivers with a recent hospitalization for acute psychosis and 440,543 of 819,113 drivers without recent psychosis were deemed responsible for their crash (75.7% vs 53.8%; aOR, 2.38; 95%CI, 1.75-3.24; p<0.001).ConclusionsThe 6-week interval following a hospitalization for acute psychosis is associated with increased odds of crash and increased likelihood of a driver being deemed responsible for contributing to their crash. More stringent temporary driving restrictions after an episode of acute psychosis might reduce crash risk.KEY POINTSQuestionsDoes a recent episode of acute psychosis increase a driver’s likelihood of being involved in a motor vehicle crash?FindingsUsing population-based administrative health and driving data, investigators found that the odds of crash were higher in the first 6 weeks after a hospital stay for acute psychosis than during control periods. A responsibility analysis accounting for changes in road exposure found drivers were also more likely to be deemed responsible for contributing to their crash during this period.MeaningMore stringent driving restrictions in the first 6 weeks after an episode of acute psychosis might reduce crash risk.
Impact of the Covid-19 pandemic on elective and trauma orthopaedic surgery in a tertiary referral hospital in Kenya: A retrospective cross-sectional study
Authors: Baraza Njalalle , Odari Ian , Lomole Emmanuel Marsuk , Karanja Sarah , Ating’a Mordicai 
Published: December 2024

ABSTRACTThe impact of the COVID-19 pandemic is still being felt in multiple spheres of life. In healthcare, COVID-19 noticeably affected surgical practice in sub-Saharan Africa indicated by a reduction in elective cases with prioritisation of cancer and emergency cases. This study sought to describe the impact of COVID-19 on orthopaedic surgery volumes in a private tertiary referral hospital.Ethical approval was obtained for this retrospective cross-sectional study carried out at the Aga Khan University Hospital, Nairobi. The orthopaedic data was collected using the Electronic Healthcare Record (EHR) system in the hospital. Elective and trauma caseloads recorded during COVID-19 were compared with similar quarters in the pre and post COVID-19 periods.In the third quarter before the COVID-19 pandemic, there were 15 arthroplasty, 53 arthroscopy and 31 implant removal cases. During the pandemic, there was an expected fall in the numbers of procedures by 33%, 30% and 13% respectively compared to the previous (pre pandemic) year. There was also the expected drop in the number of adult trauma cases, however, there was an increase in paediatric fracture fixation with k-wires. In spinal surgery, there was a 71% increase in the number of laminectomies and anterior cervical decompression and fusions (ACDF) from the pre pandemic 21 cases recorded.The COVID-19 pandemic had an impact on elective and emergency orthopaedic procedure volumes. There was a reduction in the number of elective arthroplasty, arthroscopy, nailing and orthopaedic implant removal procedures. On the other hand there was a significant increase in the number of paediatric fracture fixation and with K-wires and ACDF/laminectomy volumes.
Wnt target IQGAP3 promotes Wnt signaling via disrupting Axin1-CK1α interaction
Authors: Rahmat Muhammad Bakhait , Hussain Aashiq , Xuan Teh Yu , Dutta Bibek , Pundrik Sumedha , Kappei Dennis , Ito Yoshiaki 
Published: December 2024

ABSTRACTThe scaffold protein IQGAP3 is highly upregulated in most epithelial cancers. While recent studies have highlighted its pivotal roles in cancer cell proliferation and metastasis, a deeper mechanistic understanding of IQGAP3 is currently lacking. We have here used TurboID to map IQGAP3 proximity partners and identified the Wnt signaling members Axin1 and CK1α as IQGAP3-interacting proteins. Our functional studies demonstrated that overexpression of IQGAP3 increases β-catenin levels, while IQGAP3 depletion reduces β-catenin levels in gastric cancer cells. Mechanistically, IQGAP3 disrupts Axin1-CK1α interaction, thereby inhibiting β- catenin phosphorylation and ultimately leading to its accumulation. Importantly, we discovered that IQGAP3 itself is regulated by Wnt signaling, suggesting its involvement in a positive feedback loop in Wnt/β-catenin signaling through interactions with Axin1 and CK1α. These findings identify IQGAP3 as a novel mediator of β-catenin stabilization and underscore its potential as a target for cancer therapy.
Cytoplasmic calcium influx mediated by Lr14a regulates stomatal immunity against leaf rust in wheat
Authors: Yue Lili , Wang Limin , Neuhäuser Benjamin , Zhang Songyuan , Herren Gerhard , Heuberger Matthias , Jung Esther , Ludewig Uwe , Zipfel Cyril , Keller Beat 
Published: December 2024

AbstractThe race-specific resistance geneLr14ain wheat confers a unique type of heterogenous resistance reaction. It encodes an ankyrin-repeat transmembrane domain protein that confers immunity against the fungal pathogenPuccinia triticina. Here, we show that Lr14a functions as a calcium-permeable channel, mediating cytoplasmic Ca²⁺ influx that is crucial for leaf rust resistance in wheat. Infection with avirulent isolates inducedLr14aexpression predominantly in mesophyll cells while triggering cell death in guard cells in wheat. This study revealed a mechanism by which the product of anRgene regulates stomatal immunity non-cell autonomously through the mediation of calcium signaling.
Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state
Authors: Hyvärinen Tanja , Lotila Johanna , Giudice Luca , Tujula Iisa , Nylund Marjo , Ohtonen Sohvi , Scoyni Flavia , Jäntti Henna , Pihlava Sara , Skottman Heli , Narkilahti Susanna , Airas Laura , Malm Tarja , Hagman Sanna 
Published: December 2024

AbstractAberrant and sustained activation of microglia is implicated in the progression and severity of multiple sclerosis (MS). However, whether intrinsic alterations in microglial function impact the pathogenesis of this disease remains unclear.We conducted transcriptomic and functional analyses of microglia-like cells (iMGLs) differentiated from induced pluripotent stem cells (iPSCs) from patients with MS (pwMS) to answer this question.We generated iPSCs from six pwMS showing increased microglial activity via translocator protein (TSPO)-PET imaging. We demonstrated that the differentiated iMGL transcriptional profile resembled the microglial signature found in MS lesions. Importantly, compared with healthy controls, MS iMGLs presented cell-autonomous differences in their regulation of inflammation, both in the basal state and following inflammatory lipopolysaccharide challenge. Through transcriptomic profiling, we showed that MS iMGLs display increased expression of genes known to be upregulated in MS microglia. Furthermore, upregulated genes in MS iMGLs were associated with immune receptor activation, antigen presentation, and the complement system, with known MS implications. Finally, functional analyses indicated that the transcriptional changes in MS iMGLs corresponded with alterations in the secretion of inflammatory cytokines and chemokines and increased phagocytosis.Together, our results provide evidence of putative cell-autonomous microglial activation in pwMS and identify transcriptomic and functional changes that recapitulate the phenotypes observedin vivoin microglia from pwMS. These findings indicate that MS disease-specific iPSCs are valuable tools for studying disease-specific microglial activationin vitroand highlight microglia as potential therapeutic targets in MS.
Engineering a Biosynthetic Pathway for the Production of (+)-Brevianamides A and B inEscherichia coli
Authors: Sandoval Hurtado Casandra P , Kelly Samantha P , Shende Vikram , Perez Makayla , Curtis Brian J , Newmister Sean A , Ott Kaleb , Pereira Filipa , Sherman David H 
Published: December 2024

AbstractThe privileged fused-ring system comprising the bicyclo[2.2.2]diazaoctane (BDO) core is prevalent in diketopiperazine (DKP) natural products with potent and diverse biological activities, with some being explored as drug candidates. Typically, only low yields of these compounds can be extracted from native fungal producing strains and the available synthetic routes remain challenging due to their structural complexity. BDO-containing DKPs including (+)-brevianamides A and B are assembled via multi-component biosynthetic pathways incorporating non-ribosomal peptide synthetases, prenyltransferases, flavin monooxygenases, cytochrome P450s and semi-pinacolases. To simplify access to this class of alkaloids, we designed an engineered biosynthetic pathway inEscherichia coli, composed of six enzymes sourced from different kingdoms of life. The pathway includes a cyclodipeptide synthase (NascA), a cyclodipeptide oxidase (DmtD2/DmtE2), a prenyltransferase (NotF), a flavin-dependent monooxygenase (BvnB), and kinases (PhoN and IPK). Cultivated in glycerol supplemented with prenol, the engineeredE. colistrain produces 5.3 mg/L of (-)-dehydrobrevianamide E (4), which undergoes a terminal,ex vivolithium hydroxide catalyzed rearrangement reaction to yield (+)-brevianamides A and B with a 46% yield and a 92:8 diastereomeric ratio. Additionally, titers of4were increased eight-fold by enhancing NADPH pools in the engineeredE. colistrain. Our study combines synthetic biology, biocatalysis and synthetic chemistry approaches to provide a five-step engineered biosynthetic pathway for producing complex indole alkaloids inE. coli.Abstract Figure
Enhancing RNA Delivery: Practical Insights into NeoLNP™ Transfection Reagent
Authors: Chen Xiaobao , Wu Yan , Liu Li , Wang Wei 
Published: December 2024

AbstractThe rapid advancement of RNA-based therapeutics, particularly in the wake of COVID-19 vaccine success, has prompted significant research into optimizing RNA delivery mechanisms. This study evaluates the NeoLNP™ RNA Transfection Kit developed by Scindy Pharmaceutical, which utilizes lipid nanoparticles (LNPs) for efficient RNA encapsulation and delivery. We systematically investigate various parameters affecting transfection efficiency, including RNA concentration, RNA/LNP volume ratios, mixing techniques, LNP stability, and culture media. Our results demonstrate that the optimal RNA concentration for transfection efficiency is around 40-60 ng/µL, with a 1:0.75-1:1 RNA-to-LNP ratio yielding the highest protein expression. Additionally, we find that gentle mixing techniques outperform harsher methods, and the stability of LNP-RNA complexes significantly influences transfection outcomes. This research provides practical guidelines for enhancing RNA transfection efficiency, paving the way for more effective RNA therapeutics.