The role of the (in)accessibility of social media data for infodemic management: a public health perspective on the situation in the European Union in March 2024.

Public health institutions rely on the access to social media data to better understand the dynamics and impact of infodemics - an overabundance of information during a disease outbreak, potentially including mis-and disinformation. The scope of the COVID-19 infodemic has led to growing concern in the public health community. The spread of harmful information or information voids may negatively impact public health. In this context, social media are of particular relevance as an integral part of our society, where much information is consumed. In this perspective paper, we discuss the current state of (in)accessibility of social media data of the main platforms in the European Union. The European Union's relatively new Digital Services Act introduces the obligation for platforms to provide data access to a wide range of researchers, likely including researchers at public health institutions without formal academic affiliation. We examined eight platforms (Facebook, Instagram, LinkedIn, Pinterest, Snapchat, TikTok, X, YouTube) affected by the new legislation in regard to data accessibility. We found that all platforms apart from TikTok offer data access through the Digital Services Act. Potentially, this presents a fundamentally new situation for research, as before the Digital Services Act, few platforms granted data access or only to very selective groups of researchers. The access regime under the Digital Services Act is, however, still evolving. Specifics such as the application procedure for researcher access are still being worked out and results can be expected in spring 2024. The impact of the Digital Services Act on research will therefore only become fully apparent in the future.

Benzodiazepine Boom: Tracking Etizolam, Pyrazolam, and Flubromazepam from Pre-UK Psychoactive Act 2016 to Present Using Analytical and Social Listening Techniques.

INTRODUCTION: The designer benzodiazepine (DBZD) market continues to expand whilst evading regulatory controls. The widespread adoption of social media by pro-drug use communities encourages positive discussions around DBZD use/misuse, driving demand. This research addresses the evolution of three popular DBZDs, etizolam (E), flubromazepam (F), and pyrazolam (P), available on the drug market for over a decade, comparing the quantitative chemical analyses of tablet samples, purchased from the internet prior to the implementation of the Psychoactive Substances Act UK 2016, with the thematic netnographic analyses of social media content. METHOD: Drug samples were purchased from the internet in early 2016. The characterisation of all drug batches were performed using UHPLC-MS and supported with 1H NMR. In addition, netnographic studies across the platforms X (formerly Twitter) and Reddit, between 2016-2023, were conducted. The latter was supported by both manual and artificial intelligence (AI)-driven thematic analyses, using numerous.ai and ChatGPT, of social media threads and discussions. RESULTS: UHPLC-MS confirmed the expected drug in every sample, showing remarkable inter/intra batch variability across all batches (E = 13.8 ± 0.6 to 24.7 ± 0.9 mg; F = 4.0 ± 0.2 to 23.5 ± 0.8 mg; P = 5.2 ± 0.2 to 11.5 ± 0.4 mg). 1H NMR could not confirm etizolam as a lone compound in any etizolam batch. Thematic analyses showed etizolam dominated social media discussions (59% of all posts), with 24.2% of posts involving sale/purchase and 17.8% detailing new administration trends/poly-drug use scenarios. Artificial intelligence confirmed three of the top five trends identified manually. CONCLUSIONS: Purity variability identified across all tested samples emphasises the increased potential health risks associated with DBZD consumption. We propose the global DBZD market is exacerbated by surface web social media discussions, recorded across X and Reddit. Despite the appearance of newer analogues, these three DBZDs remain prevalent and popularised. Reporting themes on harm/effects and new developments in poly-drug use trends, demand for DBZDs continues to grow, despite their potent nature and potential risk to life. It is proposed that greater controls and constant live monitoring of social media user content is warranted to drive active regulation strategies and targeted, effective, harm reduction strategies.

WITHDRAWN: ALERRT's "BATH" Assessment Algorithm No Longer Meets the Needs of American Law Enforcement Personnel or the Public They Serve.

This article has been witdrawn at the request of the author(s). The Publisher apologizes for any inconvenience this may cause.

A Visual, In-Expensive, and Wireless Capillary Rheometer for Characterizing Wholly-Cellular Bioinks.

Rheological measurements with in situ visualization can elucidate the microstructural origin of complex flow behaviors of an ink. However, existing commercial rheometers suffer from high costs, the need for dedicated facilities for microfabrication, a lack of design flexibility, and cabling that complicates operation in sterile or enclosed environments. To address these limitations, a low-cost ($300) visual, in-expensive and wireless rheometer (VIEWR) using 3D-printed and off-the-shelf components is presented. VIEWR measurements are validated by steady-state and transient flow responses for different complex fluids, and microstructural flow profiles and evolution of yield-planes are revealed via particle image velocimetry. Using the VIEWR, a wholly-cellular bioink system comprised of compacted cell aggregates is characterized, and complex yield-stress and viscoelastic responses are captured via concomitantly visualizing the spatiotemporal evolution of aggregate morphology. A symmetric hyperbolic extensional-flow geometry is further constructed inside a capillary tube using digital light processing. Such geometries allow for measuring the extensional viscosity at varying deformation rates and further visualizing the alignment and stretching of aggregates under external flow. Synchronized but asymmetric evolution of aggregate orientation and strain through the neck is visualized. Using varying geometries, the jamming and viscoelastic deformation of aggregates are shown to contribute to the extensional viscosity of the wholly-cellular bioinks.

Control of CCR5 Cell-Surface Targeting by the PRAF2 Gatekeeper.

The cell-surface targeting of neo-synthesized G protein-coupled receptors (GPCRs) involves the recruitment of receptors into COPII vesicles budding at endoplasmic reticulum exit sites (ERESs). This process is regulated for some GPCRs by escort proteins, which facilitate their export, or by gatekeepers that retain the receptors in the ER. PRAF2, an ER-resident four trans- membrane domain protein with cytoplasmic extremities, operates as a gatekeeper for the GB1 protomer of the heterodimeric GABAB receptor, interacting with a tandem di-leucine/RXR retention motif in the carboxyterminal tail of GB1. PRAF2 was also reported to interact in a two-hybrid screen with a peptide corresponding to the carboxyterminal tail of the chemokine receptor CCR5 despite the absence of RXR motifs in its sequence. Using a bioluminescence resonance energy transfer (BRET)-based subcellular localization system, we found that PRAF2 inhibits, in a concentration-dependent manner, the plasma membrane export of CCR5. BRET-based proximity assays and Co-IP experiments demonstrated that PRAF2/CCR5 interaction does not require the presence of a receptor carboxyterminal tail and involves instead the transmembrane domains of both proteins. The mutation of the potential di-leucine/RXR motif contained in the third intracellular loop of CCR5 does not affect PRAF2-mediated retention. It instead impairs the cell-surface export of CCR5 by inhibiting CCR5's interaction with its private escort protein, CD4. PRAF2 and CD4 thus display opposite roles on the cell-surface export of CCR5, with PRAF2 inhibiting and CD4 promoting this process, likely operating at the level of CCR5 recruitment into COPII vesicles, which leave the ER.

Pharmacological Inhibition of PTEN Rescues Dopaminergic Neurons by Attenuating Apoptotic and Neuroinflammatory Signaling Events.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN's novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1ß (IL-1ß) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD.

Rapid model-guided design of organ-scale synthetic vasculature for biomanufacturing.

Our ability to produce human-scale bio-manufactured organs is critically limited by the need for vascularization and perfusion. For tissues of variable size and shape, including arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion has posed a major hurdle. Here, we introduce a model-driven design pipeline combining accelerated optimization methods for fast synthetic vascular tree generation and computational hemodynamics models. We demonstrate rapid generation, simulation, and 3D printing of synthetic vasculature in complex geometries, from small tissue constructs to organ scale networks. We introduce key algorithmic advances that all together accelerate synthetic vascular generation by more than 230 -fold compared to standard methods and enable their use in arbitrarily complex shapes through localized implicit functions. Furthermore, we provide techniques for joining vascular trees into watertight networks suitable for hemodynamic CFD and 3D fabrication. We demonstrate that organ-scale vascular network models can be generated in silico within minutes and can be used to perfuse engineered and anatomic models including a bioreactor, annulus, bi-ventricular heart, and gyrus. We further show that this flexible pipeline can be applied to two common modes of bioprinting with free-form reversible embedding of suspended hydrogels and writing into soft matter. Our synthetic vascular tree generation pipeline enables rapid, scalable vascular model generation and fluid analysis for bio-manufactured tissues necessary for future scale up and production.

Does lower extremity fracture fixation technique influence neurologic outcomes in patients with traumatic brain injury? The EAST Brain vs. Bone multicenter trial.

OBJECTIVE: This study aimed to determine whether lower extremity fracture fixation technique and timing (≤24 vs. >24 hours) impact neurologic outcomes in TBI patients. METHODS: A prospective observational study was conducted across 30 trauma centers. Inclusion criteria were age 18 years and older, head Abbreviated Injury Scale (AIS) score of >2, and a diaphyseal femur or tibia fracture requiring external fixation (Ex-Fix), intramedullary nailing (IMN), or open reduction and internal fixation (ORIF). The analysis was conducted using analysis of variamce, Kruskal-Wallis, and multivariable regression models. Neurologic outcomes were measured by discharge Ranchos Los Amigos Revised Scale (RLAS-R). RESULTS: Of the 520 patients enrolled, 358 underwent Ex-Fix, IMN, or ORIF as definitive management. Head AIS was similar among cohorts. The Ex-Fix group experienced more severe lower extremity injuries (AIS score, 4-5) compared with the IMN group (16% vs. 3%, p = 0.01) but not the ORIF group (16% vs. 6%, p = 0.1). Time to operative intervention varied between the cohorts with the longest time to intervention for the IMN group (median hours: Ex-Fix, 15 [8-24] vs. ORIF, 26 [12-85] vs. IMN, 31 [12-70]; p < 0.001). The discharge RLAS-R score distribution was similar across the groups. After adjusting for confounders, neither method nor timing of lower extremity fixation influenced the discharge RLAS-R. Instead, increasing age and head AIS score were associated with a lower discharge RLAS-R score (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002-1.03 and OR, 2.37; 95% CI, 1.75-3.22), and a higher Glasgow Coma Scale motor score on admission (OR, 0.84; 95% CI, 0.73-0.97) was associated with higher RLAS-R score at discharge. CONCLUSION: Neurologic outcomes in TBI are impacted by severity of the head injury and not the fracture fixation technique or timing. Therefore, the strategy of definitive fixation of lower extremity fractures should be dictated by patient physiology and the anatomy of the injured extremity and not by the concern for worsening neurologic outcomes in TBI patients. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial.

BACKGROUND: Ondansetron may be beneficial in irritable bowel syndrome with diarrhoea (IBS-D). AIM: To conduct a 12-week parallel group, randomised, double-blind, placebo-controlled trial of ondansetron 4 mg o.d. (titrated up to 8 mg t.d.s.) in 400 IBS-D patients. PRIMARY ENDPOINT: % responders using the Food and Drug Administration (FDA) composite endpoint. Secondary and mechanistic endpoints included stool consistency (Bristol Stool Form Scale) and whole gut transit time (WGTT). After literature review, results were pooled with other placebo-controlled trials in a meta-analysis to estimate relative risks (RR), 95% confidence intervals (CIs) and number needed to treat (NNT). RESULTS: Eighty patients were randomised. On intention-to-treat analysis, 15/37 (40.5%; 95% CI 24.7%-56.4%) met the primary endpoint on ondansetron versus 12/43 (27.9%; 95% CI 14.5%-41.3%) on placebo (p = 0.19). Ondansetron improved stool consistency compared with placebo (adjusted mean difference - 0.7; 95% CI -1.0 to-0.3, p < 0.001). Ondansetron increased WGTT between baseline and week 12 (mean (SD) difference 3.8 (9.1) hours, versus placebo -2.2 (10.3) hours, p = 0.01). Meta-analysis of 327 patients from this, and two similar trials, demonstrated ondansetron was superior to placebo for the FDA composite endpoint (RR of symptoms not responding = 0.86; 95% CI 0.75-0.98, NNT = 9) and stool response (RR = 0.65; 95% CI 0.52-0.82, NNT = 5), but not abdominal pain response (RR = 0.95; 95% CI 0.74-1.20). CONCLUSIONS: Although small numbers meant the primary endpoint was not met in this trial, when pooled with other similar trials meta-analysis suggests ondansetron improves stool consistency and reduces days with loose stool and urgency. Trial registration - http://www.isrctn.com/ISRCTN17508514.

Handheld Raman Spectroscopy in the First UK Home Office Licensed Pharmacist-Led Community Drug Checking Service.

Across the world, the interest in point-of-care drug checking as a harm-reduction intervention is growing. This is an attempt to improve intelligence about current drug trends and reduce drug-related morbidity and mortality. In the UK, drug-related harm is increasing exponentially year after year. As such, specialist community treatment services are exploring new methods to improve engagement with people who use drugs (PWUD), who may require support for their problematic drug use. This need has driven the requirement to pilot an on-site, time-responsive, readily available drug-checking service at point-of-support centres. In this study, we piloted the UK's first Home Office-licensed drug-checking service that was embedded into a community substance-misuse service and had all on-site analysis and harm-reduction interventions led and delivered by pharmacists. We report on the laboratory findings from the associated confirmatory analysis (UHPLC-MS, GC-MS, and 1H NMR) to assess the performance of the on-site hand-held Raman spectrometer and outline the challenges of providing real-time analysis of psychoactive substances in a clinical setting. Whilst acknowledging the limitation of the small sample size (n = 13), we demonstrate the potential suitability of using this technology for the purposes of screening substances in community-treatment services. Portability of equipment and timeliness of results are important and only very small samples may be provided by people who use the service. The challenges of accurately identifying substances from complex mixtures were equally found with both point-of-care Raman spectroscopy and laboratory confirmatory-analysis techniques. Further studies are required to confirm these findings.

ED to ED transfer does not prolong emergency department stays in a rural trauma system.

BACKGROUND: In many rural trauma systems injured patients are initially evaluated at a local hospital, and once stabilized transferred to a trauma center for definitive care. In the U.S. most trauma transfers occur as emergency department (ED) to ED transfers, however there is little evidence to guide systems in whether this is beneficial. We implemented a practice change in August 2018, changing from commonly admitting trauma transfers directly to the floor, to a protocol for ED to ED transfer for all trauma patients. We aimed to evaluate this practice change and its effects on outcomes and ED length of stay. METHODS: We retrospectively reviewed all trauma transfers to our Level 1 trauma center between 8/1/2017-8/30/2020. Study groups were created based on the presence of a transfer protocol: a control group with no protocol, a selective ED pitstop protocol group and a systemwide ED pitstop protocol group. We compared patient and injury factors between groups, and evaluated each group's hospital mortality, unplanned ICU admission within 24 h, need for return to radiology for imaging, and ED length of stay. RESULTS: 1,987 patients were transferred during the study period. In our control group 37% of transfers were directly admitted. Implementing a selective ED pitstop decreased direct admissions to 17% and a systemwide ED pitstop decreased direct admissions to 10%. There was no difference in mortality between groups. Protocol implementation decreased unplanned ICU admissions from 2% to 1% in the selective protocol and 0.8% in the systemwide protocol, as well as decreasing the need for further diagnostic imaging (5% to 2.5% and 2%; in each group respectively). ED length of stay was not different between time periods. CONCLUSIONS: Implementing an ED pitstop protocol for trauma transfers led to decreased direct admissions, without increasing the ED length of stay, and less need for delayed imaging.

Large-Scale Production of Wholly Cellular Bioinks via the Optimization of Human Induced Pluripotent Stem Cell Aggregate Culture in Automated Bioreactors.

Combining the sustainable culture of billions of human cells and the bioprinting of wholly cellular bioinks offers a pathway toward organ-scale tissue engineering. Traditional 2D culture methods are not inherently scalable due to cost, space, and handling constraints. Here, the suspension culture of human induced pluripotent stem cell-derived aggregates (hAs) is optimized using an automated 250 mL stirred tank bioreactor system. Cell yield, aggregate morphology, and pluripotency marker expression are maintained over three serial passages in two distinct cell lines. Furthermore, it is demonstrated that the same optimized parameters can be scaled to an automated 1 L stirred tank bioreactor system. This 4-day culture results in a 16.6- to 20.4-fold expansion of cells, generating approximately 4 billion cells per vessel, while maintaining >94% expression of pluripotency markers. The pluripotent aggregates can be subsequently differentiated into derivatives of the three germ layers, including cardiac aggregates, and vascular, cortical and intestinal organoids. Finally, the aggregates are compacted into a wholly cellular bioink for rheological characterization and 3D bioprinting. The printed hAs are subsequently differentiated into neuronal and vascular tissue. This work demonstrates an optimized suspension culture-to-3D bioprinting pipeline that enables a sustainable approach to billion cell-scale organ engineering.

Sensory attenuation from action observation.

A central claim of many embodied approaches to cognition is that understanding others' actions is achieved by covertly simulating the observed actions and their consequences in one's own motor system. If such a simulation occurs, it may be accomplished through forward models, a component of the motor system already known to perform simulations of actions and their consequences in order to support sensory-monitoring of one's own actions. Forward-model simulations cause an attenuation of sensory intensity, so if the simulations hypothesized by embodied cognition are indeed provided by forward models, then action observation should trigger this sensory attenuation. To test this hypothesis, the experiments reported here measured the perceived intensity of a touch sensation on the finger when participants observed an active touch (a finger reaching to touch a ball) vs. a passive touch (a ball rolling to touch an unmoving finger). The touch sensation was perceived as less intense during observation of active touch in comparison with observation of passive touch, providing evidence that forward models are indeed engaged during action observation. The strength of this sensory attenuation is compared and contrasted with a well-established sensory-amplification effect caused by visual attention. This sensory-amplification effect has not generally been considered in studies related to sensory attenuation in action observation, which may explain conflicting results reported in the field.

Phage Diving: An Exploration of the Carcharhinid Shark Epidermal Virome.

The epidermal microbiome is a critical element of marine organismal immunity, but the epidermal virome of marine organisms remains largely unexplored. The epidermis of sharks represents a unique viromic ecosystem. Sharks secrete a thin layer of mucus which harbors a diverse microbiome, while their hydrodynamic dermal denticles simultaneously repel environmental microbes. Here, we sampled the virome from the epidermis of three shark species in the family Carcharhinidae: the genetically and morphologically similar Carcharhinus obscurus (n = 6) and Carcharhinus galapagensis (n = 10) and the outgroup Galeocerdo cuvier (n = 15). Virome taxonomy was characterized using shotgun metagenomics and compared with a suite of multivariate analyses. All three sharks retain species-specific but highly similar epidermal viromes dominated by uncharacterized bacteriophages which vary slightly in proportional abundance within and among shark species. Intraspecific variation was lower among C. galapagensis than among C. obscurus and G. cuvier. Using both the annotated and unannotated reads, we were able to determine that the Carcharhinus galapagensis viromes were more similar to that of G. cuvier than they were to that of C. obscurus, suggesting that behavioral niche may be a more prominent driver of virome than host phylogeny.

Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites.

The endoplasmic reticulum exit of some polytopic plasma membrane proteins (PMPs) is controlled by arginin-based retention motifs. PRAF2, a gatekeeper which recognizes these motifs, was shown to retain the GABAB-receptor GB1 subunit in the ER. We report that PRAF2 can interact on a stoichiometric basis with both wild type and mutant F508del Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR), preventing the access of newly synthesized cargo to ER exit sites. Because of its lower abundance, compared to wild-type CFTR, CFTR-F508del recruitment into COPII vesicles is suppressed by the ER-resident PRAF2. We also demonstrate that some pharmacological chaperones that efficiently rescue CFTR-F508del loss of function in CF patients target CFTR-F508del retention by PRAF2 operating with various mechanisms. Our findings open new therapeutic perspectives for diseases caused by the impaired cell surface trafficking of mutant PMPs, which contain RXR-based retention motifs that might be recognized by PRAF2.

Degradation of red blood cell deformability during cold storage in blood bags.

Red blood cells (RBCs) stored in blood bags develop a storage lesion that include structural, metabolic, and morphologic transformations resulting in a progressive loss of RBC deformability. The speed of RBC deformability loss is donor-dependent, which if properly characterized, could be used as a biomarker to select high-quality RBC units for sensitive recipients or to provide customized storage timelines depending on the donor. We used the microfluidic ratchet device to measure the deformability of red blood cells stored in blood bags every 14 days over a span of 56 days. We observed that storage in blood bags generally prevented RBC deformability loss over the current standard 42-day storage window. However, between 42 and 56 days, the deformability loss profile varied dramatically between donors. In particular, we observed accelerated RBC deformability loss for a majority of male donors, but for none of the female donors. Together, our results suggest that RBC deformability loss could be used to screen for donors who can provide stable RBCs for sensitive transfusion recipients or to identify donors capable of providing RBCs that could be stored for longer than the current 42-day expiration window.

SUMOylation does not affect cardiac troponin I stability but alters indirectly the development of force in response to Ca2.

Post-translational modification of the myofilament protein troponin I by phosphorylation is known to trigger functional changes that support enhanced contraction and relaxation of the heart. We report for the first time that human troponin I can also be modified by SUMOylation at lysine 177. Functionally, TnI SUMOylation is not a factor in the development of passive and maximal force generation in response to calcium, however this modification seems to act indirectly by preventing SUMOylation of other myofilament proteins to alter calcium sensitivity and cooperativity of myofilaments. Utilising a novel, custom SUMO site-specific antibody that recognises only the SUMOylated form of troponin I, we verify that this modification occurs in human heart and that it is upregulated during disease.

Biomanufacturing human tissues via organ building blocks.

The construction of human organs on demand remains a tantalizing vision to solve the organ donor shortage. Yet, engineering tissues that recapitulate the cellular and architectural complexity of native organs is a grand challenge. The use of organ building blocks (OBBs) composed of multicellular spheroids, organoids, and assembloids offers an important pathway for creating organ-specific tissues with the desired cellular-to-tissue-level organization. Here, we review the differentiation, maturation, and 3D assembly of OBBs into functional human tissues and, ultimately, organs for therapeutic repair and replacement. We also highlight future challenges and areas of opportunity for this nascent field.