Influence of examiner calibration on clinical and mri diagnosis of temporomandibular joint disc displacement: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to verify the accuracy of clinical protocols for the diagnosis of disc displacement (DD) compared with magnetic resonance imaging (MRI), considering examiners' calibration. METHODS: PubMed, Cochrane (Central), Scopus, Web of Science, LILACS, Embase, Science Direct, Google Scholar, and DANS EASY Archive databases were searched. Two reviewers independently screened and selected the studies. A meta-analysis was conducted using the R Statistical software. Results are shown using sensitivity and specificity, and 95% confidence intervals. RESULTS: Of the 20 studies included in the systematic review, only 3 were classified as low risk of bias. Seventeen studies were included in the meta-analysis. Compared to MRI, clinical protocols showed overall sensitivity and specificity of 0.75 (0.63-0.83) and 0.73 (0.59-0.84) for DD diagnosis, respectively. For DD with reduction, sensitivity was 0.64 (0.48-0.77) and specificity was 0.72 (0.48-0.87). For DD without reduction, sensitivity was 0.58 (0.39-0.74) and specificity 0.93 (0.83-0.97). Only 8 studies reported examiner calibration when performing clinical and/or MRI evaluation; nevertheless, calibration showed a tendency to improve the diagnosis of DD. CONCLUSION: The sensitivity and specificity of clinical protocols in the diagnosis of DD are slightly below the recommended values, as well as the studies lack calibration of clinical and MRI examiners. Examiner calibration seems to improve the diagnosis of DD.

A neural signature for brain compensation in stroke with EEG and TMS: Insights from the DEFINE cohort study.

OBJECTIVE: This study aimed to explore the relationships between potential neurophysiological biomarkers and upper limb motor function recovery in stroke patients, specifically focusing on combining two neurophysiological markers: electroencephalography (EEG) and transcranial magnetic stimulation (TMS). METHODS: This cross-sectional study analyzed neurophysiological, clinical, and demographical data from 102 stroke patients from the DEFINE cohort. We searched for correlations of EEG and TMS measurements combined to build a prediction model for upper limb motor functionality, assessed by five outcomes, across five assessments: Fugl-Meyer Assessment (FMA), Handgrip Strength Test (HST), Finger Tapping Test (FTT), Nine-Hole Peg Test (9HPT), and Pinch Strength Test (PST). RESULTS: Our multivariate models agreed on a specific neural signature: higher EEG Theta/Alpha ratio in the frontal region of the lesioned hemisphere is associated with poorer motor outcomes, while increased MEP amplitude in the non-lesioned hemisphere correlates with improved motor function. These relationships are held across all five motor assessments, suggesting the potential of these neurophysiological measures as recovery biomarkers. CONCLUSION: Our findings indicate a potential neural signature of brain compensation in which lower frequencies of EEG power are increased in the lesioned hemisphere, and lower corticospinal excitability is also increased in the non-lesioned hemisphere. We discuss the meaning of these findings in the context of motor recovery in stroke.

DOUBLE-ARC SLOW-COAGULATION TRANSSCLERAL CYCLOPHOTOCOAGULATION LASER PROTOCOL: ONE-YEAR EFFECTIVENESS AND SAFETY OUTCOMES.

PURPOSE: To report the short-term efficacy and safety results of a new continuous laser protocol, double-arc slow-coagulation transscleral cyclophotocoagulation (DA-TSCPC). DESIGN: Multicenter retrospective study. PARTICIPANTS: Refractory glaucoma patients that had undergone DA-TSCPC between April 2019 and July 2022, with at least 12 months of postoperative follow-up, were consecutively enrolled. METHODS: The technique was standardized (energy: 1400mW; duration: 4s; 28 applications). The applications were divided into 2 rows (upper and lower arcs). For each arc, 7 spots were applied over the ciliary body shadow and 7 spots 1.5mm behind, sparing the 3 and 9 o'clock meridians. MAIN OUTCOME MEASURES: Success was defined as postoperative intraocular pressure (IOP) between 6 and 18 mmHg, and an IOP reduction of 30% (without oral acetazolamide). For eyes with no light perception (NLP), in which treatment goal was pain relief, success was defined as a 30% IOP reduction and no pain (without oral acetazolamide). Patients were divided according to visual acuity: ≥20/400 (group 1) and <20/400 (group 2). RESULTS: Ninety eyes of 90 patients (mean age: 61±15 years) were included. Glaucoma diagnosis frequency was: neovascular glaucoma (38%), open-angle glaucoma (28%), silicone oil secondary glaucoma (17%) and others (18%). Overall, the mean IOP was significantly reduced from 35±12 to 22±14 mmHg (p<0.01) at the last follow-up visit. The number of hypotensive eye drops (2.6±1 to 2.3±1; p=0.02) and the use of oral acetazolamide (61% to 11%; p<0.01) were also reduced. Kaplan-Meier survival analysis revealed a global success rate of 65.6% after 12 months. A higher success rate was found for group 1 (78.6%) compared to group 2 (59.6%; p=0.047; logrank test). The main complications observed were corneal ulcer (4.4%), macular edema (1.1%) and hyphema (1.1%). Among the 26 eyes with NLP, 65% achieved success criteria at 12 months and 2 (7.7%) developed phthisis. CONCLUSION: Based on these initial retrospective data, the DA-TSCPC protocol seems to be an alternative for refractory glaucoma management, presenting significant IOP reduction and a good safety profile after one year. Better outcomes were observed in eyes with less severe functional damage.

Horizontal gene transfer of the Mer operon is associated with large effects on the transcriptome and increased tolerance to mercury in nitrogen-fixing bacteria.

BACKGROUND: Mercury (Hg) is highly toxic and has the potential to cause severe health problems for humans and foraging animals when transported into edible plant parts. Soil rhizobia that form symbiosis with legumes may possess mechanisms to prevent heavy metal translocation from roots to shoots in plants by exporting metals from nodules or compartmentalizing metal ions inside nodules. Horizontal gene transfer has potential to confer immediate de novo adaptations to stress. We used comparative genomics of high quality de novo assemblies to identify structural differences in the genomes of nitrogen-fixing rhizobia that were isolated from a mercury (Hg) mine site that show high variation in their tolerance to Hg. RESULTS: Our analyses identified multiple structurally conserved merA homologs in the genomes of Sinorhizobium medicae and Rhizobium leguminosarum but only the strains that possessed a Mer operon exhibited 10-fold increased tolerance to Hg. RNAseq analysis revealed nearly all genes in the Mer operon were significantly up-regulated in response to Hg stress in free-living conditions and in nodules. In both free-living and nodule environments, we found the Hg-tolerant strains with a Mer operon exhibited the fewest number of differentially expressed genes (DEGs) in the genome, indicating a rapid and efficient detoxification of Hg from the cells that reduced general stress responses to the Hg-treatment. Expression changes in S. medicae while in bacteroids showed that both rhizobia strain and host-plant tolerance affected the number of DEGs. Aside from Mer operon genes, nif genes which are involved in nitrogenase activity in S. medicae showed significant up-regulation in the most Hg-tolerant strain while inside the most Hg-accumulating host-plant. Transfer of a plasmid containing the Mer operon from the most tolerant strain to low-tolerant strains resulted in an immediate increase in Hg tolerance, indicating that the Mer operon is able to confer hyper tolerance to Hg. CONCLUSIONS: Mer operons have not been previously reported in nitrogen-fixing rhizobia. This study demonstrates a pivotal role of the Mer operon in effective mercury detoxification and hypertolerance in nitrogen-fixing rhizobia. This finding has major implications not only for soil bioremediation, but also host plants growing in mercury contaminated soils.

An essential host dietary fatty acid promotes TcpH inhibition of TcpP proteolysis promoting virulence gene expression in Vibrio cholerae.

Vibrio cholerae is a Gram-negative gastrointestinal pathogen responsible for the diarrheal disease cholera. Expression of key virulence factors, cholera toxin and toxin-coregulated pilus, is regulated directly by ToxT and indirectly by two transmembrane transcription regulators (TTRs), ToxR and TcpP, that promote the expression of toxT. TcpP abundance and activity are controlled by TcpH, a single-pass transmembrane protein, which protects TcpP from a two-step proteolytic process known as regulated intramembrane proteolysis (RIP). The mechanism of TcpH-mediated protection of TcpP represents a major gap in our understanding of V. cholerae pathogenesis. The absence of tcpH leads to unimpeded degradation of TcpP in vitro and a colonization defect in a neonate mouse model of V. cholerae colonization. Here, we show that TcpH protects TcpP from RIP via direct interaction. We also demonstrate that α-linolenic acid, a dietary fatty acid, promotes TcpH-dependent inhibition of RIP via co-association of TcpP and TcpH molecules within detergent-resistant membranes (DRMs) in a mechanism requiring the TcpH transmembrane domain. Taken together, our data support a model where V. cholerae cells use exogenous α-linolenic acid to remodel the phospholipid bilayer in vivo, leading to co-association of TcpP and TcpH within DRMs where RIP of TcpP is inhibited by TcpH, thereby promoting V. cholerae pathogenicity. IMPORTANCE: Vibrio cholerae continues to pose a significant global burden on health and an alternative therapeutic approach is needed, due to evolving multidrug resistance strains. Transcription of toxT, stimulated by TcpP and ToxR, is essential for V. cholerae pathogenesis. Our results show that TcpP, one of the major regulators of toxT gene expression, is protected from proteolysis by TcpH, via direct interaction. Furthermore, we identified a gut metabolite, α-linolenic acid, that stimulates the co-association of TcpP and TcpH within detergent-resistant membranes (also known as lipid-ordered membrane domains), thereby supporting TcpH-dependent antagonism of TcpP proteolysis. Data presented here extend our knowledge of RIP, virulence gene regulation in V. cholerae, and, to the best of our knowledge, provides the first evidence that lipid-ordered membranes exist within V. cholerae. The model presented here also suggests that TTRs, common among bacteria and archaea, and co-component signal transduction systems present in Enterobacteria, could also be influenced similarly.

Public Health Involvement in United States' Vision Zero Initiatives: A Mixed-Methods Study.

CONTEXT: Vision Zero (VZ) aims to reduce fatalities and serious injuries from road traffic crashes to zero through multidisciplinary coordination. While public health officials are often recognized as critical to VZ, their involvement in VZ across the United States has not been quantified. OBJECTIVE: To explore how United States public health officials were involved in VZ development and implementation. DESIGN: We used a mixed-method design including a quantitative assessment of VZ plans and in-depth interviewing with VZ coordinators. SETTING: United States. PARTICIPANTS: Twenty-two in-depth interviews with municipal (n = 12) and regional (n = 10) VZ coordinators and 43 VZ plans were reviewed. MAIN OUTCOME MEASURE: Public health involvement in VZ development and implementation. RESULTS: In the United States, 64 municipalities and 21 regional entities had first-time VZ plans published between 2014 and 2022. We abstracted a sample of municipal (n = 22) and all (n = 21) regional plans. Most plans described key groups involved in plan development (municipal 81.8%, regional 100%). About two-thirds (67.4%; 59.1% municipal, 76.2% regional) of the plans noted public health officials in the plan development. Most plans described the principles forming the foundation of their plan (83.7%), but few mentioned public health as part of the plan principles (22.7% municipal, 14.3% regional). Public health officials were involved in engaging the community (9.1% municipal, 33.3% regional) and providing data (22.7% municipal, 52.4% regional) for plan development, as documented in the plans. For proposed implementation, public health officials were identified as involved in: community engagement (31.8% municipal, 42.9% regional), sharing/analyzing data (40.9% municipal, 33.3% regional), and identifying/providing funding sources (13.6% municipal, 4.8% regional). The in-depth interviews provided further context and a more detailed understanding of public health involvement in VZ. CONCLUSIONS: Evidence from the VZ plans and interviews provided examples of how public health officials engaged in the development and implementation of VZ initiatives.

Pediatric Facial Fracture Associated Craniofacial and Cervical Spine Injury.

Management of pediatric facial fractures depends on location and severity, age, and associated injuries. Accurate diagnosis of associated injuries is crucial for effective treatment. This study evaluates the incidence of associated injuries and seeks to determine the influencing factors to provide imaging guidance. A retrospective review of pediatric facial fractures from the American College of Surgeons National Trauma Data Bank from 2017 to 2021 was completed. Associated cervical spine (c-spine), skull fracture, traumatic brain injury (TBI), and intracranial bleeding were evaluated. Demographics, fracture patterns, mechanisms, protective devices, and the Glasgow Coma Scale (GCS) were reviewed. A total of 44,781 pediatric patients with 65,613 facial fractures were identified. Of the total, 5.47% had a c-spine injury, 21.86% had a skull fracture, 18.82% had TBI, and 5.76% had intracranial bleeding. Multiple fractures significantly increased the rate of all associated cranial and c-spine injuries. Single midface fractures had the highest c-spine, TBI, and intracranial bleeding rates. With increasing age, there was a significant increase in c-spine injury and TBI, while there was a decrease in skull fractures. Motor vehicle accidents and GCS <13 were associated with significantly increased rates of all injuries. Among pediatric patients with facial fractures, 5.47% had a c-spine injury, 21.86% had a skull fracture, 18.82% had TBI, and 5.76% had intracranial bleeding. The authors' findings recommend c-spine imaging in older age and cranial imaging in younger patients. Multiple facial fractures, fractures of the midface, decreased GCS, and motor vehicle accidents increase the need for both c-spine and cranial imaging.

A Multiomics Perspective on Plant Cell Wall-Degrading Enzyme Production: Insights from the Unexploited Fungus Trichoderma erinaceum.

Trichoderma erinaceum is a filamentous fungus that was isolated from decaying sugarcane straw at a Brazilian ethanol biorefinery. This fungus shows potential as a source of plant cell wall-degrading enzymes (PCWDEs). In this study, we conducted a comprehensive multiomics investigation of T. erinaceum to gain insights into its enzymatic capabilities and genetic makeup. Firstly, we performed genome sequencing and assembly, which resulted in the identification of 10,942 genes in the T. erinaceum genome. We then conducted transcriptomics and secretome analyses to map the gene expression patterns and identify the enzymes produced by T. erinaceum in the presence of different substrates such as glucose, microcrystalline cellulose, pretreated sugarcane straw, and pretreated energy cane bagasse. Our analyses revealed that T. erinaceum highly expresses genes directly related to lignocellulose degradation when grown on pretreated energy cane and sugarcane substrates. Furthermore, our secretome analysis identified 35 carbohydrate-active enzymes, primarily PCWDEs. To further explore the enzymatic capabilities of T. erinaceum, we selected a ß-glucosidase from the secretome data for recombinant production in a fungal strain. The recombinant enzyme demonstrated superior performance in degrading cellobiose and laminaribiose compared to a well-known enzyme derived from Trichoderma reesei. Overall, this comprehensive study provides valuable insights into both the genetic patterns of T. erinaceum and its potential for lignocellulose degradation and enzyme production. The obtained genomic data can serve as an important resource for future genetic engineering efforts aimed at optimizing enzyme production from this fungus.

Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms.

BACKGROUND AND PURPOSE: Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects. EXPERIMENTAL APPROACH: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood-brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound. KEY RESULTS: In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood-brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT2A-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. CONCLUSIONS AND IMPLICATIONS: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.

Experimental and Theoretical Study on Electron Ionization and Fragmentation of Propylene Oxide─the First Chiral Molecule Detected in the Interstellar Medium.

Propylene oxide, CH3CHOCH2, is the first chiral molecule detected in space and the third C3 oxide detected toward the Sagittarius B2 (Sgr B2 (N)) molecular cloud, the others being propanal, CH3CH2CHO, and acetone, (CH3)2CO. With homochirality being ubiquitous in the building blocks of living matter, the formation and decay paths of propylene oxide in space are of specific interest. Motivated by the significant role of photo- and secondary electrons in astrochemistry, we have studied electron ionization and fragmentation of propylene oxide. Ion appearance energies are determined and compared to threshold values for the respective processes calculated at the G4MP2 level of theory, and potential reaction pathways are computed at the DFT level of theory. Electron ionization is found to destabilize propylene oxide, leading to barrierless opening of the C1-C2 bond of the epoxy ring, hydrogen transfer, and fragmentation over the methyl vinyl ether or rupture of the C2-O bond of the epoxy ring and fragmentation of the allyl alcohol cation as an intermediate, rather than direct bond ruptures.

Impact of quality and transparency in scientific writing on the reduction of animal usage in experimental protocols: a review based in pertinent literature.

The irreproducibility in scientific research has become a critical issue. Despite the essential role of rigorous methodology in constructing a scientific article, more than half of publications, on average, are considered non-reproducible. The implications of this irreproducibility extend to reliability problems, hindering progress in technological production and resulting in substantial financial losses. In the context of laboratory animal research, this work emphasizes the importance of choosing an appropriate experimental model within the 3R's principle (Refine, Reduce, Replace). This study specifically addresses a deficiency in data specification in scientific articles, revealing inadequacies in the description of crucial details, such as environmental conditions, diet, and experimental procedures. For this purpose, 124 articles from journals with relevant impact factors were analyzed, conducting a survey of data considered important for the reproducibility of studies. Important flaws in the presentation of data were identified in most of the articles evaluated. The results of this study highlight the need to improve the description of essential information, standardizing studies, and ensuring the reproducibility of experiments in areas such as metabolism, immunity, hormones, stress, among others, to enhance the reliability and reproduction of experimental results, aligning with international guidelines such as ARRIVE and PREPARE.

Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey.

Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited UBE3A allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited UBE3A allele is epigenetically silenced in neurons during development by a noncoding transcript (UBE3A-ATS). The absence of neuronal UBE3A results in severe neurological symptoms, including speech and language impairments, intellectual disability, and seizures. While no cure exists, therapies aiming to restore UBE3A function-either by gene addition or by targeting UBE3A-ATS-are under development. Progress in developing these treatments relies heavily on inferences drawn from mouse studies about the function of UBE3A in the human brain. To aid translational efforts and to gain an understanding of UBE3A and UBE3A-ATS biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and UBE3A-ATS expression in the developing brain of the rhesus macaque, a species that exhibits complex social behaviors, resembling aspects of human behavior to a greater degree than mice. Combining immunohistochemistry and in situ hybridization, we mapped UBE3A and UBE3A-ATS regional and cellular expression in normal prenatal, neonatal, and adolescent rhesus macaque brains. We show that key hallmarks of UBE3A biology, well-known in rodents, are also present in macaques, and suggest paternal UBE3A silencing in neurons-but not glial cells-in the macaque brain, with onset between gestational day 48 and 100. These findings support proposals that early-life, perhaps even prenatal, intervention is optimal for overcoming the maternal allele loss of UBE3A linked to AS.

Quantifying the Potential for Nitrate-Dependent Iron Oxidation on Early Mars: Implications for the Interpretation of Gale Crater Organics.

Geological evidence and atmospheric and climate models suggest habitable conditions occurred on early Mars, including in a lake in Gale crater. Instruments aboard the Curiosity rover measured organic compounds of unknown provenance in sedimentary mudstones at Gale crater. Additionally, Curiosity measured nitrates in Gale crater sediments, which suggests that nitrate-dependent Fe2+ oxidation (NDFO) may have been a viable metabolism for putative martian life. Here, we perform the first quantitative assessment of an NDFO community that could have existed in an ancient Gale crater lake and quantify the long-term preservation of biological necromass in lakebed mudstones. We find that an NDFO community would have the capacity to produce cell concentrations of up to 106 cells mL-1, which is comparable to microbes in Earth's oceans. However, only a concentration of <104 cells mL-1, due to organisms that inefficiently consume less than 10% of precipitating nitrate, would be consistent with the abundance of organics found at Gale. We also find that meteoritic sources of organics would likely be insufficient as a sole source for the Gale crater organics, which would require a separate source, such as abiotic hydrothermal or atmospheric production or possibly biological production from a slowly turning over chemotrophic community.

Early human contact and housing for pigs - part 1: responses to humans, novelty and isolation.

The development of fear and stress responses in animals can be influenced by early life experiences, including interactions with humans, maternal care, and the physical surroundings. This paper is the first of three reporting on a large experiment examining the effects of the early housing environment and early positive human contact on stress resilience in pigs. This first paper reports on the responses of pigs to humans, novelty, and social isolation. Using a 2 × 2 factorial design, 48 litters of pigs were reared in either a conventional farrowing crate (FC) where the sow was confined or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely throughout the farrowing and lactation period. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0-4 weeks of age. The positive handling treatment was highly effective in reducing piglets' fear of humans, based on +HC piglets showing greater approach and less avoidance of an unfamiliar person at 3 weeks of age. There was evidence that this reduction in fear of humans lasted well beyond when the treatment was applied (lactation), with +HC pigs showing greater approach and less avoidance of humans in tests at 6, 9 and 14 weeks of age. The +HC treatment also reduced piglets' fear of a novel object at 3 weeks of age, and for pigs in FC, the cortisol response after social isolation at 7 weeks of age. Rearing in FC compared to LP reduced piglets' fear of novelty at 3 weeks of age, as well as their vocalisations and cortisol response to isolation at 7 weeks of age. The FC pigs showed greater approach and less avoidance of humans compared to LP pigs at 3, 4 and 6 weeks of age, but not at 9 and 14 weeks of age. These results show that positive handling early in life can reduce pigs' fear of humans, fear of novelty and physiological stress response to social isolation. The LP pigs were reared in a more isolated environment with less overall contact with stockpeople and other pigs, which may have increased their fear responses to humans and novel situations, suggesting that different housing systems can modulate these pigs' responses.

Early human contact and housing for pigs - part 3: ability to cope with the environment.

Early experiences can have long-term impacts on stress adaptability. This paper is the last of three in a series on early experiences and stress in pigs, and reports on the effects of early human contact and housing on the ability of pigs to cope with their general environment. Using a 2 × 2 factorial design, 48 litters of pigs were reared in either a farrowing crate (FC) or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0 to 4 weeks of age. At 4 weeks of age (preweaning), C piglets that were reared in FC had considerably lower concentrations of serum brain-derived neurotrophic factor (BDNF) than piglets from the other treatment combinations. Compared to C pigs, +HC pigs had fewer injuries at 4 weeks of age. There were no clear effects of human contact on BDNF concentrations or injuries after weaning, or on basal cortisol or immunoglobulin-A concentrations, behavioural time budgets, tear staining, growth, or piglet survival. Compared to FC piglets, LP piglets showed more play behaviour and interactions with the dam and less repetitive nosing towards pen mates during lactation. There was no evidence that early housing affected pigs' behavioural time budgets or physiology after weaning. Tear staining severity was greater in LP piglets at 4 weeks of age, but this may have been associated with the higher growth rates of LP piglets preweaning. There was no effect of lactation housing on growth after weaning. Preweaning piglet mortality was higher in the loose system. The findings on BDNF concentrations, injuries and play behaviour suggest improved welfare during the treatment period in +HC and LP piglets compared to C and FC piglets, respectively. These results together with those from the other papers in this series indicate that positive human interaction early in life promotes stress adaptability in pigs. Furthermore, while the farrowing crate environment deprives piglets of opportunities for play behaviour and sow interaction, there was no evidence that rearing in crates negatively affected pig welfare or stress resilience after weaning. Whether these findings are specific to the two housing systems studied here, or can be generalised to other housing designs, warrants further research.

Early human contact and housing for pigs - part 2: resilience to routine husbandry practices.

The ability of pigs to cope with routine farming practices can affect their welfare. This paper is part of a series on early experiences and stress, and reports on the effects of early human contact and housing on the responses of pigs to routine husbandry practices. Using a 2 × 2 factorial design, 48 litters of pigs were raised in either a conventional farrowing crate (FC) or a loose farrowing pen (LP; PigSAFE pen) which was larger, more physically complex and allowed the sow to move freely. Piglets were provided with either routine contact from stockpeople (C), or routine contact plus regular opportunities for positive human contact (+HC) involving 5 min of scratching, patting and stroking imposed to the litter 5 days/week from 0 to 4 weeks of age. At 4 weeks of age, piglets were weaned and re-housed with controlled mixing of litters within treatment. At 4 days of age, after only 3 bouts of the handling treatment, +HC pigs showed less escape behaviour than C pigs after capture by a stockperson for vaccinations and tail docking, and shorter durations of vocalisations throughout the procedures. The  +HC pigs also showed less escape behaviour when captured by a stockperson at 3 weeks of age. The FC pigs showed less escape behaviour than LP pigs after capture by a stockperson at 4 days of age but not at 3 weeks of age. Serum cortisol concentrations were lower in FC pigs than LP pigs 2 h after weaning but not at 49 h after weaning, whereas serum cortisol concentrations were lower in  +HC pigs than C pigs at 49 h after weaning but not at 2 h after weaning. In the period from 0 to 1 h after weaning, C pigs from LP performed the most escape attempts, although escape attempts were rare overall. When being moved out of the home pen by a stockperson at 21 weeks of age, FC pigs showed less baulking than LP pigs, but there were no detected effects of human contact treatment. In conclusion, both housing system and human contact during lactation affected the stress responses of pigs to routine husbandry practices. The +HC and FC pigs appeared to cope better than C and LP pigs, based on lower responses indicative of stress including escape behaviour, vocalisations and cortisol concentrations. These findings are consistent with corresponding reductions in fear that were reported in Part 1 of this series of papers.

Dehydrodieugenol isolated from Ocotea cymbarum induces cell death in human breast cancer cell lines by dysregulation of intracellular copper concentration.

In this work, two neolignans - dehydrodieugenol (1) and dehydrodieugenol B (2) - were isolated from leaves of Ocotea cymbarum (H. B. K.) Ness. (Lauraceae). When tested against two human breast cancer cell lines (MCF7 and MDA-MB-231), compound 1 was inactive (IC50 > 500 µM) whereas compound 2 displayed IC50 values of 169 and 174 µM, respectively. To evaluate, for the first time in the literature, the synergic cytotoxic effects of compounds 1 and 2 with ion Cu2+, both cell lines were incubated with equimolar solutions of these neolignans and Cu(ClO4)2·6H2O. Obtained results revealed no differences in cytotoxicity upon the co-administration of compound 2 and Cu2+. However, the combination of compound 1 and Cu2+ increases the cytotoxicity against MCF7 and MDA-MB-231 cells, with IC50 values of 165 and 204 µM, respectively. The activity of compound 1 and Cu2+ in MCF7 spheroids regarding the causes/effects considering the tumoral microenvironment were accessed using fluorescence staining and imaging by fluorescence microscopy. This analysis enabled the observation of a higher red filter fluorescence intensity in the quiescence zone and the necrotic core, indicating a greater presence of dead cells, suggesting that the combination permeates the spheroid. Finally, using ICP-MS analysis, the intracellular copper disbalance caused by mixing compound 1 and Cu2+ was determined quantitatively. The findings showcased a 50-fold surge in the concentration of Cu2+ compared with untreated cells (p > 0.0001) - 18.7 ng of Cu2+/mg of proteins and 0.37 ng of Cu2+/mg of protein, respectively. Conversely, the concentration of Cu2+ in cells treated with compound 1 was similar to values of the negative control group (0.29 ng of Cu2+/mg of protein). This alteration allowed us to infer that compound 1 combined with Cu2+ induces cell death through copper homeostasis dysregulation.

Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?

OBJECTIVES: The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. METHODS: Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. RESULTS: A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). CONCLUSION: Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.

MRIO: the Magnetic Resonance Imaging Acquisition and Analysis Ontology.

Magnetic resonance imaging of the brain is a useful tool in both the clinic and research settings, aiding in the diagnosis and treatments of neurological disease and expanding our knowledge of the brain. However, there are many challenges inherent in managing and analyzing MRI data, due in large part to the heterogeneity of data acquisition. To address this, we have developed MRIO, the Magnetic Resonance Imaging Acquisition and Analysis Ontology. MRIO provides well-reasoned classes and logical axioms for the acquisition of several MRI acquisition types and well-known, peer-reviewed analysis software, facilitating the use of MRI data. These classes provide a common language for the neuroimaging research process and help standardize the organization and analysis of MRI data for reproducible datasets. We also provide queries for automated assignment of analyses for given MRI types. MRIO aids researchers in managing neuroimaging studies by helping organize and annotate MRI data and integrating with existing standards such as Digital Imaging and Communications in Medicine and the Brain Imaging Data Structure, enhancing reproducibility and interoperability. MRIO was constructed according to Open Biomedical Ontologies Foundry principles and has contributed several classes to the Ontology for Biomedical Investigations to help bridge neuroimaging data to other domains. MRIO addresses the need for a "common language" for MRI that can help manage the neuroimaging research, by enabling researchers to identify appropriate analyses for sets of scans and facilitating data organization and reporting.