Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic considerations surrounding the use of levetiracetam for seizure prophylaxis in neurocritical care – an overview

ABSTRACT Introduction Levetiracetam (LEV) is one of the most widely used anti-seizure medications (ASMs) in clinical practice. This is due both to a different mechanism of action when compared to other ASMs and its easy handling. Indeed, because of its interesting pharmacokinetic properties, it is often used outside of the labeled indications, notably in the neurocritical setting as prophylaxis of epileptic seizures. Areas covered A literature search was conducted and the most relevant studies on the pharmacokinetic properties of LEV were selected by two independent investigators. Current evidence on the use of ASM prophylaxis in the neurocritical setting was also reviewed, highlighting and discussing the strengths and limits of LEV as drug of choice for anti-epileptic prophylaxis in this scenario. Expert opinion LEV has a ‘near-ideal’ pharmacokinetic profile, which makes it an attractive drug for ASM prophylaxis in neurocritical care. However, current recommendations restrict ASMs prophylaxis to very selected circumstances and the role of LEV is marginal. Moreover, studies are generally designed to compare LEV versus phenytoin, whereas studies comparing LEV versus placebo are lacking. Further, randomized trials will be needed to better elucidate LEV utility and its neuroprotective role in the neurocritical setting.
Statistical analysis of characteristics of Infant-Directed-Interaction with respect to action structure

Acoustic packaging, intersensory redundancy, motherese and motionese are the main concepts, which describe how acoustic features and body movements of caretakers are adapted intuitively in adult-child-interaction. This thesis will approach the question,whether feature characteristics highlight certain parts of child-directed actions. The main part focuses on the statistical examination of four features, Eye-Gaze, Intonation, Word, Velocity of Hand Motion of child-directed demonstrations. The auditory and visual signals of the recorded toy demonstrations were divided into meaningful segments for this examination. Then the composition of each feature and its values (fc) in each segment is analysed. A conditional probability model P(Segment_x|fc_j) is computed to answer the question: in which segment (Segment_x) is, an already appeared feature characteristic fc_j , likely to occur? Patterns of high conditional probability values have been identified for distinct feature characteristics and provide a basis for a future automatic classification.
Developmental plasticity in thermal tolerance: Ontogenetic variation, persistence, and future directions

Abstract Understanding the factors affecting thermal tolerance is crucial for predicting the impact climate change will have on ectotherms. However, the role developmental plasticity plays in allowing populations to cope with thermal extremes is poorly understood. Here, we meta‐analyse how thermal tolerance is initially and persistently impacted by early (embryonic and juvenile) thermal environments by using data from 150 experimental studies on 138 ectothermic species. Thermal tolerance only increased by 0.13°C per 1°C change in developmental temperature and substantial variation in plasticity (~36%) was the result of shared evolutionary history and species ecology. Aquatic ectotherms were more than three times as plastic as terrestrial ectotherms. Notably, embryos expressed weaker but more heterogenous plasticity than older life stages, with numerous responses appearing as non‐adaptive. While developmental temperatures did not have persistent effects on thermal tolerance overall, persistent effects were vastly under‐studied, and their direction and magnitude varied with ontogeny. Embryonic stages may represent a critical window of vulnerability to changing environments and we urge researchers to consider early life stages when assessing the climate vulnerability of ectotherms. Overall, our synthesis suggests that developmental changes in thermal tolerance rarely reach levels of perfect compensation and may provide limited benefit in changing environments.
The economic burden of biologic disease-modifying antirheumatic drugs in rheumatoid arthritis patients in the United States

ABSTRACT Background Previous U.S. economic burden estimates for rheumatoid arthritis (RA) varied from $85.6 to $148.1 billion annually. However, these estimates do not reflect comparative amounts spent on RA treatment options in addition to other medical expenditures. Therefore, this study’s goal was to comparatively analyze the overall economic burden of U.S. patients treated for RA using conventional disease-modifying antirheumatic drugs (DMARDs) versus TNF alpha biologic DMARDs. Research Design and Methods This retrospective observational study analyzed Medical Expenditure Panel Survey Household Component data from 2016 to 2018. Healthcare utilization, total medical expenditures, and out-of-pocket expenditures were compared between RA medication groups. Results Three hundred twenty-five adult RA patients experiencing 603 RA-related events, including at least one medical visit, were identified. Rheumatic arthritis-attributable medical expenditures among patients prescribed DMARDs were $11.4 billion. Average total medical expenditures were significantly higher for the TNF alpha biologic group $26,216.67 (95% CI: $19,502.84–$32,930.5) versus $5,388.52 (95% CI: $2,768.25–$8,008.79) for the conventional DMARD group (p < 0.001). Conclusions RA patients receiving TNF alpha biologics experienced significantly higher total medical and out-of-pocket expenditures; however, they experienced fewer or no occurrences of high-cost drivers of healthcare utilization compared to patients receiving conventional DMARDs. Plain Language Summary This study shows that rheumatoid arthritis (RA) patients with biologic-containing disease-modifying antirheumatic drugs (DMARDs) encountered significantly higher total medical expenditures as well as out-of-pocket (OOP) expenditures versus those with conventional DMARDs. The average total medical expenditures were $26,216.67 in the tumor necrosis factor (TNF) alpha biologic group and $5,388.52 in the conventional DMARD group. However, even with higher total medical expenditures, data suggests the TNF alpha biologic group experienced fewer emergency room visits, less home health services, and no hospitalizations compared to the conventional DMARD group.
Comparison of prognostic scores for inpatients with COVID-19: a retrospective monocentric cohort study

Background The SARS-CoV-2 pandemic led to a steep increase in hospital and intensive care unit (ICU) admissions for acute respiratory failure worldwide. Early identification of patients at risk of clinical deterioration is crucial in terms of appropriate care delivery and resource allocation. We aimed to evaluate and compare the prognostic performance of Sequential Organ Failure Assessment (SOFA), Quick Sequential Organ Failure Assessment (qSOFA), Confusion, Uraemia, Respiratory Rate, Blood Pressure and Age ≥65 (CURB-65), Respiratory Rate and Oxygenation (ROX) index and Coronavirus Clinical Characterisation Consortium (4C) score to predict death and ICU admission among patients admitted to the hospital for acute COVID-19 infection. Methods and analysis Consecutive adult patients admitted to the Geneva University Hospitals during two successive COVID-19 flares in spring and autumn 2020 were included. Discriminative performance of these prediction rules, obtained during the first 24 hours of hospital admission, were computed to predict death or ICU admission. We further exluded patients with therapeutic limitations and reported areas under the curve (AUCs) for 30-day mortality and ICU admission in sensitivity analyses. Results A total of 2122 patients were included. 216 patients (10.2%) required ICU admission and 303 (14.3%) died within 30 days post admission. 4C score had the best discriminatory performance to predict 30-day mortality (AUC 0.82, 95% CI 0.80 to 0.85), compared with SOFA (AUC 0.75, 95% CI 0.72 to 0.78), qSOFA (AUC 0.59, 95% CI 0.56 to 0.62), CURB-65 (AUC 0.75, 95% CI 0.72 to 0.78) and ROX index (AUC 0.68, 95% CI 0.65 to 0.72). ROX index had the greatest discriminatory performance (AUC 0.79, 95% CI 0.76 to 0.83) to predict ICU admission compared with 4C score (AUC 0.62, 95% CI 0.59 to 0.66), CURB-65 (AUC 0.60, 95% CI 0.56 to 0.64), SOFA (AUC 0.74, 95% CI 0.71 to 0.77) and qSOFA (AUC 0.59, 95% CI 0.55 to 0.62). Conclusion Scores including age and/or comorbidities (4C and CURB-65) have the best discriminatory performance to predict mortality among inpatients with COVID-19, while scores including quantitative assessment of hypoxaemia (SOFA and ROX index) perform best to predict ICU admission. Exclusion of patients with therapeutic limitations improved the discriminatory performance of prognostic scores relying on age and/or comorbidities to predict ICU admission.
Understanding the effects of a complex psychological intervention on symptoms of depression in Goa, India: findings from a causal mediation analysis

Background Understanding how and under what circumstances a highly effective psychological intervention, improved symptoms of depression is important to maximise its clinical effectiveness. Aims To address this complexity, we estimate the indirect effects of potentially important mediators to improve symptoms of depression (measured with the Patient Health Questionnaire (PHQ-9)) in the Healthy Activity Program trial. Method Interventional in(direct) effects were used to decompose the total effect of the intervention on PHQ-9 scores into the direct and indirect effects. The following indirect effects were considered: characteristics of sessions, represented by the number of sessions and homework completed; behavioural activation, according to an adapted version of the Behavioural Activation for Depression Scale – Short Form; and extra sessions offered to participants who did not respond to the intervention. Results Of the total effect of the intervention measured through the difference in PHQ-9 scores between treatment arms (mean difference: −2.1, bias-corrected 95% CI −3.2 to −1.5), 34% was mediated through improved levels of behavioural activation (mean difference: −0.7, bias-corrected 95% CI −1.2 to −0.4). There was no evidence to support the mediating role of characteristics of the sessions nor the extra sessions offered to participants who did not respond to the treatment. Conclusions Findings from our robust mediation analyses confirmed the importance of targeting behavioural activation. Contrary to published literature, our findings suggest that neither the number of sessions nor proportion of homework completed improved outcomes. Moreover, in this context, alternative treatments other than extra sessions should be considered for patients who do not respond to the intervention.
Costs of implementing universal test and treat in three correctional facilities in South Africa and Zambia

Introduction Universal test and treat (UTT) is a population-based strategy that aims to ensure widespread HIV testing and rapid antiretroviral therapy (ART) for all who have tested positive regardless of CD4 count to decrease HIV incidence and improve health outcomes. Little is known about the specific resources required to implement UTT in correctional facilities for incarcerated people. The primary aim of this study was to describe the resources used to implement UTT and to provide detailed costing to inform UTT scale-up in similar settings. Methods The costing study was a cross-sectional descriptive study conducted in three correctional complexes, Johannesburg Correctional Facility in Johannesburg (>4000 inmates) South Africa, and Brandvlei (~3000 inmates), South Africa and Lusaka Central (~1400 inmates), Zambia. Costing was determined through a survey conducted between September and December 2017 that identified materials and labour used for three separate components of UTT: HIV testing services (HTS), ART initiation, and ART maintenance. Our study participants were staff working in the correctional facilities involved in any activity related to UTT implementation. Unit costs were reported as cost per client served while total costs were reported for all clients seen over a 12-month period. Results The cost of HIV testing services (HTS) per client was $ 92.12 at Brandvlei, $ 73.82 at Johannesburg, and $ 65.15 at Lusaka. The largest cost driver for HIV testing at Brandvlei were staff costs at 55.6% of the total cost, while at Johannesburg (56.5%) and Lusaka (86.6%) supplies were the largest contributor. The cost per client initiated on ART was $917 for Brandvlei, $421.8 for Johannesburg, and $252.1 for Lusaka. The activity cost drivers were adherence counselling at Brandvlei (59%), and at Johannesburg and Lusaka it was the actual ART initiation at 75.6% and 75.8%, respectively. The annual unit cost for ART maintenance was $2,640.6 for Brandvlei, $710 for Johannesburg, and $385.5 for Lusaka. The activity cost drivers for all three facilities were side effect monitoring, and initiation of isoniazid preventive treatment (IPT), cotrimoxazole, and fluconazole, with this comprising 44.7% of the total cost at Brandvlei, 88.9% at Johannesburg, and 50.5% at Lusaka. Conclusion Given the needs of this population, the opportunity to reach inmates at high risk for HIV, and overall national and global 95-95-95 goals, the UTT policies for incarcerated individuals are of vital importance. Our findings provide comparator costing data and highlight key drivers of UTT cost by facility.
Evidentiality, Part II

Ross's underlying performative can now be reinterpreted in terms of Cinque's adverbial MoodevidentialP. The `default' interpretation of MoodevidentialP, in the absence of other indications, is that the speaker (source of information) assumes responsibility (evidence type) for a sentence uttered (Cinque, 1999). This speaker can be represented by a 1st person feature in the Moodevidential° of main clauses. Such a formalization immediately evokes a host of questions with respect to the representation of MoodevidentialP in complementation, more in particular in direct and indirect speech. Such a discussion is important here in view of the evident relationship between direct speech and the evidential category of quotative. Reinterpreting ideas of Ban®eld (1982), I would like to propose that the person features which function as `Source of information' in Moodevidential° differ considerably in direct and indirect speech. The data in (43a,b) suggest that the person features in Moodevidential° of indirect speech are anaphoric in nature: they take the matrix subject as the `Source of information'. This analysis also re ects the idea that the matrix subject is responsible for the information status of the sentential complement. This does not mean that the matrix subject is necessarily responsible for the degree of reliability with which the sentential complement is presented. With verbs of saying and believing, the degree of reliability covaries with the reliability of the matrix subject, but with factive verbs, the degree of reliability of the sentential complement is entirely independent of the reliability of the matrix subject, and is presented as a fact. In direct speech complements, the person feature functioning as `Source of information' in Moodevidential° could be argued to be identical to that in main clauses, i.e. 1st person. A comparison of direct speech in (45) with the sentences in (43) shows that the `point of view' adjunct as for my/himself in (45) patterns with main clauses, not with embedded clauses:
Lab-Attenuated Rabies Virus Facilitates Opening of the Blood-Brain Barrier by Inducing Matrix Metallopeptidase 8

The ability to change BBB permeability was associated with the pathogenicity of RABV. BBB permeability was enhanced by infection with lab-attenuated RABV instead of wt RABV, allowing immune cells to infiltrate into the CNS. ABSTRACT Infection with laboratory-attenuated rabies virus (RABV), but not wild-type (wt) RABV, can enhance the permeability of the blood-brain barrier (BBB), which is considered a key determinant for RABV pathogenicity. A previous study showed that the enhancement of BBB permeability is directly due not to RABV infection but to virus-induced inflammatory molecules. In this study, the effect of the matrix metallopeptidase (MMP) family on the permeability of the BBB during RABV infection was evaluated. We found that the expression level of MMP8 was upregulated in mice infected with lab-attenuated RABV but not with wt RABV. Lab-attenuated RABV rather than wt RABV activates inflammatory signaling pathways mediated by the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Activated NF-κB (p65) and AP-1 (c-Fos) bind to the MMP8 promoter, resulting in upregulation of its transcription. Analysis of mouse brains infected with the recombinant RABV expressing MMP8 indicated that MMP8 enhanced BBB permeability, leading to infiltration of inflammatory cells into the central nervous system (CNS). In brain-derived endothelial cells, treatment with MMP8 recombinant protein caused the degradation of tight junction (TJ) proteins, and the application of an MMP8 inhibitor inhibited the degradation of TJ proteins after RABV infection. Furthermore, an in vivo experiment using an MMP8 inhibitor during RABV infection demonstrated that BBB opening was diminished. In summary, our data suggest that the infection of lab-attenuated RABV enhances the BBB opening by upregulating MMP8. IMPORTANCE The ability to change BBB permeability was associated with the pathogenicity of RABV. BBB permeability was enhanced by infection with lab-attenuated RABV instead of wt RABV, allowing immune cells to infiltrate into the CNS. We found that MMP8 plays an important role in enhancing BBB permeability by degradation of TJ proteins during RABV infection. Using an MMP8 selective inhibitor restores the reduction of TJ proteins. We reveal that MMP8 is upregulated via the MAPK and NF-κB inflammatory pathways, activated by lab-attenuated RABV infection but not wt RABV. Our findings suggest that MMP8 has a critical role in modulating the opening of the BBB during RABV infection, which provides fresh insight into developing effective therapeutics for rabies and infection with other neurotropic viruses.
Psychotic experiences in the general population, a review; definition, risk factors, outcomes and interventions

Abstract Psychotic experiences (PE) are common in the general population, in particular in childhood, adolescence and young adulthood. PE have been shown to be associated with an increased risk for later psychotic disorders, mental disorders, and poorer functioning. Recent findings have highlighted the relevance of PE to many fields of healthcare, including treatment response in clinical services for anxiety & depression treatment, healthcare costs and service use. Despite PE relevance to many areas of mental health, and healthcare research, there remains a gap of information between PE researchers and experts in other fields. With this review, we aim to bridge this gap by providing a broad overview of the current state of PE research, and future directions. This narrative review aims to provide an broad overview of the literature on psychotic experiences, under the following headings: (1) Definition and Measurement of PE; (2) Risk Factors for PE; (3) PE and Health; (4) PE and Psychosocial Functioning; (5) Interventions for PE, (6) Future Directions.
Effective Connectivity Analysis and Classification of Action Observation From Different Perspectives: An fMRI Study

Objective: Analyzing the effective connectivity characteristics of brain networks in the process of action observation is helpful for understanding the neurodynamic mechanisms during action observation. Method: In this study, functional magnetic resonance imaging (fMRI) images were obtained from 20 participants who performed hand-object interaction observation tasks from the first-person perspective (1PP) and third-person perspective (3PP). On the basis of a meta-analysis, 11 key brain regions were extracted as nodes to build an action observation network. The weighted and directional connections between all of the nodes were investigated using partial directional coherence (PDC) analysis in five narrow frequency bands. Results: The statistical analysis indicated that the ultra-low frequency band ($\leq$ 0.04 Hz) exhibited significant activation compared with other frequency bands for both 1PP and 3PP. In addition, it was found that 3PP induced significantly stronger brain activation than 1PP in the ultra-low frequency band. Moreover, this study attempted to classify fMRI data corresponding to different perspectives using brain network features. A comparative analysis revealed that the weighted and binary PDC matrix methods achieved classification accuracies of 86.3% and 80.8%, respectively. Significance: The weighted PDC analysis exhibits a more comprehensive understanding of neural mechanisms during action observation in different visual perspectives. It also has potential applications value in human-computer interaction in the future.
Acrodysostosis and pseudohypoparathyroidism (PHP): adaptation of Japanese patients with a newly proposed classification and expanding the phenotypic spectrum of variants

Objective This study aimed to report on 15 Japanese patients with acrodysostosis and pseudohypoparathyroidism (PHP) and analyze them using the newly proposed classification of the EuroPHP network to determine whether this classification system is suitable for Japanese patients. Design We divided the patients into three groups based on hormone resistance, the number of fingers with short metacarpals, the existence of cone-shaped epiphyses and gene defects. Methods We carried out clinical, radiological and genetic evaluations of two patients in group A (iPPSD5), six patients in group B (iPPDS4) and seven patients in group C (iPPSD2). Results Group A consisted of two siblings without hormone resistance who had the most severe bone and physical developmental delays. PDE4D gene defects were detected in both cases. Group B consisted of six patients who showed hormone resistance without hypocalcemia. Short metacarpal bones with corn-shaped epiphyses were observed in all patients. In two cases, PRKAR1A gene defects were detected; however, their clinical and radiological features were not identical. The facial dysmorphism and developmental delay were less severe and PRKAR1A gene defects were detected in case B-3. Severe facial dysmorphism and deformity of metacarpal bones were observed, but no gene defect was detected in case B-1. Group C consisted of seven patients with PHP1a, four of whom had maternally inherited heterozygous inactivating mutations in one of the GNAS genes. The clinical and radiological features of the patients in group C were not identical either. Conclusions The newly proposed classification is suitable for Japanese patients; however, heterogeneities still existed within groups B and C.