Antidotal efficacies of the cyanide antidote candidate dimethyl trisulfide alone and in combination with cobinamide derivatives.

Formulation optimization and antidotal combination therapy are the two important tools to enhance the antidotal protection of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The focus of this study is to demonstrate how the formulation with polysorbate 80 (Poly80), an excipient used in pharmaceutical technology, and the combinations with other CN antidotes having different mechanisms of action enhance the antidotal efficacy of the unformulated (neat) DMTS. The LD50 for CN was determined by the statistical Dixon up-and-down method on mice. Antidotal efficacy was expressed as antidotal potency ratio (APR). CN was injected subcutaneously one minute prior to the antidotes' injection intramuscularly. The APR values of 1.17 (dose: 25 mg/kg bodyweight) and 1.45 (dose: 50 mg/kg bodyweight) of the neat DMTS were significantly enhanced by the Poly80 formulation at both investigated doses to 2.03 and 2.33, respectively. The combination partners for the Poly80 formulated DMTS (DMTS-Poly80; 25 and 50 mg/kg bodyweight) were 4-nitrocobinamide (4NCbi) (20 mg/kg bodyweight) and aquohydroxocobinamide (AHCbi; 50, 100, and 250 mg/kg bodyweight). When DMTS-Poly80 (25 and 50 mg/kg bodyweight; APR = 2.03 and 2.33, respectively) was combined with 4NCbi (20 mg/kg bodyweight; APR = 1.35), significant increase in the APR values were noted at both DMTS doses (APR = 2.38 and 3.12, respectively). AHCbi enhanced the APR of DMTS-Poly80 (100 mg/kg bodyweight; APR = 3.29) significantly only at the dose of 250 mg/kg bodyweight (APR = 5.86). These studies provided evidence for the importance of the formulation with Poly80 and the combinations with cobinamide derivatives with different mechanisms of action for DMTS as a CN antidote candidate.

The evolution of fluid intelligence meets formative g.

The argument by Burkart et al. in the target article relates to fluid (not general) intelligence: a domain-general ability involved in complex, novel problem solving, and strongly related to working memory and executive functions. A formative framework, under which the general factor of intelligence is the common consequence, not the common cause of the covariance among tests is more in line with an evolutionary approach.

Parenteral dosage form development and testing of dimethyl trisulfide, as an antidote candidate to combat cyanide intoxication.

This study focused on the solubility enhancement and the in vivo antidotal efficacy testing of a new potential cyanide (CN) countermeasure, dimethyl trisulfide (DMTS). Various FDA approved cyclodextrins (HPßCD, RMßCD, HPγCD), cosolvents (ethanol, polyethylene glycols, propylene glycol), surfactants (cremophor EL, cremophor RH 40, sodium cholate, sodium deoxycholate, polysorbate 80) and their combinations were applied. Based on the solubility enhancing potential of the tested systems, polysorbate 80 was chosen for further in vivo efficacy studies. A composition comprising 15% polysorbate 80 and 50 mg/ml DMTS with the applied DMTS dose of 100 mg/kg provided a therapeutic antidotal protection of 3.4 × LD50. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 × LD50 protection, and at the dose of 200 mg/kg, the LD50 was enhanced by 1.3 times. No difference in the therapeutic protection by DMTS was detected when the concentration of polysorbate 80 was increased to 20% (3.2 × LD50 protection). These data demonstrate the potential importance of DMTS as a CN countermeasure, and the formulation comprising polysorbate 80 provides the base of an injectable intramuscular dosage form that can later serve as a CN antidotal kit suitable for mass scenario.

Measuring Process Factors of Fluid Reasoning Using Multidimensional Computerized Adaptive Testing.

Although many fluid reasoning (Gf) tests have been developed, there is a lack of figural tests measuring its lower-order process factors simultaneously. The present article introduces the development of the Multidimensional Induction-Deduction Computerized Adaptive Test (MID-CAT) to measure two process factors of Gf. The MID-CAT is designed to provide an instrument that is flexible, efficient, and entirely free for non-commercial use. We created 530 items and administered them to a sample of N = 2,247. Items were fitted and calibrated using the Rasch model. The results indicate that the final item pool has a wide range of difficulties that could precisely measure a wide range of test-takers' abilities. A simulation study also indicates that MID-CAT provides greater measurement efficiency than separate-unidimensional CAT or fixed-item test. In the discussion, we provide perspectives on how the MID-CAT can be used for future research.

TRPS1 expression in breast angiosarcoma.

Angiosarcoma (AS) of the breast, a rare mesenchymal neoplasm, exhibits distinct forms based on etiological and genetic features. While cases with typical clinical presentation and morphology allow for a straightforward diagnosis, challenges arise when clinical data are scarce, diagnostic material is limited, or morphological characteristics overlap with other tumors, including undifferentiated carcinomas. The trichorhinophalangeal syndrome protein 1 (TRPS1), once regarded as highly specific for breast carcinomas, now faces doubts regarding its reliability. This study explores TRPS1 expression in breast AS. Our investigation revealed that 60% of AS cases displayed TRPS1 labeling, contrasting with the 40% lacking expression. Scoring by four independent readers established a consensus, designating 12/35 ASs as unequivocally TRPS1-positive. However, uncertainty surrounded nine further cases due to a lack of reader agreement (being substantial as reflected by a kappa value of 0.76). These findings challenge the perceived specificity of TRPS1, shedding light on its presence in a noteworthy proportion of breast ASs. Consequently, the study underscores the importance of a comprehensive approach in evaluating breast ASs and expands the range of entities within the differential diagnosis associated with TRPS1 labeling.

William Stern: The Relevance of His Program of 'Differential Psychology' for Contemporary Intelligence Measurement and Research.

William Stern is mostly renowned for inventing the IQ formula. However, he is also the originator of the term 'differential psychology' itself. His program of differential psychology synthesized population-based correlational studies as well as idiosyncratic approaches focusing on unique profiles of individuals. We argue that his approach still offers valuable ideas to this day; in particular, the individualistic sub-programme of Stern's differential psychology corresponds to a large extent to ipsative testing that emphasizes a profile-based analysis of individual strengths and weaknesses.

The Effect of Computerized Adaptive Testing on Motivation and Anxiety: A Systematic Review and Meta-Analysis.

Although many studies have been carried out on the psychometric aspects of computerized adaptive testing (CAT), its psychological aspects are less researched. Early studies claimed that CAT can be more motivating and induce less anxiety than traditional fixed-item tests (FIT). The purpose of this systematic review and meta-analysis was to gain a comprehensive understanding of the effects of CAT on motivation and anxiety in comparison to traditional fixed-item testing. Seven databases were examined. Articles were eligible if they employed an empirical study containing a direct comparison between CAT and FIT. Meta-analytical results showed no overall effect of test type on anxiety and motivation when comparing CAT with FIT (k = 11, g+ = 0.06, p = .28). However, easier CAT had positive effect compared with FIT (k = 2, g+ = .22, p < .001). Certain modifications in CAT administration can provide positive psychological effects for test-takers.

Immune cells as messengers from the CNS to the periphery: the role of the meningeal lymphatic system in immune cell migration from the CNS.

In recent decades there has been a large focus on understanding the mechanisms of peripheral immune cell infiltration into the central nervous system (CNS) in neuroinflammatory diseases. This intense research led to several immunomodulatory therapies to attempt to regulate immune cell infiltration at the blood brain barrier (BBB), the choroid plexus (ChP) epithelium, and the glial barrier. The fate of these infiltrating immune cells depends on both the neuroinflammatory environment and their type-specific interactions with innate cells of the CNS. Although the fate of the majority of tissue infiltrating immune cells is death, a percentage of these cells could become tissue resident immune cells. Additionally, key populations of immune cells can possess the ability to "drain" out of the CNS and act as messengers reporting signals from the CNS toward peripheral lymphatics. Recent data supports that the meningeal lymphatic system is involved not just in fluid homeostatic functions in the CNS but also in facilitating immune cell migration, most notably dendritic cell migration from the CNS to the meningeal borders and to the draining cervical lymph nodes. Similar to the peripheral sites, draining immune cells from the CNS during neuroinflammation have the potential to coordinate immunity in the lymph nodes and thus influence disease. Here in this review, we will evaluate evidence of immune cell drainage from the brain via the meningeal lymphatics and establish the importance of this in animal models and humans. We will discuss how targeting immune cells at sites like the meningeal lymphatics could provide a new mechanism to better provide treatment for a variety of neurological conditions.

Is There a "Gifted Personality"? Initial Evidence for Differences between MENSA and General Population Members in the HEXACO Personality Inventory.

Contrary to the common notion that personality and intelligence are unrelated constructs, numerous correlational studies have demonstrated substantial associations between the two domains. Moreover, samples of intellectually gifted individuals have been found to differ from the general population in specific aspects of their personalities. However, most studies so far have relied on the Five-Factor Model of Personality (FFM), while none have investigated this phenomenon using the HEXACO personality framework. We recruited 617 adult members of the international high-IQ society MENSA and compared them to 3 reference samples (combined N = 112,637) regarding their personalities as measured by the HEXACO-60 personality inventory. We found that gifted persons scored higher in Honesty-Humility and Conscientiousness but lower in Emotionality compared to reference samples. Interestingly, gifted individuals scored only slightly higher in Openness to Experience, and no consistent differences emerged for Agreeableness. We demonstrate that some known personality differences between gifted and non-gifted persons translate from the FFM to the HEXACO model, while others do not. Our results indicate that within the HEXACO factor structure differences in sociability are more pronounced, while intellect-related differences are comparatively weak.

Bright, but allergic and neurotic? A critical investigation of the "overexcitable genius" hypothesis.

Introduction: Higher intelligence has been associated with improved health and longevity. However, recent findings have claimed that exceptional intelligence may come at a cost. Individuals at the upmost end of the intelligence distribution are reported to be disproportionately afflicted by a set of stress-related physical and mental health conditions: so-called overexcitabilities. Few accounts have investigated this issue and no studies are available for non-US samples yet. Here, we aimed to replicate and extend previous work by examining hitherto unaddressed overexcitabilities in a European high-IQ sample. Methods: We carried out a preregistered survey among members of MENSA, the world's largest high-IQ society. In total, 615 (307 male) members from Austria, Germany, Hungary, Switzerland, and the United Kingdom participated. Results and Discussion: Compared to the general population, our sample exhibited considerably elevated prevalences in autism spectrum disorders (risk ratio/RR = 2.25), chronic fatigue syndrome (RR = 5.69), depression (RR = 4.38), generalized anxiety (RR = 3.82), and irritable bowel syndrome (RR = 3.76). Contrary to previous accounts, neither asthma, allergies, nor autoimmune diseases were elevated. We show that this subsample of intellectually gifted persons faces specific health challenges compared to the general population. The reasons for this remain speculative, as we find little evidence for previously proposed immunological explanations. However, it is possible that the effects are caused by sample selectiveness (i.e., membership in a high-IQ society) rather than high IQ itself.

Ultrasonic bone age fractionates cognitive abilities in adolescence.

Adolescent development is not only shaped by the mere passing of time and accumulating experience, but it also depends on pubertal timing and the cascade of maturational processes orchestrated by gonadal hormones. Although individual variability in puberty onset confounds adolescent studies, it has not been efficiently controlled for. Here we introduce ultrasonic bone age assessment to estimate biological maturity and disentangle the independent effects of chronological and biological age on adolescent cognitive abilities. Comparing cognitive performance of female participants with different skeletal maturity we uncover the impact of biological age on both IQ and specific abilities. We find that biological age has a selective effect on abilities: more mature individuals within the same age group have higher working memory capacity and processing speed, while those with higher chronological age have better verbal abilities, independently of their maturity. Based on our findings, bone age is a promising biomarker of adolescent maturity.

HunCRC: annotated pathological slides to enhance deep learning applications in colorectal cancer screening.

Histopathology is the gold standard method for staging and grading human tumors and provides critical information for the oncoteam's decision making. Highly-trained pathologists are needed for careful microscopic analysis of the slides produced from tissue taken from biopsy. This is a time-consuming process. A reliable decision support system would assist healthcare systems that often suffer from a shortage of pathologists. Recent advances in digital pathology allow for high-resolution digitalization of pathological slides. Digital slide scanners combined with modern computer vision models, such as convolutional neural networks, can help pathologists in their everyday work, resulting in shortened diagnosis times. In this study, 200 digital whole-slide images are published which were collected via hematoxylin-eosin stained colorectal biopsy. Alongside the whole-slide images, detailed region level annotations are also provided for ten relevant pathological classes. The 200 digital slides, after pre-processing, resulted in 101,389 patches. A single patch is a 512 × 512 pixel image, covering 248 × 248 µm2 tissue area. Versions at higher resolution are available as well. Hopefully, HunCRC, this widely accessible dataset will aid future colorectal cancer computer-aided diagnosis and research.

Investigating the Prognostic Relevance of Tumor Immune Microenvironment and Immune Gene Assembly in Breast Carcinoma Subtypes.

We hypothesized that different BC subtypes are characterized by spatially distinct tumor immune microenvironment (TIME) and that immune gene assembly of metastatic (Met) and non-metastatic (Ctrl) BCs vary across subtypes. Peritumoral, stromal and intratumoral TIL was assessed on 309 BC cases. Hot, cold and immune-excluded groups were defined, and the prognostic role of this classification was assessed. CD4+/CD8+ positivity was analyzed in 75 cases in four systematically predefined tumor regions. Immune gene expression of Met and Ctrl HER2-negative BCs was compared by using NanoString nCounter technology. The amount of TIL infiltration varied greatly within all BC subtypes. Two-third of the cases were cold tumors with no significant survival difference compared to hot tumors. A lower CD4+/CD8+ ratio at the stromal internal tumor region was significantly associated with longer distant metastasis-free survival. The differentially expressed immune genes between Met and Ctrl varied across the studied BC subtypes with TNBC showing distinct features from the luminal subtypes. The TIME is characterized by a considerable heterogeneity; however, low level of TILs does not equate to disease progression. The differences in immune gene expression observed between Met and Ctrl breast carcinomas call attention to the important role of altered immune function in BC progression.

Individual Differences in Attention and Intelligence: A United Cognitive/Psychometric Approach.

Process overlap theory (POT) is a new theoretical framework designed to account for the general factor of intelligence (g). According to POT, g does not reflect a general cognitive ability. Instead, g is the result of multiple domain-general executive attention processes and multiple domain-specific processes that are sampled in an overlapping manner across a battery of intelligence tests. POT explains several benchmark findings on human intelligence. However, the precise nature of the executive attention processes underlying g remains unclear. In the current paper, we discuss challenges associated with building a theory of individual differences in attention and intelligence. We argue that the conflation of psychological theories and statistical models, as well as problematic inferences based on latent variables, impedes research progress and prevents theory building. Two studies designed to illustrate the unique features of POT relative to previous approaches are presented. In Study 1, a simulation is presented to illustrate precisely how POT accounts for the relationship between executive attention processes and g. In Study 2, three datasets from previous studies are reanalyzed (N = 243, N = 234, N = 945) and reveal a discrepancy between the POT simulated model and the unity/diversity model of executive function. We suggest that this discrepancy is largely due to methodological problems in previous studies but also reflects different goals of research on individual differences in attention. The unity/diversity model is designed to facilitate research on executive function and dysfunction associated with cognitive and neural development and disease. POT is uniquely suited to guide and facilitate research on individual differences in cognitive ability and the investigation of executive attention processes underlying g.

Revisiting the Coreceptor Function of Complement Receptor Type 2 (CR2, CD21); Coengagement With the B-Cell Receptor Inhibits the Activation, Proliferation, and Antibody Production of Human B Cells.

The positive coreceptor function of complement receptor type 2 [CR2 (CD21)] on B cells is generally accepted, although its role in the enhancement of antibody production had only been proven in mice. The importance of this phenomenon prompted reinvestigation of the functional consequences of coclustering CD21 and the B cell receptor (BCR) on primary human cells. We found that, at non-stimulatory concentrations of anti-IgG/A/M, coclustering the BCR and CR2 enhanced the Ca2+ response, while activation marker expression, cytokine production, proliferation, and antibody production were all inhibited upon the coengagement of CR2 and BCR on human B cells. Thus, the "textbook dogma" claiming that C3d acts as an adjuvant to enhance humoral immunity is relevant only to mice and not to humans.

Investigating the Structure of Intelligence Using Latent Variable and Psychometric Network Modeling: A Commentary and Reanalysis.

In a recent publication in the Journal of Intelligence, Dennis McFarland mischaracterized previous research using latent variable and psychometric network modeling to investigate the structure of intelligence. Misconceptions presented by McFarland are identified and discussed. We reiterate and clarify the goal of our previous research on network models, which is to improve compatibility between psychological theories and statistical models of intelligence. WAIS-IV data provided by McFarland were reanalyzed using latent variable and psychometric network modeling. The results are consistent with our previous study and show that a latent variable model and a network model both provide an adequate fit to the WAIS-IV. We therefore argue that model preference should be determined by theory compatibility. Theories of intelligence that posit a general mental ability (general intelligence) are compatible with latent variable models. More recent approaches, such as mutualism and process overlap theory, reject the notion of general mental ability and are therefore more compatible with network models, which depict the structure of intelligence as an interconnected network of cognitive processes sampled by a battery of tests. We emphasize the importance of compatibility between theories and models in scientific research on intelligence.

New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4.

The involvement of complement in the regulation of antibody responses has been known for long. By now several additional B cell functions - including cytokine production and antigen presentation - have also been shown to be regulated by complement proteins. Most of these important activities are mediated by receptors interacting with activation fragments of the central component of the complement system C3, such as C3b, iC3b and C3d, which are covalently attached to antigens and immune complexes. This review summarizes the role of complement receptors interacting with these ligands, namely CR1 (CD35), CR2 (CD21), CR3 (CD11b/CD18) and CR4 (CD11c/CD18) expressed by B cells in health and disease. Although we focus on human B lymphocytes, we also aim to call the attention to important differences between human and mouse systems.

Composition optimization and stability testing of a parenteral antifungal solution based on a ternary solvent system.

An intravenous solution is a dosage forms intended for administration into the bloodstream. This route is the most rapid and the most bioavailable method of getting drugs into systemic circulation, and therefore it is also the most liable to cause adverse effects. In order to reduce the possibility of side effects and to ensure adequate clinical dosage of the formulation, the primarily formulated composition should be optimized. It is also important that the composition should retain its therapeutic effectiveness and safety throughout the shelf-life of the product. This paper focuses on the optimization and stability testing of a parenteral solution containing miconazole and ketoconazole solubilized with a ternary solvent system as model drugs. Optimization of the solvent system was performed based on assessing the risk/benefit ratio of the composition and its properties upon dilution. Stability tests were conducted based on the EMEA (European Medicines Agency) "guideline on stability testing: stability testing of existing active substances and related finished products". Experiments show that both the amount of co-solvent and surface active agent of the solvent system could substantially be reduced, while still maintaining adequate solubilizing power. It is also shown that the choice of various containers affects the stability of the compositions. It was concluded that by assessing the risk/benefit ratio of solubilizing power versus toxicity, the concentration of excipients could be considerably decreased while still showing a powerful solubilizing effect. It was also shown that a pharmaceutically acceptable shelf-life could be assigned to the composition, indicating good long-term stability.

Evaluation of drug release from coated pellets based on isomalt, sugar, and microcrystalline cellulose inert cores.

The objective of the present study was to investigate the effect of the pellet core materials isomalt, sugar, and microcrystalline cellulose on the in vitro drug release kinetics of coated sustained-release pellets as well as to evaluate the influence of different ratios of polymethacrylate copolymers exhibiting different permeability characteristics on the drug release rate. For characterization of the drug release process of pellets, the effect of osmolality was studied using glucose as an osmotically active agent in the dissolution medium. The pellet cores were layered with diclofenac sodium as model drug and coated with different ratios of Eudragit RS30D and Eudragit RL30D (ERS and ERL; 0:1 and 0.5:0.5 and 1:0 ratio) in a fluid bed apparatus. Physical characteristics such as mechanical strength, shape, and size proved that the inert cores were adequate for further processing. The in vitro dissolution tests were performed using a USP Apparatus I (basket method). The results demonstrated that, besides the ratio of the coating polymers (ERS/ERL), the release mechanism was also influenced by the type of starter core used. Sugar- and isomalt-type pellet cores demonstrated similar drug release profiles.

The Mitochondrial Theory of g Is Incompatible with Genetic Evidence and Does Not Explain Statistical Phenomena.

In two recent reviews (Geary 2018; Geary 2019) [...].