Genetic contributions of the serotonin transporter to social learning of fear and economic decision making

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social–emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity.     

Occupational exposure limits for manufactured nanomaterials,a systematic review

Background: The toxicological properties of manufactured nanomaterials (MNMs) can be different from their bulk-material and uncertainty remains about the adverse health effects they may have on humans. Proposals for OELs have been put forward which can be useful for risk management and workers’ protection. We performed a systematic review of proposals for OELs for MNMs to better understand the extent of such proposals, as well as their derivation methods.

Methods: We searched PubMed and Embase with an extensive search string and also assessed the references in the included studies. Two authors extracted the data independently.

Results: We identified 20 studies that proposed in total 56 OEL values. Of these, two proposed a generic level for all MNMs, 14 proposed a generic OEL for a category of MNMs and 40 proposed an OEL for a specific nanomaterial. For specific fibers, four studies proposed a similar value but for carbon nanotubes (CNTs) the values differed with a factor ranging from 30 to 50 and for metals with a factor from 100 to 300. The studies did not provide explanations for this variation. We found that exposure to MNMs measured at selected workplaces may exceed even the highest proposed OEL. This indicates that the application and use of OELs may be useful for exposure reduction.

Conclusion: OELs can provide a valuable reference point for exposure reduction measures in workplaces. There is a need for more and better supported OELs based on a more systematic approach to OEL derivation.     

Are common disease susceptibility alleles the same in outbred and founder populations?

Founder populations have been the subjects of complex disease studies because of their decreased genetic heterogeneity, increased linkage disequilibrium and more homogeneous environmental exposures. However, it is possible that disease alleles identified in founder populations may not contribute significantly to susceptibility in outbred populations. In this study we examine the Hutterites, a founder population of European descent, for 103 polymorphisms in 66 genes that are candidates for cardiovascular or inflammatory diseases. We compare the frequencies of alleles at these loci in the Hutterites to their frequencies in outbred European-American populations and test for associations with cardiovascular disease-associated phenotypes in the Hutterites. We show that alleles at these loci are found at similar frequencies in the Hutterites and in outbred populations. In addition, we report associations between 39 alleles or haplotypes and cardiovascular disease phenotypes (P<0.05), with five loci remaining significant after adjusting for multiple comparisons. These data indicate that this founder population is informative and offers considerable advantages for genetic studies of common complex diseases.     

Linking the human cytogenetic map with nucleotide sequence: the CCAP clone set

We present the completed dataset and clone repository of the Cancer Chromosome Aberration Project (CCAP), an initiative developed and funded through the intramural program of the U.S. National Cancer Institute, to provide seamless linkage of human cytogenetic markers with the primary nucleotide sequence of the human genome. Spaced at 1-2 Mb intervals across the human genome, 1,339 bacterial artificial chromosome (BAC) clones have been localized to chromosomal bands through high-resolution fluorescence in situ hybridization (FISH) mapping. Of these clones, 99.8% can be positioned on the primary human genome sequence and 95% are placed at or close to their precise nucleotide starts and stops. This dataset can be studied and manipulated within generally available public Web sites. The clones are available from a commercial repository. The CCAP BAC clone set provides anchors for the interrogation of gene and sequence involvement in oncogenic and developmental disorders when the starting point is the recognition of a structural, numerical, or interstitial chromosomal aberration. This dataset also provides a current view of the quality and coherence of the available genome sequence and insight into the nucleotide and three-dimensional structures that manifest as Giemsa light and dark chromosomal banding patterns.     

Accuracy of quantitative ultrasound parameters in the diagnosis of osteoporosis

Quantitative ultrasound (QUS) is of increasing interest for evaluation of osteoporosis because, compared with dual-energy X-ray absorptiometry (DXA), it is portable, less expensive, and radiation-free. The aim of our study was to determine the sensitivity, specificity, and cut-off values of quantitative ultrasound parameters in identifying patients with osteoporosis compared to the World Health Organization (WHO) standard definition. We performed a cross-sectional investigational study of 73 subjects, and determined total hip and lumbar spine T-scores by dual-energy X-ray absorptiometry (DXA) (Prodigy Advance Lunar-GE). The QUS parameters (broadband ultrasound attenuation [BUA], speed of sound, bone mineral density, the stiffness index, and QUS T-score) were determined with Sahara Hologic equipment. The AUC was 0.81 (95% CI 0.67–0.95, p<0.05) for speed of sound (SOS) and 0.76 (95% CI 0.62–0.90, p<0.05) for BUA for the patients with DXA T-scores ≥ −1 DS; the cut-off values were 1542.2 meters per second for SOS and 63.3 dB/MHz for BUA. In patients with DXA T-scores ≤ − 2.5 DS, AUC was 0.80 (95% CI 0.70–0.90, p<0.05) for SOS, and 0.76 (95% CI 0.65–0.87, p<0.05) for BUA. The cut-off values were 1504.95 meters per second for SOS and 49.5 dB/MHz for BUA. Pearson correlation coefficients were positive and statistically significant (> 50%) for all QUS parameters in both groups, (2-tailed, p<0.05). QUS parameters correctly identified normal patients (false negative 34.21% and false positive 2.53%) and those with osteoporosis (false negative 8.55% and false positive 7.82%). The patients with QUS parameters between the cut-off values corresponding to DXA T-scores of −1 SD and − 2.5 SD should be further evaluated by DXA.     

The relation of cognitive load and pupillary unrest

Objective  

This study examines the relationship between pupillary unrest (PU) and cognitive load.     

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma

Background

Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC-1 study. Cytokine release syndrome (CRS), a known manifestation of T-cell redirection, was observed in 119 of 165 patients (72.1%).

Methods

Patients received once-weekly teclistamab 1.5 mg/kg subcutaneously after two step-up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids.

Results

Most cases of CRS occurred during the step-up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity.

Conclusions

Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T-cell–engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab.

Plain language summary

• Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC-1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation.
• Most CRS occurred during the step-up schedule, requiring vigilance during treatment initiation.
• Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step-up schedule or administering the next teclistamab dose, to avoid exacerbating CRS.
• Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab.
• No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

     

Investigation into Thermomechanical Response of Polymer Composite Materials Produced through Additive Manufacturing Technologies

This paper presents the static mechanical behavior and the dynamic thermomechanical properties of four market-available reinforced and non-reinforced thermoplastics and photopolymer materials used as precursors in different additive manufacturing technologies. This article proposes a characterization approach to further address development of aeronautic secondary structures via 3D-printed composite materials replacing conventional manufactured carbon fiber reinforced polymer (CFRP) composites. Different 3D printing materials, technologies, printing directions, and parameters were investigated. Experimental results showed that carbon-reinforced ONYX_R material exhibits a transition point at 114 °C, a 600 MPa tensile strength, and an average tensile strain of 2.5%, comparable with conventional CFRP composites manufactured via autoclave, making it a suitable candidate for replacing CFRP composites, in the aim of taking advantage of 3D printing technologies. ONYX material exhibits higher stiffness than Acrylonitrile-Butadiene-Styrene Copolymer (ABS), or conventional Nylon 6/6 polyamide, the flexural modulus being 2.5 GPa; nevertheless, the 27 °C determined transition temperature limits its stability at higher temperature. Daylight High Tensile (further called HTS) resin exhibits a tensile strength and strain increase when shifting the printing direction from transversal to longitudinal, while no effect was observed in HighTemp DL400 resin (further called HTP).