Salivary cortisol response to psychosocial stress in patients with first-episode psychosis

AimTo analyze the difference in the salivary cortisol response to psychosocial stress between the patients with the first episode of psychosis (FEP) and the control group.MethodsWe performed a cross-sectional analysis of the baseline measurements of a prospective cohort study conducted from 2015 to 2018 at two Croatian psychiatric hospitals. The study consecutively enrolled 53 patients diagnosed with FEP and 63 healthy controls. The primary outcome was the difference in the changes of salivary cortisol concentration during the stress test. The secondary outcome was the difference in the baseline levels of salivary cortisol between patients with FEP and controls. The tertiary outcome were the correlations of salivary cortisol levels with the results of the Positive and Negative Syndrome Scale for Schizophrenia, Rosenberg Self-Esteem Scale, and the International Personality Item Pool.ResultsPatients with FEP had significantly higher baseline salivary cortisol than controls, but their salivary cortisol increased significantly less during the stress test.ConclusionPatients with FEP respond differently to stressful stimuli than controls, as shown by the increased baseline salivary cortisol and blunted cortisol response, possibly indicating a greater vulnerability to psychosocial stress.

Schizophrenia is one of the most complex psychiatric disorders (1), and in most cases, a long-term condition characterized by alternating periods of acute psychosis and remission. The first episode of psychosis (FEP) is usually preceded by a prodromal phase with non-specific symptoms, followed by psychotic symptoms pertaining to five dimensions: positive, negative, affective, cognitive, and psychomotor. While the pathogenesis is largely unknown, different streams of research consistently show that schizophrenia results from a complex gene-environment interaction (2), in line with the stress-diathesis model of schizophrenia etiology (3). According to this model, genetic and environmental factors lead to vulnerability to schizophrenia (2), and schizophrenia occurs when the vulnerable person experiences “enough” stress (4). For the majority of people, significant distress is associated with major stressors, eg, death in the family, serious illness, or separation (5). However, in persons prone to psychosis significant distress is caused even by minor stressors, also known as daily hassles (6).Response to stress involves the activation of the hypothalamic-pituitary-adrenal axis (HPA): the hypothalamus secretes corticotropin-releasing factor (CRF), which stimulates the secretion of adrenocorticotropic hormone (ACTH) from the front pituitary gland. ACTH then stimulates the release of cortisol from the adrenal gland, causing the cascading effect of several bodily systems (immune, neuroendocrine, inflammatory response to the organism, etc) (7). In the central nervous system, increased cortisol levels can lead to the sensitization of dopaminergic response to stress, which can lead to an excessive dopamine release and psychotic symptoms (6). Indeed, various indicators of altered stress response have been confirmed in the population at risk for psychosis compared with healthy population (8,9).While it has been suggested that persons with schizophrenia show a blunted cortisol response following experimentally induced psychosocial stress (10,11), these findings should be further elucidated considering the heterogeneous research results. Some of these discrepancies may arise from the heterogeneity of the samples and different confounding factors but also from different stress response across illness types and stages (12).Generally, persons with FEP show higher basal cortisol values than the healthy population (8,13,14), a finding that possibly indicates their increased basic HPA hyperactivity, which contributes to their higher vulnerability to stressors. HPA axis hyperactivity indicated by elevated basal cortisol levels in individuals with psychosis is expected to also produce a higher acute elevation of cortisol concentrations in response to acute stressful situation (11). However, studies on FEP are not uniform in their findings (5-7). A small study with eleven medication-naive patients found an attenuated response of cortisol to psychosocial stress (15). Furthermore, Pruessner et al (16) reported significantly lower cortisol levels and systolic blood pressure during the psychosocial stress task in an ultra-high-risk group compared with controls; the lower cortisol levels were associated with higher self-rated stress in the past year. The authors suggested that in these patients attenuated stress response reflects the vulnerability to stressors. A recent study among patients with FEP obtained contrary results, ie, lower salivary cortisol levels at baseline but no difference in the cortisol response during psychosocial stress challenge test compared with healthy controls (17). Another study found no differences in baseline salivary cortisol levels between patients with FEP and controls, but a blunted cortisol response to stressors in FEP, both on and off medication, compared with controls (18). Finally, individuals with schizophrenia have shown lower cortisol levels both in anticipation and after exposure to social stress compared with controls, even though there were no differences in cortisol production rate (19).Of note, people with posttraumatic stress syndrome (20) and those with high anxiety traits (21) showed higher salivary baseline cortisol, but a blunted response to psychosocial stress compared with healthy controls (22), which suggests a deficient acute neuroendocrine stress response.Thus, the aim of our study was to assess the difference in the salivary cortisol response to the psychosocial stress between the patients with FEP and healthy controls. We enrolled only patients with FEP who were homogeneous in age, duration of illness, phase of illness, and with minimal exposure to medication to limit some of the major confounding factors from other studies. We hypothesized that patients with FEP showed higher baseline salivary cortisol levels, which indicates increased basic HPA hyperactivity, and a lower cortisol increase in response to psychosocial stressor compared with HC, as an indicator of an aberrant response to psychosocial stress. Our exploratory aim was to analyze the correlation of other clinical factors, including psychopathology, personality traits, and stressful life events with salivary cortisol levels.     

Preparation of Cast Metallic Foams with Irregular and Regular Inner Structure

The aim of this paper is to summarize the possibilities of foundry methods for the production of metallic foams. At present, there are a number of production technologies for this interesting material, to which increasing attention has been paid in recent years. What is unique about metallic foams is the combination of their physical and mechanical properties. As part of our research, we designed and verified four main methods of metallic foam production by the foundry technology, whose products are metallic foam castings with regular and irregular arrangements of internal cavities. All these methods use materials and processes commonly used in conventional foundry technologies. The main idea of the research is to highlight such technologies for the production of metallic foams that could be provided by manufacturing companies without the need to introduce changes in production. Moreover, foundry methods for the production of metallic foams have the unique advantage of being able to produce even complex shaped parts and can thus be competitive compared to today’s established technologies, the output of which is usually only a semi-finished product for further processing. This fact was the main motivation for the research.     

Individualized VDJ recombination predisposes the available Ig sequence space

The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual''s naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also nongenetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor–based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.

The diversity, and thus antigen recognition breadth, of adaptive immune receptor (AIR) repertoires (AIRR) is influenced by the statistics of V, D, and J gene (and allele) segment recombination (Chi et al. 2020). Specifically, germline genes (and alleles), as well as their frequencies, have been linked to antibody neutralization breadth in infection (Avnir et al. 2016; Sangesland et al. 2020; Mikocziova et al. 2021a), the occurrence of precursor sequences of broadly neutralizing antibodies in the context of vaccine genetics (Lee et al. 2021), and autoantigen-specific binding in autoimmunity (Raposo et al. 2014; Parks et al. 2017).With the advent of adaptive high-throughput AIRR sequencing (Weinstein et al. 2009), it has been observed that certain germline genes, and consequently recombined AIRs, occur more often than others (Weinstein et al. 2009; Rubelt et al. 2016; Greiff et al. 2017a; Elhanati et al. 2018; Dupic et al. 2021). It has been shown that the occurrence of naive AIRs could be predicted using a mathematical (explicit Bayesian or deep generative) model of VDJ recombination (Elhanati et al. 2018; Marcou et al. 2018; Olson and Matsen 2018; Davidsen et al. 2019; Remmel and Ackerman 2021)—hereafter called repertoire generation model (RGM). The Bayesian RGM parameters (RGMPs) correspond largely to those biological parameters that determine the biological mechanisms of VDJ recombination (Fig. 1A). Importantly, RGMPs enable computing the generation probability (Pgen) of a given AIR sequence. Although previous reports suggested that RGMP values differ across individuals (Marcou et al. 2018; Briney et al. 2019), the extent of this potential variation was neither quantified nor statistically verified (Fig. 1B). Inter-individual RGMP variation would imply that Pgens for identical AIR sequences differed across individuals. If this hypothesis is correct, it will implicate that each individual is biased toward exploring different AIR sequence spaces (Fig. 1C), which in turn has implications for the susceptibility to autoimmunity, cancer, and infectious diseases. For example, potentially important precursor AIRs for vaccine responses (Sangesland et al. 2019; Lee et al. 2021) or potentially damaging autospecific AIRs would occur more or less often depending on the individual''s RGM.Open in a separate windowFigure 1.Comparison of AIR repertoire generation models. (A) The process of recombining variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual''s naive Ig repertoire and, consequently, (auto)antigen recognition. VDJ recombination follows probabilistic rules that can be described statistically as repertoire generation models (RGMs). So far, it remains unknown whether VDJ recombination rules differ across individuals. We set out to resolve this question by developing a distance measure that enables the quantification of RGM parameter (RGMP) similarity. (B) Accounting for several sources of noise in murine and human Ig sequencing data (by leveraging various types of replicates), as well as allelic diversity, (C) we were able to implement a noise-aware, sensitivity-tested statistical test for comparing RGM similarity. We call our method desYgnator for DEtection of SYstematic differences in GeneratioN of Adaptive immune recepTOr Repertoires (desYgnator). Using desYgnator, we found that replicate samples of the same subject are consistently more similar to each other than to samples from other unrelated individuals or even monozygotic twins (or inbred mice) indicating that not only genetic but also nongenetic factors contribute to the individualization of an RGM. We validated desYgnator by showing that RGM did not differ across synthetic and experimental replicates. We quantified the implication of individual RGMs on Ig repertoire architecture in a data set of approximately 100 human individuals by showing that the same (antigen-annotated) Ig sequence can have different generation probabilities across individuals. Thus, the available Ig sequence space is individually biased, predisposed by the individual RGM.In this study, we aimed to measure the magnitude of the inter-individual RGMP variation and its effect on the immunoglobulin (Ig) sequence Pgens.     

Structural and Electrical Characterization of Pure and Al-Doped ZnO Nanorods

Pure and Al-doped (3 at.%) ZnO nanorods were prepared by two-step synthesis. In the first step, ZnO thin films were deposited on silicon wafers by spin coating; then, ZnO nanorods (NR) and Al-doped ZnO NR were grown using a chemical bath method. The structural properties of zincite nanorods were determined by X-ray diffraction (XRD) and corroborated well with the morphologic properties obtained by field-emission gun scanning electron microscopy (FEG SEM) with energy-dispersive X-ray spectroscopy (EDS). Morphology results revealed a minute change in the nanorod geometry upon doping, which was also visible by Kelvin probe force microscopy (KPFM). KPFM also showed preliminary electrical properties. Detailed electrical characterization of pure and Al-doped ZnO NR was conducted by temperature-dependent current–voltage (I–V) measurements on Au/(Al)ZnO NR/n-Si junctions. It was shown that Al doping increases the conductivity of ZnO NR by an order of magnitude. The I–V characteristics of pure and Al-doped ZnO NR followed the ohmic regime for lower voltages, whereas, for the higher voltages, significant changes in electric conduction mechanisms were detected and ascribed to Al-doping. In conclusion, for future applications, one should consider the possible influence of the geometry change of (Al)ZnO NRs on their overall electric transport properties.     

Veno-Arterial Extracorporeal Membrane Oxygenation in the Adult: A Bridge to the State of the Art

Despite the technological advancements in the last 40 years, conditions such as refractory cardiogenic shock and cardiac arrest still present a very high mortality rate in real-world clinical practice.In this light, we have reviewed the techniques, indications, contraindications, and results of the so- called Veno-Arterial Extracorporeal Circulatory Membrane Oxygenation (VA-ECMO) in the adult population to evaluate the current results of this temporary cardio-pulmonary support as salvage and/or bridge therapy in the patient suffering from refractory cardiogenic shock or cardio-circulatory arrest.The results are encouraging, especially in the setting of refractory cardiogenic shock and in-hospital cardiac arrest. Among a selected population, the prompt institution of a VA-ECMO may radically change the prognosis by sustaining vital functions while looking for the leading cause or waiting for the reversal of the temporary cardio-respiratory negative condition.The future directions aim to standardized and shared protocols, miniaturization of the machines, and possibly the institution of specialized “ECMO teams” for in and the out-of-hospital institution of the tool.     

From presentation to paper: Gender disparities in oncological research

Gender disparities in scientific publications have been identified in oncological research. Oral research presentations at major conferences enhance visibility of presenters. The share of women presenting at such podia is unknown. We aim to identify gender-based differences in contributions to presentations at two major oncological conferences. Abstracts presented at plenary sessions of the American Society of Clinical Oncology (ASCO) Annual Meetings and European Society for Medical Oncology (ESMO) Congresses were collected. Trend analyses were used to analyze female contribution over time. The association between presenter's sex, study outcome (positive/negative) and journals' impact factors (IFs) of subsequently published papers was assessed using Chi-square and Mann–Whitney U tests. Of 166 consecutive abstracts presented at ASCO in 2011–2018 (n = 34) and ESMO in 2008–2018 (n = 132), 21% had female presenters, all originating from Northern America (n = 17) or Europe (n = 18). The distribution of presenter's sex was similar over time (p = 0.70). Of 2,425 contributing authors to these presented abstracts, 28% were women. The proportion of female abstract authors increased over time (p < 0.05) and was higher in abstracts with female (34%) compared to male presenters (26%; p < 0.01). Presenter's sex was not associated with study outcome (p = 0.82). Median journals' IFs were lower in papers with a female first author (p < 0.05). In conclusion, there is a clear gender disparity in research presentations at two major oncological conferences, with 28% of authors and 21% of presenters of these studies being female. Lack of visibility of female presenters could impair acknowledgement for their research, opportunities in their academic career and even hamper heterogeneity in research.     

Detection of somatic mutations in peritoneal lavages and plasma of endometrial cancer patients: A proof-of-concept study

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Although most patients are diagnosed at early stages, 15–20% will relapse despite local treatment. Presently, there are no reliable markers to identify patients with worse outcomes who may benefit from adjuvant treatments, such as chemotherapy, and liquid biopsies may be of use in this setting. Peritoneal lavages are systematically performed during endometrial surgery but little data are available about their potential as liquid biopsies. We analyzed KRAS and PIK3CA mutations in paired surgical biopsies, blood and cytology-negative peritoneal lavages in a cohort of 50 EC patients. Surgical biopsies were submitted to next-generation sequencing (NGS) while circulating-free DNA (cfDNA) purified from plasma and peritoneal lavages was analyzed for KRAS and PIK3CA hotspot mutations using a sensitive quantitative polymerase chain reaction (PCR) assay. NGS of biopsies revealed KRAS, PIK3CA or concomitant KRAS + PIK3CA mutations in 33/50 (66%) EC patients. Of those, 19 cases carried hotspot mutations. Quantitative PCR revealed KRAS and/or PIK3CA mutations in the lavages of 9/19 (47.4%) hotspot EC patients. In contrast, only 2/19 (10.5%) blood samples from hotspot EC patients were positive. Mutations found in cfDNA consistently matched those in paired biopsies. One of the two patients positive in plasma and lavage died in less than 6 months. In conclusion, mutational analysis in peritoneal lavages and blood from early stage EC is feasible. Further studies are warranted to determine if it might help to identify patients with worse prognosis. Human genes discussed: KRAS, KRAS proto-oncogene, GTPase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.