Perceptions of lecturers and students regarding discriminatory experiences and sexual harassment in academic medicine - results from a faculty-wide quantitative study.

BACKGROUND: Discrimination and sexual harassment are prevalent in higher education institutions and can affect students, faculty members and employees. Herein the aim was to assess the extent of discriminatory experiences and sexual harassment of students and lecturers at one of the largest teaching hospitals in Europe. We analyze whether there are differences between lecturers and students, different study programs as well as sex/gender differences. METHODS: In an interdisciplinary, iterative process, a semi-standardized questionnaire was developed and sent to N = 7095 students (S) of all study programs and N = 2528 lecturers (L) at Charité-Universitätsmedizin Berlin, Germany. The study was conducted from November 2018 to February 2019. Besides a broad range of questions on sociodemographic background allowing for diversity sensitive data analysis, they were asked if they had witnessed and/or experienced any form of discrimination or sexual harassment at the medical faculty, if yes, how often, the perceived reasons, situational factors and perpetrators. RESULTS: The response rate was 14% (n = 964) for students and 11% (n = 275) for lecturers. A proportion of 49.6% of students (L: 31%) reported that they have witnessed and/or experienced discriminatory behavior. Sexual harassment was witnessed and/or experienced by 23.6% of students (L: 19.2%). Lecturers (85.9%) were identified as the main source of discriminatory behavior by students. Directors/supervisors (47.4%) were stated as the main source of discriminatory behavior by lecturers. As the most frequent perceived reason for discriminatory experiences sex/gender (S: 71%; L: 60.3%) was reported. Women and dental students experienced more discriminatory behavior and sexual harassment. CONCLUSIONS: Discriminatory behavior is experienced by a significant number of students and lecturers, with power structures having a relevant impact. Dental students and women appear to be particularly exposed. Specific institutional measures, such as training programs for lecturers and students are necessary to raise awareness and provide resources. Furthermore, national preventive strategies should be thoroughly implemented to fight discrimination and harassment at the workplace.

How do medical students learn conceptual knowledge? High-, moderate- and low-utility learning techniques and perceived learning difficulties.

BACKGROUND: Acquiring medical knowledge is a key competency for medical students and a lifelong requirement for physicians. Learning techniques can improve academic success and help students cope with stressors. To support students' learning process medical faculties should know about learning techniques. The purpose of this study is to analyse the preferred learning techniques of female and male as well as junior and senior medical students and how these learning techniques are related to perceived learning difficulties. METHODS: In 2019, we conducted an online survey with students of the undergraduate, competency-based curriculum of medicine at Charité - Universitätsmedizin Berlin. We chose ten learning techniques of high, moderate and low utility according to Dunlosky et al. (2013) and we asked medical students to rate their preferred usage of those techniques using a 5-point Likert scale. We applied t-tests to show differences in usage between female and male as well as junior and senior learners. Additionally, we conducted a multiple regression analysis to explore the predictive power of learning techniques regarding perceived difficulties. RESULTS: A total of 730 medical students (488 women, 242 men, Mage = 24.85, SD = 4.49) use three techniques the most: 'highlighting' (low utility), 'self-explanation' (moderate utility) and 'practice testing' (high utility). Female students showed a significantly higher usage of low-utility learning techniques (t(404.24) = -7.13, p < .001) and a higher usage of high-utility learning techniques (t(728) = -2.50, p < .05) than male students (M = 3.55, SD = .95). Compared to junior students (second to sixth semester; M = 3.65, SD = .71), senior students (seventh semester to final clerkship year; M = 3.52, SD = .73) showed a lower use of low-utility learning techniques (t(603) = 2.15, p < .05). Usage of low-utility techniques is related to more difficulties (ß = .08, t(724) = 2.13, p < .05). Usage of moderate-utility techniques is related to less learning difficulties (ß = -.13, t(599) = -3.21, p < .01). CONCLUSIONS: Students use a wide range of low-, moderate- and high-utility learning techniques. The use of learning techniques has an influence on the difficulties perceived by students. Therefore, they could benefit from knowing about and using high-utility learning techniques to facilitate their learning. Faculties should inform their students about effective learning and introduce them to useful learning techniques.

A VNTR Regulates miR-137 Expression Through Novel Alternative Splicing and Contributes to Risk for Schizophrenia.

The MIR137HG gene encoding microRNA-137 (miR-137) is genome-wide associated with schizophrenia (SZ), however, the underlying molecular mechanisms remain unknown. Through cloning and sequencing of individual transcripts from fetal and adult human brain tissues we describe novel pri-miR-137 splice variants which exclude the mature miR-137 sequence termed 'del-miR-137' that would function to down-regulate miR-137 expression. Sequencing results demonstrate a significant positive association between del-miR-137 transcripts and the length of a proximal variable number tandem repeat (VNTR) element. Additionally, a significantly higher proportion of sequenced transcripts from fetal brain were del-miR-137 transcripts indicating neurodevelopmental splicing regulation. In-silico results predict an independent regulatory function for del-miR-137 transcripts through competitive endogenous RNA function. A case-control haplotype analysis (n = 998) in SZ implicates short VNTR length in risk, with longer lengths imparting a protective effect. Rare high risk haplotypes were also observed indicating multiple risk variants within the region. A second haplotype analysis was performed to evaluate recombination effects excluding the VNTR and results indicate that recombination of the region was found to independently contribute to risk. Evaluation of the evolutionary conservation of the VNTR reveals a human lineage specific expansion. These findings shed further light on the risk architecture of the miR-137 region and provide a novel regulatory mechanism through VNTR length and alternative MIR137HG transcripts which contribute to risk for SZ.

Transcription of PIK3CD in human brain and schizophrenia: regulation by proinflammatory cytokines.

PIK3CD encodes the phosphoinositide 3-kinase (PI3K) catalytic subunit, p110δ, a lipid kinase linked to neurodevelopmental disorders, including schizophrenia (SZ). PIK3CD is regulated at the transcript level through alternate use of 5' untranslated exons (UTRs), promoters, and proinflammatory cytokines. Increases in global PIK3CD expression and downregulation by neuroleptics are observed in SZ, and preclinical efficacy of a p110δ-selective inhibitor is seen in rodent models of risk. Here, we cloned PIK3CD alternative transcripts in human brain and evaluated temporal- and tissue-specific expression. We quantified PIK3CD transcripts in B-lymphoblastoid cells from patients with SZ and examined 5' UTR transcriptional regulation by tumor necrosis factor α (TNFα) and interleukin-1ß (IL1ß) in patient-derived fibroblasts. We report that PIK3CD transcripts are differentially expressed in human brain in a developmental-specific manner. Transcripts encoding 5' UTRs -2A and alternative exon -1 (Alt1), P37 and AS1 and AS2 were increased in SZ. Alt1, P37, and AS2 were also preferentially expressed in fetal brain, and all transcripts were regulated by TNFα and IL1ß. Our findings provide novel insight into the complexity of PIK3CD regulation in human brain, implicate PIK3CD in human neurodevelopment, and identify isoform-specific disruption in SZ.

Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia.

OBJECTIVE: The chromosomal region, 15q13-q14, including the α7 nicotinic acetylcholine receptor gene, CHRNA7, is a replicated region for schizophrenia. This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7. METHODS: Family-based and case-control association studies were performed on Caucasian-non-Hispanic and African-American individuals from 120 families as well as 468 individual patients with schizophrenia and 144 well-characterized controls. Single-nucleotide polymorphism (SNP) markers were genotyped, and association analyses carried out for the outcomes of schizophrenia, smoking, and smoking in schizophrenia. RESULTS: Three genes were associated with schizophrenia in both ethnic populations: TRPM1, KLF13, and RYR3. Two SNPs in CHRNA7 were associated with schizophrenia in African-Americans, and a second SNP in CHRNA7 was significant for an association with smoking and smoking in schizophrenia in Caucasians. CONCLUSION: Results of these studies support association of the 15q13-q14 region with schizophrenia. The broad positive association suggests that more than one 15q gene may be contributing to the disorder, either in combination or through a regulatory mechanism.

The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function.

The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the α7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca(2+), that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of α7*nAChR, as measured by binding of the ligand [(125)I]-α-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of α7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with α7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans.

Strain dependent effects of prenatal stress on gene expression in the rat hippocampus.

Multiple animal models have been developed to recapitulate phenotypes of the human disease, schizophrenia. A model that simulates many of the cognitive and sensory deficits of the disorder is the use of random variable prenatal stress (PS) in the rat. These deficits suggest a molecular origin in the hippocampus, a brain region that plays a role in the regulation of stress. To study both hippocampal gene expression changes in offspring of prenatally stressed dams and to address genetic variability, we used a random array of prenatal stressors in three different rat strains with diverse responses to stress: Fischer, Sprague-Dawley, and Lewis rats. Candidate genes involved in stress, schizophrenia, cognition, neurotrophic effects, and immunity were selected for assessment by real-time quantitative PCR under resting conditions and following a brief exposure to restraint stress. PS resulted in significant differences in gene expression in the offspring that were strain dependent. mRNA expression for the N-methyl-D-aspartate receptor subtype 2B (Grin2b) was increased, and tumor necrosis factor-alpha (Tnfα) transcript was decreased in PS Sprague-Dawley and Lewis rats, but not in the Fischer rats. Expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus was increased after an acute stress in all controls of each strain, yet a decrease was seen after acute stress in the PS Sprague-Dawley and Lewis rats. Expression of the glucocorticoid receptor (Nr3c1) was decreased in the Fischer strain when compared to Lewis or Sprague-Dawley rats, though the Fischer rats had markedly higher α7 nicotinic receptor (Chrna7) expression. The expression differences seen in these animals may be important elements of the phenotypic differences seen due to PS and genetic background.

Maternal stress during pregnancy causes sex-specific alterations in offspring memory performance, social interactions, indices of anxiety, and body mass.

Prenatal stress (PS) impairs memory function; however, it is not clear whether PS-induced memory deficits are specific to spatial memory, or whether memory is more generally compromised by PS. Here we sought to distinguish between these possibilities by assessing spatial, recognition and contextual memory functions in PS and nonstressed (NS) rodents. We also measured anxiety-related and social behaviors to determine whether our unpredictable PS paradigm generates a behavioral phenotype comparable to previous studies. Female Sprague-Dawley rats were exposed to daily random stress during the last gestational week and behavior tested in adulthood. In males but not females, PS decreased memory for novel objects and novel spatial locations, and facilitated memory for novel object/context pairings. In the elevated zero maze, PS increased anxiety-related behavior only in females. Social behaviors also varied with sex and PS condition. Females showed more anogenital sniffing regardless of stress condition. In contrast, prenatal stress eliminated a male-biased sex difference in nonspecific bodily sniffing by decreasing sniffing in males, and increasing sniffing in females. Finally, PS males but not females gained significantly more weight across adulthood than did NS controls. In summary, these data indicate that PS differentially impacts males and females resulting in sex-specific adult behavioral and bodily phenotypes.

Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers.

The alpha7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the alpha7* receptor, as measured by [(125)I]alpha-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the alpha7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor.

Regulation of a novel alphaN-catenin splice variant in schizophrenic smokers.

The alphaN-catenin (CTNNA2) gene represents a promising candidate gene for schizophrenia based upon previous genetic linkage, expression, and mouse knockout studies. CTNNA2 is differentially regulated by smoking in schizophrenic patients. In this report, the genomic structure of a primate-specific alphaN-catenin splice variant (alphaN-catenin III) is described. A comparison of alphaN-catenin III mRNA expression across postmortem hippocampi from schizophrenic and non-mentally ill smokers and non-smokers revealed a significant decrease in expression among patient non-smokers compared to all other groups. The recent evolutionary divergence of this gene, as well as the differences in gene expression in postmortem brain of schizophrenic non-smokers, supports the role of alphaN-catenin III as a novel disease susceptibility gene.

Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects.

The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal.

Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia.

BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects. METHODS: Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded. RESULTS: Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response. CONCLUSIONS: Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.