Rezension: JÖRG ROCHE and THOMAS SALUMETS (Eds.): Germanics Under Construction. Intercultural and Interdisciplinary Prospects

To review an anthology is always problematic. Of course, the quality of contributions will differ widely and some of them will actually expand the field and others will only marginally contribute to it. In the case of Germanics under Construction: Intercultural and Interdisciplinary Prospects, edited by Jörg Roche and Thomas Salumets (both from the University of British Columbia), this does not seem to be the case. Although there are differences in the quality and length of the contributions, all in all this anthology does fulfil its goal, namely to "explore the potential" of German Studies without being restricted to 'things German' but rather including "the study of a national culture in a 'foreign' country" (7). Continuing the discussion begun by the special issues of German Quarterly (1989), German Studies Review (1990), and the Monatshefte issue on New Historicism and German Studies (1992), this anthology traces the recent developments in German Studies and gives an overview of various approaches to the field. What makes this anthology particularly interesting is that it does not focus on one aspect of German Studies, i.e. literary/cultural theories or didactics, but rather allows the reader to form an informed opinion of the state of German Studies in the mid-1990s

E/Valuating new media in language development

This paper addresses the need for a new approach to the educational evaluation of software that falls under the rubric "new media" or "multimedia" as distinct from previous generations of Computer-Assisted Language Learning (CALL) software. The authors argue that present approaches to CALL software evaluation are not appropriate for a new genre of CALL software distinguished by its shared assumptions about language learning and teaching as well as by its technical design. The paper sketches a research-based program called "E/Valuation" that aims to assist language educators to answer questions about the educational effectiveness of recent multimedia language learning software. The authors suggest that such program needs to take into account not only the nature of the new media and its potential to promote language learning in novel ways, but also current professional knowledge about language learning and teaching

Administration of a VEGFR‑2-specific MRI contrast agent to assess orthodontic tooth movement

Purpose It is thought that orthodontic forces initially reduce periodontal blood flow during orthodontic tooth movement (OTM) via tissue compression with cells responding to concomitant oxygen deprivation with expression of vascular endothelial growth factor (VEGF) triggering angiogenesis via binding to its receptor VEGFR‑2. To test this hypothesis, we performed a pilot study to establish a protocol for molecular magnetic resonance imaging (MRI) of rat jaws administering a VEGFR-2-specific contrast agent. Methods Mesial OTM of a first upper left rat molar was initiated in one male Fischer 344 rat 4 days prior to MRI by insertion of an elastic band between the first and second upper molars with the contralateral side left untreated (internal control). T1-weighted MRI sequences including dynamic contrast-enhanced MRI (DCE-MRI) were recorded before and after administration of a molecular VEGFR‑2 MRI marker with a 7 T MRI dedicated for small animal use. Results After injection of anti-VEGFR2-albumin-gadolinium-DTPA, volume enhancement on T1-weighted images was increased at the OTM side distally of the moved first upper molar (M1) compared to the control side, whereas the T1 relaxation time was reduced on the OTM side. DCE-MRI resulted in an increased area under the curve (AUC), whereas time-to-peak (TTP) and washout rate were reduced during OTM distally of the moved M1 compared to the contralateral side. Conclusions OTM resulted in uptake of the VEGFR-2-specific MRI contrast agent in tension areas of the periodontal ligament. The imaging protocol presented here is useful for the assessment of VEGFR‑2 expression in tension areas of the periodontal ligament in vivo

Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology

COVID-19 in German Competitive Sports: Protocol for a Prospective Multicenter Cohort Study (CoSmo-S)

Objective: It is unclear whether and to what extent COVID-19 infection poses health risks and a chronic impairment of performance in athletes. Identification of individual health risk is an important decision-making basis for managing the pandemic risk of infection with SARS-CoV-2 in sports and return to play (RTP). Methods: This study aims 1) to analyze the longitudinal rate of seroprevalence of SARSCoV- 2 in German athletes, 2) to assess health-related consequences in athletes infected with SARS-CoV-2, and 3) to reveal effects of the COVID-19 pandemic in general and of a cleared SARS-CoV-2 infection on exercise performance. CoSmo-S is a prospective observational multicenter study establishing two cohorts: 1) athletes diagnosed positive for COVID-19 (cohort 1) and 2) federal squad athletes who perform their annual sports medical preparticipation screening (cohort 2). Comprehensive diagnostics including physical examination, laboratory blood analyses and blood biobanking, resting and exercise electrocardiogram (ECG), echocardiography, spirometry and exercise testing added by questionnaires are conducted at baseline and follow-up. Results and Conclusion: We expect that the results obtained, will allow us to formulate recommendations regarding RTP on a more evidence-based level

Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

[Background]: Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome-wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. [Methods]: To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent-trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV-carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population-matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome-wide association data, expression, protein–protein-interactions), were used for final prioritization. [Conclusion]: In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re-sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.The present study was supported by the German Research Foundation (DFG)-Grants BE 3828/8-1, LU 1944/2-1, MA 2546/5-1, and LU1944/3-1

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

Objectives Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. Methods Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. Results Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. Conclusions These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these association