CRISPR/Cas9-induced (CTG⋅CAG)n repeat instability in the myotonic dystrophy type 1 locus: implications for therapeutic genome editing

Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG)n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5′ or 3′ unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1

A Psychometric Analysis of the Structured Clinical Interview for the DSM-5 Alternative Model for Personality Disorders Module I (SCID-5-AMPD-I):Level of Personality Functioning Scale

The current study aims to examine the psychometric properties of the Structured Clinical Interview for the DSM-5 Alternative Model for Personality Disorders Module I (SCID-5-AMPD-I) assessing the Level of Personality Functioning Scale (LPFS) in a heterogeneous sample of 282 nonpsychotic patients. Latent variable models were used to investigate the dimensionality of the LPFS. The results indicate that the LPFS, as assessed by the SCID-5-AMPD-I, can be considered as a unidimensional construct that can be measured reliably across a wide range of the latent trait. Threshold parameters for the 12 indicators of the LPFS increased gradually over the latent scale, indicating that the five LPFS levels were ordered as predicted by the model. In general, the increase of threshold parameters was relatively small for the shift from Level 2 to Level 3. A better distinction among the different severity levels might be obtained by fine-tuning the interview guidelines or the Level 2 indicators themselves

PHAryngeal electrical STimulation for early decannulation in TRACheotomised stroke patients with neurogenic dysphagia (PHAST-TRAC): a prospective randomised single-blinded trial

Background Dysphagia after stroke is common, especially in severely affected, tracheotomised patients. In a pilot trial, pharyngeal electrical stimulation (PES) improved swallowing function in this group of patients. The PHAryngeal electrical STimulation for early decannulation in TRACheotomised stroke patients with neurogenic dysphagia trial (PHAST-TRAC) was designed to replicate and extend this single-centre experience. Methods Patients with recent stroke who required tracheotomy were randomised to receive three days of PES or sham. All patients had the stimulation catheter inserted; sham treatment was applied by connecting the base station to a simulator box instead of the catheter. Randomisation was done via a computerised interactive system with randomisation (stratified by site) in blocks of 4 patients per site. Patients and investigators applying PES were not masked. The primary-endpoint was assessed blinded to treatment assignment by a separate investigator at each site. The primary outcome was readiness for decannulation 24-72 hours post-treatment, assessed using fiberoptic endoscopic evaluation of swallowing and based on a standardised protocol including absence of massive saliva, presence of spontaneous swallows and laryngeal sensation. We planned a sequential statistical analysis of superiority for the primary endpoint. Interim analyses were to be performed after primary outcome data were available for 50 patients (futility), 70 patients, and every additional 10 patients thereafter up to 140. Analysis was by intention-to-treat. The trial was registered as ISRCTN18137204. Findings From 29th May 2015 to 5th July 2017, 69 patients (PES 35, sham 34) from 9 sites (7 acute care hospitals, 2 rehabilitation facilities) in Germany, Austria and Italy were included: PES group mean age 61.7 (SD 13.0) years, 8 (23%) patients with haemorrhagic stroke, median time onset to randomisation 28.0 [IQR 20, 49] days; sham group age 66.8 (10.3) years, 12 (35%) patients with haemorrhagic stroke, onset to randomisation 28.0 [18, 40] days). The Independent Data & Safety Monitoring Board recommended to stop the trial early for efficacy after 70 patients had been recruited and primary endpoint data of 69 patients were available. This decision was approved by the steering committee. PES was associated with more patients being ready for decannulation as compared to sham: 17 (49%) vs. 3 (9%), odds ratio (OR) 7.00 (2.41-19.88), p=0.00082). No patient required recannulation within 48 hours or during their documented follow-up period up to 30 days or hospital discharge. Adverse events (AEs) were reported in 24 patients (69%) of the PES group and 24 patients (71%) of the sham group. The number of patients with at least one serious adverse event (SAE) did not differ between the groups: 10 (29%) vs. 8 (23%), OR 1.3 (0.44-3.83), p=0.7851). 7 patients (20%) from the PES group and 3 patients (9%) from the sham group died during the study period. None of the patient deaths or SAEs reported were judged to be PES-treatment- or investigational device-related. Interpretation PES increased the proportion of patients with stroke and subsequent tracheotomy who were ready for decannulation in this study population, many of whom received PES within a month of their stroke. Future trials should confirm whether PES is beneficial in tracheostomised patients who receive stimulation similarly early after stroke and explore its effects in other cohorts

The Theater of Franz Xaver Kroetz (Germany).

In West German theater, the decade of the seventies has been marked by growing doubts as to the efficacy of theater in adequately representing social reality and effecting social change. With their apparent faith in the transparency and changeability of existing conditions, the critical "Volksstucke" of Franz Xaver Kroetz represent an interesting phenomenon within the contemporary theatrical l and scape. By exploring the ways in which Kroetz's theater seeks to bridge the modern chasm between language and social reality, between theater and politics, the present study yields insight into the nature and function of the Kroetzian "Volksstuck," and locates it firmly within the context of contemporary aesthetic concerns. The dissertation challenges criticism which sees in Kroetz's theater an essentially mimetic approach ("Widerspiegelungsrealismus") by showing how and to what extent it both reflects and resists the linguistic and political skepticism of the contemporary avant-garde. After outlining some of the central aesthetic issues--particularly with regard to problems of intention and reception--involved in the dramaturgical conception of the critical "Volksstuck," and discussing these issues within the context of contemporary West German theater in general, the dissertation focuses on Kroetz's own particular "solutions." From a detailed analysis of the various linguistic, structural, and thematic patterns that emerge in major and representative plays from Mannersache to Furcht und Hoffnung der BRD, an aesthetic "model" is established which derives its effectiveness from the tension between naturalistic and abstract, compassion and critique, resignation and resistance. In underscoring the inner consistency of Kroetz's plays with regard to purpose and technique, the model corrects the common view that Kroetz has moved from a "descriptive" to a "socialist" realism. At the same time, it provides a critical apparatus by which to account for the relative success or failure of the various extensions Kroetz attempted throughout his career. Tracing the model through these extensions, the dissertation offers an interpretation that sees in Kroetz's development an increasingly self-reflective character which both illuminates and challenges contemporary theatrical trends.Ph.D.German literatureTheaterUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161739/1/8801439.pd

A Psychometric Analysis of the Structured Clinical Interview for the DSM-5 Alternative Model for Personality Disorders Module I (SCID-5-AMPD-I): Level of Personality Functioning Scale

The current study aims to examine the psychometric properties of the Structured Clinical Interview for the DSM-5 Alternative Model for Personality Disorders Module I (SCID-5-AMPD-I) assessing the Level of Personality Functioning Scale (LPFS) in a heterogeneous sample of 282 nonpsychotic patients. Latent variable models were used to investigate the dimensionality of the LPFS. The results indicate that the LPFS, as assessed by the SCID-5-AMPD-I, can be considered as a unidimensional construct that can be measured reliably across a wide range of the latent trait. Threshold parameters for the 12 indicators of the LPFS increased gradually over the latent scale, indicating that the five LPFS levels were ordered as predicted by the model. In general, the increase of threshold parameters was relatively small for the shift from Level 2 to Level 3. A better distinction among the different severity levels might be obtained by fine-tuning the interview guidelines or the Level 2 indicators themselves

A psychometric analysis of the structured clinical interview for the DSM-5 alternative model for personality disorders module I (SCID-5-AMPD-I): Level of personality functioning scale

The current study aims to examine the psychometric properties of the Structured Clinical Interview for the DSM-5 Alternative Model for Personality Disorders Module I (SCID-5-AMPD-I) assessing the Level of Personality Functioning Scale (LPFS) in a heterogeneous sample of 282 nonpsychotic patients. Latent variable models were used to investigate the dimensionality of the LPFS. The results indicate that the LPFS, as assessed by the SCID-5-AMPD-I, can be considered as a unidimensional construct that can be measured reliably across a wide range of the latent trait. Threshold parameters for the 12 indicators of the LPFS increased gradually over the latent scale, indicating that the five LPFS levels were ordered as predicted by the model. In general, the increase of threshold parameters was relatively small for the shift from Level 2 to Level 3. A better distinction among the different severity levels might be obtained by fine-tuning the interview guidelines or the Level 2 indicators themselve