Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Beobachtung von Staubkornwachstum und -sedimentation in zirkumstellaren Scheiben

In the present thesis, the observational effects of dust grain growth and sedimentation in circumstellar discs are investigated. The growth of dust grains from some nanometres in diameter as found in the inter- stellar medium towards planetesimal bodies some meters in diameter is an important step in the formation of planets. However, this process is currently not entirely un- derstood. Especially, in the literature several ‘barriers’ are discussed that apparently prohibit an effective growth of dust grains. Hence, it is of particular interest to compare theories and observational data in this respect. State-of-the-art radiative transfer techniques allow one to derive observable quantities from theoretical models that allow this comparison. In this thesis, generic tracers of dust grain growth in spatially high resolution multi-wavelength images are identified for the first time. Further, a possibility to detect a dust trapping mechanism for dust grains by local pressure maxima using the new interferometer, ALMA, is established. By fitting parametric models to new observations of the disc in the Bok globule CB 26, unexpected features of the system are revealed, such as a large inner void and the possibility to interpret the data without the need for grain growth. In the same way, new observations and their interpretation of IRAS 04302+2247 provide evidence for the first time for radial dependent settling of dust grains in images. Moreover, in this thesis the applicability of the T Tauri disc paradigm to the high-mass disc candidate IRAS 18151-1208 is demonstrated.In der vorliegenden Dissertation werden die beobachtbaren Effekte von Staubkorn- wachstum und -sedimentation in zirkumstellaren Scheiben untersucht. Das Wachstum von Staubpartikeln in der Gr ̈oße von einigen Nanometen, wie sie im interstellaren Medium zu finden sind, hin zu Planetesimalen mit einigen Metern Durchmesser ist ein wichtiger Prozess im Zuge der Entstehung von Planeten. Allerd- ings ist dieses Wachstum gegenwa ̈rtig nicht vollst ̈andig verstanden. Insbesondere werden in der Fachliteratur einige Schranken diskutiert, die ein effektives Wachstum von Staubk ̈ornern zu verhindern scheinen. Daher ist es von besonderer Bedeutung, Theorien und Beobachtungsdaten in diesem Zusammenhang miteinander zu verglei- chen. Strahlungstransportmethoden auf dem aktuellen Stand der Technik gestatten es, aus theoretischen Modellen Beobachtungsgr ̈oßen abzuleiten, die einen solchen Vergleich erlauben. In dieser Arbeit werden zum ersten Mal generische Indikatoren des Staubkorn- wachstums in ra ̈umlich hochaufgelo ̈sten Bildern mehrerer Wellenl ̈angen identifziert. Zudem wird eine M ̈oglichkeit aufgezeigt, die es gestattet, mit Hilfe des neuen In- terferometers ALMA die Spuren von durch lokale Gasdruckmaxima eingefangenen Staubko ̈rnern zu erkennen. Durch Bestimmung der Parameter geeigneter Modelle anhand neuer Beobachtungs- daten der Scheibe im Bok-Globulus CB 26 werden neue unerwartete Eigenschaften des Systems, wie ein großer, zentraler staubfreier Bereich und die Mo ̈glichkeit, die Beobachtungsdaten ohne die Annahme von Staubkornwachstum zu interpretieren, enthu ̈llt. EbensoerlaubenneueBeobachtungenundderenDeutungvonIRAS 04302+2247 zum ersten Mal einen Hinweis in Bildern auf radiusabh ̈angige Sedimen- tation von Staubk ̈ornern. Daru ̈berhinaus wird die Anwendbarkeit des Scheibenkonzeptes von T Tauri Ster- nen auf IRAS 18151-1208, einem massereichen Protostar, gezeigt

Improved mid-term stability of MR reduction with an increased number of clips after percutaneous mitral valve repair in functional MR

Background: Percutaneous mitral valve repair (PMVR) has evolved to be a standard procedure in suitable patients with mitral regurgitation (MR) not accessible for open surgery. Here, we analyzed the influence of the number and positioning of the clips implanted during the procedure on MR reduction analyzing also sub-collectives of functional and degenerative MR (DMR). Results: We included 410 patients with severe MR undergoing PMVR using the MitraClip® System. MR and reduction of MR were analyzed by TEE at the beginning and at the end of the PMVR procedure. To specify the clip localization, we sub-divided segment 2 into 3 sub-segments using the segmental classification of the mitral valve. Results: We found an enhanced reduction of MR predominantly in DMR patients who received more than one clip. Implantation of only one clip led to a higher MR reduction in patients with functional MR (FMR) in comparison to patients with DMR. No significant differences concerning pressure gradients could be observed in degenerative MR patients regardless of the number of clips implanted. A deterioration of half a grade of the achieved MR reduction was observed 6 months post-PMVR independent of the number of implanted clips with a better stability in FMR patients, who got 3 clips compared to patients with only one clip. Conclusions: In patients with FMR, after 6 months the reduction of MR was more stable with an increased number of implanted clips, which suggests that this specific patient collective may benefit from a higher number of clips

ZFYVE27 (SPG33), a Novel Spastin-Binding Protein, Is Mutated in Hereditary Spastic Paraplegia

Spastin, the most commonly mutated protein in the autosomal dominant form of hereditary spastic paraplegia (AD-HSP) has been suggested to be involved in vesicular cargo trafficking; however, a comprehensive function of spastin has not yet been elucidated. To characterize the molecular function of spastin, we used the yeast two-hybrid approach to identify new interacting partners of spastin. Here, we report ZFYVE27, a novel member of the FYVE-finger family of proteins, as a specific spastin-binding protein, and we validate the interaction by both in vivo coimmunoprecipitation and colocalization experiments in mammalian cells. More importantly, we report a German family with AD-HSP in which ZFYVE27 (SPG33) is mutated; furthermore, we demonstrate that the mutated ZFYVE27 protein shows an aberrant intracellular pattern in its tubular structure and that its interaction with spastin is severely affected. We postulate that this specific mutation in ZFYVE27 affects neuronal intracellular trafficking in the corticospinal tract, which is consistent with the pathology of HSP

Elevated Mitral Valve Pressure Gradient Is Predictive of Long-Term Outcome After Percutaneous Edge-to-Edge Mitral Valve Repair in Patients With Degenerative Mitral Regurgitation (MR), But Not in Functional MR

Background-This study analyzed the effects on long-term outcome of residual mitral regurgitation (MR) and mean mitral valve pressure gradient (MVPG) after percutaneous edge-to-edge mitral valve repair using the MitraClip system. Methods and Results-Two hundred fifty-five patients who underwent percutaneous edge-to-edge mitral valve repair were analyzed. Kaplan-Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome. A combined clinical end point (all-cause mortality, MV surgery, redo procedure, implantation of a left ventricular assist device) was used. After percutaneous edge-to-edge mitral valve repair, mean MVPG increased from 1.6 +/- 1.0 to 3.1 +/- 1.5 mm Hg (P4.4 mm Hg was not according to Kaplan-Meier and Cox regression analyses. We then analyzed the cohort with degenerative and that with functional MR separately to account for these different entities. In the cohort with degenerative MR, elevated MVPG was associated with increased occurrence of the primary end point, whereas this was not observed in the cohort with functional MR. Conclusions-MVPG >4.4 mm Hg after MitraClip implantation was predictive of clinical outcome in the patient cohort with degenerative MR. In the patient cohort with functional MR, MVPG >4.4 mm Hg was not associated with increased clinical events

Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today

Minimum information for reporting next generation sequence genotyping (MIRING): Guidelines for reporting HLA and KIR genotyping via next generation sequencing

AbstractThe development of next-generation sequencing (NGS) technologies for HLA and KIR genotyping is rapidly advancing knowledge of genetic variation of these highly polymorphic loci. NGS genotyping is poised to replace older methods for clinical use, but standard methods for reporting and exchanging these new, high quality genotype data are needed. The Immunogenomic NGS Consortium, a broad collaboration of histocompatibility and immunogenetics clinicians, researchers, instrument manufacturers and software developers, has developed the Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines. MIRING is a checklist that specifies the content of NGS genotyping results as well as a set of messaging guidelines for reporting the results. A MIRING message includes five categories of structured information – message annotation, reference context, full genotype, consensus sequence and novel polymorphism – and references to three categories of accessory information – NGS platform documentation, read processing documentation and primary data. These eight categories of information ensure the long-term portability and broad application of this NGS data for all current histocompatibility and immunogenetics use cases. In addition, MIRING can be extended to allow the reporting of genotype data generated using pre-NGS technologies. Because genotyping results reported using MIRING are easily updated in accordance with reference and nomenclature databases, MIRING represents a bold departure from previous methods of reporting HLA and KIR genotyping results, which have provided static and less-portable data. More information about MIRING can be found online at miring.immunogenomics.org

Host KIR/HLA-C Genotypes Determine HIV-Mediated Changes of the NK Cell Repertoire and Are Associated With Vpu Sequence Variations Impacting Downmodulation of HLA-C

NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1(+) individuals. Compared to 60 HIV-1(-) controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C(+) and KIR3DL2(+) NK cell sub-populations from HIV-1(+) individuals was enlarged compared to HIV-1(-) controls. Stratification along KIR/HLA-C genotypes revealed a genotype-dependent expansion of KIR2DL1(+) NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host KIR2DL/HLA-C genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1