Modular, programmable RNA sensing using ADAR editing in living cells.

With the increasing availability of single-cell transcriptomes, RNA signatures offer a promising basis for targeting living cells. Molecular RNA sensors would enable the study of and therapeutic interventions for specific cell types/states in diverse contexts, particularly in human patients and non-model organisms. Here we describe a modular, programmable system for live RNA sensing using adenosine deaminases acting on RNA (RADAR). We validate, and then expand, our basic design, characterize its performance, and analyze its compatibility with human and mouse transcriptomes. We identify strategies to boost output levels and improve the dynamic range. Additionally, we show that RADAR enables compact AND logic. In addition to responding to transcript levels, RADAR can distinguish disease-relevant sequence alterations of transcript identities, such as point mutations and fusions. Finally, we demonstrate that RADAR is a self-contained system with the potential to function in diverse organisms.

Impact of woodland agri-environment management on woodland structure and target bird species.

Agri-environment incentives form a central mechanism supporting changes to land management to provide public benefits. This study assesses the medium-term effects of woodland management on 13 target, specialist woodland bird species, as well as other woodland birds in a single region of the UK. The abundance of breeding birds (using two methods: point counts and territory mapping) and metrics of woodland structure were recorded on sites with Woodland Improvement Grants (improvement sites) and nearby comparison sites (control sites). Initial measurements were made prior to management and repeated 7-9 years later. A separate comparison of changes in bird abundance was made between the managed woodland sites and woodland from similar landscapes surveyed as part of the national Breeding Bird Survey (BBS). There was an increase in abundance of target species on improvement sites compared to a decrease on both control sites and BBS sites, although this was only evident from point count data. The effects on target species were stronger than for other woodland specialists and there was no apparent effect on woodland generalists, suggesting that the management interventions were appropriate for the target species. Changes in woodland structure were generally consistent with the expected effect of management, with lower tree density and greater Bramble (Rubus sp.) cover. However, contrary to the aim of increasing understorey cover, a reduction was recorded within the 2-10 m height category in improvement sites. This contrast is due to the removal of young trees during thinning affecting this height band and the short time period since management to allow regrowth. Our findings show that bespoke management supported through government agri-environment incentives can have a positive impact on target woodland birds. For managed forests, identifying species requirements and how management can be adapted to improve their habitats can be an effective way of delivering biodiversity gains when financial incentives are provided to achieve policy goals.

Practicing virology: making and knowing a mid-twentieth century experiment with Tobacco mosaic virus.

Tobacco mosaic virus (TMV) has served as a model organism for pathbreaking work in plant pathology, virology, biochemistry and applied genetics for more than a century. We were intrigued by a photograph published in Phytopathology in 1934 showing that Tabasco pepper plants responded to TMV infection with localized necrotic lesions, followed by abscission of the inoculated leaves. This dramatic outcome of a biological response to infection observed by Francis O. Holmes, a virologist at the Rockefeller Institute for Medical Research, was used to score plants for resistance to TMV infection. Our objective was to gain a better understanding of early to mid-twentieth century ideas of genetic resistance to viruses in crop plants. We investigated Holmes' observation as a practical exercise in reworking an experiment, having been inspired by Pamela Smith's innovative Making and Knowing Project. We had a great deal of difficulty replicating Holmes' experiment, finding that biological materials and experimental customs change over time, in ways that ideas do not. Using complementary tools plus careful study and interpretation of the original text and figures, we were able to rework, yet only partially replicate, this experiment. Reading peer-reviewed manuscripts that cited Holmes' 1934 report provided an additional level of insight into the interpretation and replication of this work in the decades that followed. From this, we touch on how experimental reworking can inform our strategies to address the reproducibility "crisis" in twenty-first century science.

Rationale and study design of the MINERVA study: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction-UK multicentre collaboration.

INTRODUCTION: The purpose of this study is to assess the ability of two new ECG markers (Regional Repolarisation Instability Index (R2I2) and Peak Electrical Restitution Slope) to predict sudden cardiac death (SCD) or ventricular arrhythmia (VA) events in patients with ischaemic cardiomyopathy undergoing implantation of an implantable cardioverter defibrillator for primary prevention indication. METHODS AND ANALYSIS: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction is a prospective, open label, single blinded, multicentre observational study to establish the efficacy of two ECG biomarkers in predicting VA risk. 440 participants with ischaemic cardiomyopathy undergoing routine first time implantable cardioverter-defibrillator (ICD) implantation for primary prevention indication are currently being recruited. An electrophysiological (EP) study is performed using a non-invasive programmed electrical stimulation protocol via the implanted device. All participants will undergo the EP study hence no randomisation is required. Participants will be followed up over a minimum of 18 months and up to 3 years. The first patient was recruited in August 2016 and the study will be completed at the final participant follow-up visit. The primary endpoint is ventricular fibrillation or sustained ventricular tachycardia >200 beats/min as recorded by the ICD. The secondary endpoint is SCD. Analysis of the ECG data obtained during the EP study will be performed by the core lab where blinding of patient health status and endpoints will be maintained. ETHICS AND DISSEMINATION: Ethical approval has been granted by Research Ethics Committees Northern Ireland (reference no. 16/NI/0069). The results will inform the design of a definitive Randomised Controlled Trial (RCT). Dissemination will include peer reviewed journal articles reporting the qualitative and quantitative results, as well as presentations at conferences and lay summaries. TRIAL REGISTRATION NUMBER: NCT03022487.

Reported Technical Aspects of Type II SLAP Lesion Repairs in Athletes.

PURPOSE: To systematically review the available literature to further describe and report the available data on SLAP repair techniques and the association with outcomes. METHODS: A systematic review of literature was performed on manuscripts describing type II SLAP repairs in athletes. Selection criteria included studies reporting exclusively type II SLAP tears without concomitant pathology, minimum 2-year postoperative follow-up, use of anchor fixation, and return to previous level of play data available. We extracted patient outcome as well as surgical construct details from each article. Average outcomes and return to play rates were calculated and substratified further by athlete type. Return to play rates were compared by repair constructs with the Student t test. RESULTS: Initial search resulted in 107 articles. After exclusion criteria were applied, 17 articles were included in the final analysis. Overall, 84% of patients had good-to-excellent results. Of all athletes, 66% returned to previous level of play. There was significant variation in reported technique in terms of anchor number, location, material, suture type, and knotless versus knotted constructs. No significant difference was reported in outcomes in comparison of suture type (P-value .96) or knotted versus knotless constructs (P-value .91). Given the significant variability in reporting, no statistical analysis was felt able to be performed on anchor location and number. CONCLUSIONS: Repair of type II SLAP tears in athletes is a difficult problem to treat with overall low return to play despite a high rate of "good" outcomes when assessed by outcome measures. Significant variability exists in surgical technique, as well as reporting of surgical technique, potentially limiting the ability to define the best or most effective technique for SLAP repair. LEVEL OF EVIDENCE: IV, systematic review of level III and level IV studies.

RNA silencing suppressor-influenced performance of a virus vector delivering both guide RNA and Cas9 for CRISPR gene editing.

We report on further development of the agroinfiltratable Tobacco mosaic virus (TMV)-based overexpression (TRBO) vector to deliver CRISPR/Cas9 components into plants. First, production of a Cas9 (HcoCas9) protein from a binary plasmid increased when co-expressed in presence of suppressors of gene silencing, such as the TMV 126-kDa replicase or the Tomato bushy stunt virus P19 protein. Such suppressor-generated elevated levels of Cas9 expression translated to efficient gene editing mediated by TRBO-G-3'gGFP expressing GFP and also a single guide RNA targeting the mgfp5 gene in the Nicotiana benthamiana GFP-expressing line 16c. Furthermore, HcoCas9 encoding RNA, a large cargo insert of 4.2 kb, was expressed from TRBO-HcoCas9 to yield Cas9 protein again at higher levels upon co-expression with P19. Likewise, co-delivery of TRBO-HcoCas9 and TRBO-G-3'gGFP in the presence of P19 also resulted in elevated levels percentages of indels (insertions and deletions). These data also revealed an age-related phenomenon in plants whereby the RNA suppressor P19 had more of an effect in older plants. Lastly, we used a single TRBO vector to express both Cas9 and a sgRNA. Taken together, we suggest that viral RNA suppressors could be used for further optimization of single viral vector delivery of CRISPR gene editing parts.

Native Processing of Single Guide RNA Transcripts to Create Catalytic Cas9/Single Guide RNA Complexes in Planta.

The present CRISPR/Cas9 gene editing dogma for single guide RNA (sgRNA) delivery is based on the premise that 5'-and 3'-nucleotide overhangs negate Cas9/sgRNA catalytic activity in vivo. This has led to engineering strategies designed to either avoid or remove extraneous nucleotides at the 5' and 3' termini of sgRNAs. Previously, we used a Tobacco mosaic virus viral vector to express both GFP and a sgRNA from a single virus-derived mRNA in Nicotiana benthamiana This vector yielded high levels of GFP and catalytically active sgRNAs. Here, in an effort to understand the biochemical interactions of this result, we used in vitro assays to demonstrate that nucleotide overhangs 5', but not 3', proximal to the sgRNA do in fact inactivate Cas9 catalytic activity at the specified target site. Next we showed that in planta sgRNAs bound to Cas9 are devoid of the expected 5' overhangs transcribed by the virus. Furthermore, when a plant nuclear promoter was used for expression of the GFP-sgRNA fusion transcript, it also produced indels when delivered with Cas9. These results reveal that 5' auto-processing of progenitor sgRNAs occurs natively in plants. Toward a possible mechanism for the perceived auto-processing, we found, using in vitro-generated RNAs and those isolated from plants, that the 5' to 3' exoribonuclease XRN1 can degrade elongated progenitor sgRNAs, whereas the mature sgRNA end products are resistant. Comparisons with other studies suggest that sgRNA auto-processing may be a phenomenon not unique to plants, but present in other eukaryotes as well.

Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection.

Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10%. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 h after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.

Plant Virus Vectors 3.0: Transitioning into Synthetic Genomics.

Plant viruses were first implemented as heterologous gene expression vectors more than three decades ago. Since then, the methodology for their use has varied, but we propose it was the merging of technologies with virology tools, which occurred in three defined steps discussed here, that has driven viral vector applications to date. The first was the advent of molecular biology and reverse genetics, which enabled the cloning and manipulation of viral genomes to express genes of interest (vectors 1.0). The second stems from the discovery of RNA silencing and the development of high-throughput sequencing technologies that allowed the convenient and widespread use of virus-induced gene silencing (vectors 2.0). Here, we briefly review the events that led to these applications, but this treatise mainly concentrates on the emerging versatility of gene-editing tools, which has enabled the emergence of virus-delivered genetic queries for functional genomics and virology (vectors 3.0).

The management of infected elbow arthroplasty by two-stage revision.

BACKGROUND: Deep prosthetic infection is a potentially devastating complication after total elbow arthroplasty, with an incidence of up to 12%. This study examined the demographics, microbiologic profile, and outcomes of infected total elbow arthroplasty treated with 2-stage revision in a tertiary referral unit. METHODS: We identified 19 consecutive patients (mean age, 65 years) undergoing revision arthroplasty for deep prosthetic infection. All patients underwent a first-stage procedure with removal of implants, débridement, and insertion of an antibiotic-loaded cement spacer, followed by at least 6 weeks of intravenous antibiotics. Fourteen patients required a second-stage revision. RESULTS: Five patients did not undergo a second-stage procedure because of patient choice (n = 2), medical or surgical risk factors (n = 2), and death from an unrelated cause (n = 1). Of the 19 patients undergoing a first-stage procedure, 16 (84%) remained infection free, and 11 of the 14 patients (79%) undergoing reimplantation of an elbow prosthesis remained infection free. Six patients required further surgery (3 for recurrent infection, 3 for noninfective indications). The commonest infecting organism was Staphylococcus aureus (47%). A degree of postoperative ulnar nerve dysfunction occurred in 37% of patients, but all resolved fully without further treatment. CONCLUSIONS: Management of prosthetic joint infection using 2-stage revision can result in high rates of eradication, although rates of reoperation and transient ulnar nerve dysfunction are high.

Multiplexed Gene Editing and Protein Overexpression Using a Tobacco mosaic virus Viral Vector.

Development of CRISPR/Cas9 transient gene editing screening tools in plant biology has been hindered by difficulty of delivering high quantities of biologically active single guide RNAs (sgRNAs). Furthermore, it has been largely accepted that in vivo generated sgRNAs need to be devoid of extraneous nucleotides, which has limited sgRNA expression by delivery vectors. Here, we increased cellular concentrations of sgRNA by transiently delivering sgRNAs using a Tobacco mosaic virus-derived vector (TRBO) designed with 5' and 3' sgRNA proximal nucleotide-processing capabilities. To demonstrate proof-of-principle, we used the TRBO-sgRNA delivery platform to target GFP in Nicotiana benthamiana (16c) plants, and gene editing was accompanied by loss of GFP expression. Surprisingly, indel (insertions and deletions) percentages averaged nearly 70% within 7 d postinoculation using the TRBO-sgRNA constructs, which retained 5' nucleotide overhangs. In contrast, and in accordance with current models, in vitro Cas9 cleavage assays only edited DNA when 5' sgRNA nucleotide overhangs were removed, suggesting a novel processing mechanism is occurring in planta. Since the Cas9/TRBO-sgRNA platform demonstrated sgRNA flexibility, we targeted the N. benthamiana NbAGO1 paralogs with one sgRNA and also multiplexed two sgRNAs using a single TRBO construct, resulting in indels in three genes. TRBO-mediated expression of an RNA transcript consisting of an sgRNA adjoining a GFP protein coding region produced indels and viral-based GFP overexpression. In conclusion, multiplexed delivery of sgRNAs using the TRBO system offers flexibility for gene expression and editing and uncovered novel aspects of CRISPR/Cas9 biology.

Parental perception of treatment and medical care in children with craniosynostosis.

Surgery for craniosynostosis implies a relevant strain on the child and the parents. The development of the child's self-perception and self-confidence is mainly influenced by parental attitudes. The outcomes of 46 patients were analysed, taking into consideration parental perceptions. Parents were asked to indicate their satisfaction with the medical care and treatment provided using a questionnaire. Aesthetics were evaluated by the parents and doctors using a score (1=perfect, 5=deficient). Major surgical complications (2.2%) were reported only in the case of complex synostosis. Reoperation was necessary in 2.9% of isolated cases and 45.5% of complex cases. In general, parents were satisfied with the medical (1.3) and nursing (1.6) inpatient care. Aesthetic assessments differed between parents and surgeons, although not significantly (P=0.27). The surgeons perceived the results to be better than the parents, especially for complex synostosis (1.3 vs. 2.7). Alopecia and persistent asymmetry led to a worse perception of aesthetics. Persistent bone defects did not influence parental satisfaction. All participating parents would opt for surgery again. Surgery led to satisfactory results with a low risk of severe complications. Nevertheless, the outcomes and limits of the surgical procedure must be communicated effectively to parents, especially in complex cases, to avoid a mismatch in expectations. It would be desirable to implement structured interviews with parents during regular treatment management.

Thrombocytopenia in MDS: epidemiology, mechanisms, clinical consequences and novel therapeutic strategies.

Thrombocytopenia is commonly seen in myelodysplastic syndrome (MDS) patients, and bleeding complications are a major cause of morbidity and mortality. Thrombocytopenia is an independent factor for decreased survival and has been incorporated in newer prognostic scoring systems. The mechanisms of thrombocytopenia are multifactorial and involve a differentiation block of megakaryocytic progenitor cells, leading to dysplastic, hypolobated and microscopic appearing megakaryocytes or increased apoptosis of megakaryocytes and their precursors. Dysregulated thrombopoietin (TPO) signaling and increased platelet destruction through immune or nonimmune mechanisms are frequently observed in MDS. The clinical management of patients with low platelet counts remains challenging and approved chemotherapeutic agents such as lenalidomide and azacytidine can also lead to a transient worsening of thrombocytopenia. Platelet transfusion is the only supportive treatment option currently available for clinically significant thrombocytopenia. The TPO receptor agonists romiplostim and eltrombopag have shown clinical activity in clinical trials in MDS. In addition to thrombopoietic effects, eltrombopag can inhibit leukemic cell proliferation via TPO receptor-independent effects. Other approaches such as treatment with cytokines, immunomodulating drugs and signal transduction inhibitors have shown limited activity in selected groups of MDS patients. Combination trials of approved agents with TPO agonists are ongoing and hold promise for this important clinical problem.

Shoulder linked arthroplasty in patients with obstetric brachial plexus palsy can improve quality of life and function at short-term follow-up.

BACKGROUND: Patients with obstetric brachial plexus palsy (OBPP) are prone to develop degenerative shoulder disease at a younger age than the general population. To date, no reports have been published on the complexities or outcome of shoulder arthroplasty (SA) in this unique patient group. METHODS: We reviewed of 9 SAs in 9 patients (3 men and 6 women) with OBPP with mean follow-up 5.1 years (range, 2.6-7.6 years). Patients were a mean age of 29 years (range, 16-56 years). Patients had undergone a mean of 3 previous operations (range, 2-6). All patients underwent linked constrained SA. RESULTS: The mean Oxford Shoulder Score increased from 8 (range, 3-10) preoperatively to 21 (range, 12-32) at the final follow-up (P < .001) predominantly due to pain relief. Mean range of active forward elevation and abduction improved from 35° and 39° to 46° and 45°, respectively. Patients improved significantly in 2 of 8 Short-Form 36-Item health-related quality of life domains, bodily pain (P = .013) and mental health (P = .035), and the overall physical component summary score (P = .006). Range of motion had mild improvements. Three required reoperation (33%), comprising 1 excision of heterotopic ossification, 1 trimming of a prominent screw, and 1 deltoid rupture repair. CONCLUSIONS: SA is effective at relieving pain and health-related quality of life for young patients with OBPP; however, compared with the general population, the complication rate is high and functional gains are small.

Passive stiffness of coupled wrist and forearm rotations.

Coordinated movement requires that the neuromuscular system account and compensate for movement dynamics. One particularly complex aspect of movement dynamics is the interaction that occurs between degrees of freedom (DOF), which may be caused by inertia, damping, and/or stiffness. During wrist rotations, the two DOF of the wrist (flexion-extension and radial-ulnar deviation, FE and RUD) are coupled through interaction torques arising from passive joint stiffness. One important unanswered question is whether the DOF of the forearm (pronation-supination, PS) is coupled to the two DOF of the wrist. Answering this question, and understanding the dynamics of wrist and forearm rotations in general, requires knowledge of the stiffness encountered during rotations involving all three DOF (PS, FE, and RUD). Here we present the first-ever measurement of the passive stiffness encountered during simultaneous wrist and forearm rotations. Using a wrist and forearm robot, we measured coupled wrist and forearm stiffness in 10 subjects and present it as a 3-by-3 stiffness matrix. This measurement of passive wrist and forearm stiffness will enable future studies investigating the dynamics of wrist and forearm rotations, exposing the dynamics for which the neuromuscular system must plan and compensate during movements involving the wrist and forearm.

Position-dependent characterization of passive wrist stiffness.

Because the dynamics of wrist rotations are dominated by stiffness, understanding wrist rotations requires a thorough characterization of wrist stiffness in multiple degrees of freedom. The only prior measurement of multivariable wrist stiffness was confined to approximately one-seventh of the wrist range of motion (ROM). Here, we present a precise nonlinear characterization of passive wrist joint stiffness over a range three times greater, which covers approximately 70% of the functional ROM of the wrist. We measured the torque-displacement vector field in 24 directions and fit the data using thin-plate spline smoothing optimized with generalized cross validation. To assess anisotropy and nonlinearity, we subsequently derived several different approximations of the stiffness due to this multivariable vector field. The directional variation of stiffness was more pronounced than reported previously. A linear approximation (obtained by multiple linear regression over the entire field) was significantly more anisotropic (eigenvalue ratio of 2.69 ± 0.52 versus 1.58 ± 0.39; ) though less misaligned with the anatomical wrist axes (12.1 ± 4.6° versus 21.2 ± 9.2°; ). We also found that stiffness over this range exhibited considerable nonlinearity-the error associated with a linear approximation was 20-30%. The nonlinear characterization over this greater range confirmed significantly greater stiffness in radial deviation compared to ulnar deviation. This study provides a characterization of passive wrist stiffness better suited to investigations of natural wrist rotations, which cover much of the wrist's ROM. It also provides a baseline for the study of neurological and/or orthopedic disorders that result in abnormal wrist stiffness.

Clinical and imaging findings in children with non-syndromic lambdoid synostosis.

UNLABELLED: True unilateral lambdoid synostosis is a very rare type of craniosynostosis. Patients present with unilateral posterior plagiocephaly. The differentiation between frequent, simple positional (deformational) posterior plagiocephaly and lambdoid synostosis is not easy and to date subject of controversy. Accurate and early diagnosis is important, because treatment is different. Simple positional plagiocephaly responds to conservative treatment, but craniosynostosis may require neurosurgical intervention. We analyzed clinical presentation of five patients in whom non-syndromic lambdoid synostosis was confirmed by CT imaging, in one additionally by high-resolution ultrasound, and finally neurosurgical intervention. However, clinical inspection alone did not reliably identify infants with lambdoid synostosis. CONCLUSION: Diagnosis of lambdoid synostosis is not always possible based on clinical inspection alone. To confirm the diagnosis imaging is recommended. There is evidence that high-resolution ultrasound can be used first-line in the future.

Stem cell origin of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are common hematologic disorders that are characterized by decreased blood counts due to ineffective hematopoiesis. MDS is considered a 'preleukemic' disorder linked to a significantly elevated risk of developing an overt acute leukemia. Cytopenias can be observed in all three myeloid lineages suggesting the involvement of multipotent, immature hematopoietic cells in the pathophysiology of this disease. Recent studies using murine models of MDS as well as primary patient-derived bone marrow samples have provided direct evidence that the most immature, self-renewing hematopoietic stem cells (HSC), as well as lineage-committed progenitor cells, are critically altered in patients with MDS. Besides significant changes in the number and distribution of stem as well as immature progenitor cells, genetic and epigenetic aberrations have been identified, which confer functional changes to these aberrant stem cells, impairing their ability to proliferate and differentiate. Most importantly, aberrant stem cells can persist and further expand after treatment, even upon transient achievement of clinical complete remission, pointing to a critical role of these cells in disease relapse. Ongoing preclinical and clinical studies are particularly focusing on the precise molecular and functional characterization of aberrant MDS stem cells in response to therapy, with the goal to develop stem cell-targeted strategies for therapy and disease monitoring that will allow for achievement of longer-lasting remissions in MDS.

[Competency-based medical education: National Catalogue of Learning Objectives in surgery]. / Kompetenzorientierung in der medizinischen Ausbildung: Nationaler Lernzielkatalog Chirurgie.

Competency-based medical education is a prerequisite to prepare students for the medical profession. A mandatory professional qualification framework is a milestone towards this aim. The National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) of the German Medical Faculty Association (MFT) and the German Medical Association will constitute a basis for a core curriculum of undergraduate medical training. The Surgical Working Group on Medical Education (CAL) of the German Association of Surgeons (DGCH) aims at formulating a competency-based catalogue of learning objectives for surgical undergraduate training to bridge the gap between the NKLM and the learning objectives of individual medical faculties. This is intended to enhance the prominence and visibility of the surgical discipline in the context of medical education. On the basis of different faculty catalogues of learning objectives, the catalogue of learning objectives of the German Association of Orthopedics and Orthopedic Surgery and the Swiss Catalogue of Learning Objectives representatives of all German Surgical Associations cooperated towards a structured selection process of learning objectives and the definition of levels and areas of competencies. After completion the catalogue of learning objectives will be available online on the webpage of the DGCH.