The functional complexity of the human transcriptome is not yet fully elucidated. We report a high-throughput sequence of the human transcriptome from a human embryonic kidney and a B cell line. We ...used shotgun sequencing of transcripts to generate randomly distributed reads. Of these, 50% mapped to unique genomic locations, of which 80% corresponded to known exons. We found that 66% of the polyadenylated transcriptome mapped to known genes and 34% to nonannotated genomic regions. On the basis of known transcripts, RNA-Seq can detect 25% more genes than can microarrays. A global survey of messenger RNA splicing events identified 94,241 splice junctions (4096 of which were previously unidentified) and showed that exon skipping is the most prevalent form of alternative splicing.
Global treatment budgets, i.e. predefined budgets for patients treated in hospital independent of the setting within the hospital, together with flexible and integrated treatment (FIT) have been ...introduced in some German psychiatric hospitals since 2013. We investigated pooled changes in inpatient, day-care, outpatient treatment, and continuity of care for patients with mental disorders in 12 FIT-hospitals.
We conducted a series of 12 controlled cohort studies regarding FIT hospitals using anonymized patient claims data from more than 70 German statutory health insurance funds. Each study compared one FIT-hospital to matched patients from equivalent non-FIT-hospitals (routine care). We included only those patients without treatment in the respective hospital within two years prior to first hospital treatment (either FIT or routine care). We contrasted results between the year prior to with the first and second year after patient's first treatment (treatment continuity: only group comparison) using multivariate multi-level models. To approximate the difference-in-difference effect in the meta-analysis, we used the interaction terms group (FIT hospital vs. routine care) x time (year before vs. first or second patient year after study inclusion) in the Poisson models.
The 12 studies included 36,069 patients with 2,358 patients from a Department of child and adolescent psychiatry. The pooled effect revealed a 5.1 days lower increase in inpatient treatment in FIT-hospitals during the first patient year compared to routine care. Results were statistically significant for adult care FIT-hospitals but not for child and adolescent FIT-hospitals. Utilization of day-care treatment increased more in most FIT-hospitals during the first year, while outpatient contacts increased in some and decreased in others. The odds of treatment continuity increased by 1.4 in FIT-hospitals compared to non-FIT-hospitals.
Global treatment budgets lead to the intended changes in mental health care in the majority of FIT-hospitals compared to routine care in this large real-world evidence study from Germany. For child and adolescent psychiatry, more evidence is needed to draw firm conclusions.
This study was registered in the database "Health Services Research Germany" (trial number: VVfD_EVA64_15_003713).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Model projects for flexible and integrated treatment (FIT) in Germany aim at advancing the quality of care for people with mental disorders. A new FIT model project was established in 2017 at the ...Department of child and adolescent psychiatry (KJP) of the University Hospital Tübingen (Universitätsklinikum Tübingen, UKT). The study design of EVA_TIBAS presented here describes the evaluation of the FIT model project at the KJP of the UKT. This evaluation aims at quantifying the anticipated FIT model project changes, which are to improve patients' cross-sectoral care at the same maximum cost as standard care.
EVA_TIBAS is a controlled cohort study using a mix of quantitative and qualitative methods. The FIT evaluation consists of three modules. In Module A, anonymized claims data of a statutory health insurance fund will be used to compare outcomes (duration of inpatient and day care psychiatric treatment, inpatient and day care psychiatric length of stay, outpatient psychiatric treatment in hospital, inpatient hospital readmission, emergency admission rate, direct medical costs) of patients treated in the model hospital with patients treated in structurally comparable control hospitals (estimated sample size = ca. 600 patients). In Module B, patient-reported outcomes (health related quality of life, symptom burden, return to psychosocial relationships (e.g. school, friends, hobbies), treatment satisfaction, societal costs) will be assessed quantitatively using validated questionnaires for the model and two control hospitals (estimated sample size = ca. 300 patients). A subsequent health economic evaluation will be based on cost-effectiveness analyses from both the insurance fund's and the societal perspective. In Module C, about 30 semi-structured interviews will examine the quality of offer, effects and benefits of the service offered by the social service of the AOK Baden-Württemberg (for stabilizing the overall situation of care in the family) in the model hospital. A focus group discussion will address the quality of cooperation between employees of the university hospital and the social services.
The results of this evaluation will be used to inform policy makers whether this FIT model project or aspects of it should be implemented into standard care.
This study was registered at ClinicalTrials.gov PRS (ID: NCT04727359 , date: 27 January 2021).
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Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approximately 98% of mammalian DNA is noncoding, yet we understand relatively little about the function of this enigmatic portion of the genome. The cis-regulatory elements that control gene ...expression reside in noncoding regions and can be identified by mapping the binding sites of tissue-specific transcription factors. Cone-rod homeobox (CRX) is a key transcription factor in photoreceptor differentiation and survival, but its in vivo targets are largely unknown. Here, we used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) on CRX to identify thousands of cis-regulatory regions around photoreceptor genes in adult mouse retina. CRX directly regulates downstream photoreceptor transcription factors and their target genes via a network of spatially distributed regulatory elements around each locus. CRX-bound regions act in a synergistic fashion to activate transcription and contain multiple CRX binding sites which interact in a spacing- and orientation-dependent manner to fine-tune transcript levels. CRX ChIP-seq was also performed on Nrl(-/-) retinas, which represent an enriched source of cone photoreceptors. Comparison with the wild-type ChIP-seq data set identified numerous rod- and cone-specific CRX-bound regions as well as many shared elements. Thus, CRX combinatorially orchestrates the transcriptional networks of both rods and cones by coordinating the expression of photoreceptor genes including most retinal disease genes. In addition, this study pinpoints thousands of noncoding regions of relevance to both Mendelian and complex retinal disease.
•All-cause survival after TAVI seems to be independent of prosthesis type and PM implantation.•Intrinsic AV node conduction recovers in a significant proportion of patients.•PM interrogations ...including reprogramming are required to avoid unnecessary RV stimulation.
Transcatheter aortic valve implantation (TAVI) is an established treatment option for patients with severe aortic stenosis and high surgical risk. Currently, various prosthesis types are available. Atrioventricular block (AVB) requiring pacemaker (PM) implantation is a typical complication after TAVI. This study investigated the recovery of AV node conduction and mid-term outcome of patients with or without PM implantation after TAVI according to prosthesis type.
From July 2008 to May 2015, 856 transcatheter heart valves were implanted at our center (age: 80.5±6.1 years; logistic EuroSCORE: 15.4%). These patients were followed up regularly in our outpatient clinic.
PM implantation was performed in 16.9% of patients due to severe conduction disturbances, mainly third-degree AVB. The need for PM implantation differed between the various prosthesis types: Medtronic CoreValve (Medtronic Inc., Minneapolis, MN, USA): 22.8% (n=272), Edwards Sapien XT (Edwards Lifesciences, Irvine, CA, USA): 13.0% (n=262), Edwards Sapien 3 (Edwards Lifesciences, Irvine, CA, USA): 16.2% (n=234), Direct Flow Medical (Direct Flow Medical, Santa Rosa, CA, USA): 7.3% (n=41), St. Jude Medical Portico (St. Jude Medical, St. Paul, MN, USA): 15.4% (n=26), Boston Scientific Lotus (Boston Scientific, Marlborough, MA, USA): 21.4% (n=14) and Medtronic Evolut R (Medtronic Inc., Minneapolis, MN, USA): 14.3% (n=7). Kaplan–Meier analysis for all-cause mortality did not reveal any differences between the various prosthesis types. PM implantation rates declined over the years of experience in a stable intervention team; 45% of PM patients showed sufficient AV node conduction after PM reprogramming at our follow-up examination.
Mid-term all-cause survival after TAVI seems to be independent of prosthesis type and PM implantation after TAVI. Intrinsic AV node conduction recovers in a significant proportion of patients. Therefore, regular PM interrogations including reprogramming are required to avoid unnecessary permanent right ventricular stimulation.
A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod ...versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP-Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP-Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s) for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conduction disturbance requiring permanent pacemaker (PPM) implantation is a common complication after transcatheter aortic valve implantation (TAVI) using Medtronic self-expanding CoreValve, and has ...remained common following the introduction of the new generation CoreValve Evolut R device. The aim of this study was to identify the determinants of PPM implantation after TAVI with CoreValve Evolut R. We retrospectively examined 114 patients who underwent transfemoral TAVI using CoreValve Evolut R. We excluded 17 patients with preprocedural PPM, 1 patient requiring Edwards SAPIEN 3 implantation after CoreValve Evolut R implantation, and 4 patients who died during the hospital admission. Thus, 92 patients were finally included in the analysis. Seventeen patients (18%) underwent new PPM implantation after TAVI. Preprocedural electrocardiography showed a lower ventricular rate and more right bundle branch block (RBBB) in patients with new PPM implantation compared to those without. Quantitative multidetector computed tomography assessment revealed larger aortic valve calcification (AVC) and higher asymmetry (∆AVC) in patients with new PPM implantation compared to those without. The univariate logistic regression analysis demonstrated that preprocedural ventricular rate ≤ 70 beats per minute, RBBB, AVC ≥ 110 mm
3
, and ∆AVC ≥ 45 mm
3
were associated with new PPM implantation. Number of these factors clearly stratified the risk of new PPM implantation. In conclusion, PPM implantation occurs in 18% of patients undergoing TAVI with the new generation CoreValve Evolut R. Lower preprocedural ventricular rate, RBBB, larger AVC, and higher ∆AVC are associated with new PPM implantation after TAVI using the new generation CoreValve Evolut R.
The achievement of international goals and national commitments related to forest conservation and management, climate change, and sustainable development requires credible, accurate, and reliable ...monitoring of stocks and changes in forest biomass and carbon. Most prominently, the Paris Agreement on Climate Change and the United Nations’ Sustainable Development Goals in particular require data on biomass to monitor progress. Unprecedented opportunities to provide forest biomass data are created by a series of upcoming space-based missions, many of which provide open data targeted at large areas and better spatial resolution biomass monitoring than has previously been achieved. We assess various policy needs for biomass data and recommend a long-term collaborative effort among forest biomass data producers and users to meet these needs. A gap remains, however, between what can be achieved in the research domain and what is required to support policy making and meet reporting requirements. There is no single biomass dataset that serves all users in terms of definition and type of biomass measurement, geographic area, and uncertainty requirements, and whether there is need for the most recent up-to-date biomass estimate or a long-term biomass trend. The research and user communities should embrace the potential strength of the multitude of upcoming missions in combination to provide for these varying needs and to ensure continuity for long-term data provision which one-off research missions cannot provide. International coordination bodies such as Global Forest Observations Initiative (GFOI), Committee on Earth Observation Satellites (CEOS), and Global Observation of Forest Cover and Land Dynamics (GOFC‐GOLD) will be integral in addressing these issues in a way that fulfils these needs in a timely fashion. Further coordination work should particularly look into how space-based data can be better linked with field reference data sources such as forest plot networks, and there is also a need to ensure that reference data cover a range of forest types, management regimes, and disturbance regimes worldwide.
The function of the aryl hydrocarbon receptor (AhR) in mediating the biological effect to environmental pollutants is well established. However, accumulated evidence indicates a wide range of ...physiological and pathological functions mediated by the AhR, suggesting the existence of endogenous AhR ligand(s). The nature of an AhR ligand remain elusive; however, it is known that the AhR is activated by several compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin or the tryptophan photoproduct 6-formylindolo3,2-bcarbazole. In this study, we show that physiological concentrations of tryptamine (TA) lead to induction of cytochrome P4501A1 transcription through an AhR-dependent mechanism. In addition, we show that activation of the AhR by TA requires a functional monoamino oxidase system, suggesting that TA acts as an AhR proligand possibly by converting to a high-affinity AhR ligand. Taken together, we show a possible mechanism, through which AhR signaling is activated by endogenous conversion of TA involving monoamine oxidases.
Close, continuous and efficient collaboration between different professions and sectors of care is necessary to provide patient-centered care for individuals with mental disorders. The lack of ...structured collaboration between in- and outpatient care constitutes a limitation of the German health care system. Since 2012, a new law in Germany (§64b Social code book (SGB) V) has enabled the establishment of cross-sectoral and patient-centered treatment models in psychiatry. Such model projects follow a capitation budget, i.e. a total per patient budget of inpatient and outpatient care in psychiatric clinics. Providers are able to choose the treatment form and adapt the treatment to the needs of the patients. The present study (EVA64) will investigate the effectiveness, costs and efficiency of almost all model projects established in Germany between 2013 and 2016.
A health insurance data-based controlled cohort study is used. Data from up to 89 statutory health insurance (SHI) funds, i.e. 79% of all SHI funds in Germany (May 2017), on inpatient and outpatient care, pharmaceutical and non-pharmaceutical treatments and sick leave for a period of 7 years will be analyzed. All patients insured by any of the participating SHI funds and treated in one of the model hospitals for any of 16 pre-defined mental disorders will be compared with patients in routine care. Sick leave (primary outcome), utilization of inpatient care (primary outcome), utilization of outpatient care, continuity of contacts in (psychiatric) care, physician and hospital hopping, re-admission rate, comorbidity, mortality, disease progression, and guideline adherence will be analyzed. Cost and effectivity of model and routine care will be estimated using cost-effectiveness analyses. Up to 10 control hospitals for each of the 18 model hospitals will be selected according to a pre-defined algorithm.
The evaluation of complex interventions is an important main task of health services research and constitutes the basis of evidence-guided advancement in health care. The study will yield important new evidence to guide the future provision of routine care for mentally ill patients in Germany and possibly beyond.
This study was registered in the database "Health Services Research Germany" (trial number: VVfD_EVA64_15_003713 ).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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