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Introduction: Cesarean section (CS) rates are increasing worldwide. One constant indication is the breech presentation at term. By offering external cephalic version (ECV) and vaginal breech delivery CS rates can be further reduced. Objective: This study aimed to analyze the ECV at 38 weeks of gestation with the associate uptake rate, predicting factors, success rate, and complications at a tertiary healthcare provider in Germany specializing in vaginal breech delivery. Methods: We conducted a prospective cohort study with retrospective data acquisition. All women with a singleton fetus in breech presentation presenting after 34 weeks of gestation for counseling between 2013 and 2017 were included. ECV impact factors were analyzed using logistic regression. Results: A total of 1,598 women presented for breech birth planning. ECV was performed on 353 patients. The overall success rate was 22.4%. A later week of gestation (odds ratio [OR] 1.69), an abundant amniotic fluid index (AFI score) (OR 5.74), fundal (OR 3.78) and anterior (OR 0.39) placental location, and an oblique lie (OR 9.08) were significantly associated with successful ECV in our population. No major complications were observed. The overall vaginal delivery rates could be increased to approximately 14% with ECV. Conclusion: The demand for alternative birth modes other than CS for breech birth is high in the area of Frankfurt, Germany. Our study offers evidence of the safety of ECV at 38 weeks. Centers with expertise in vaginal breech delivery and ECV can reduce CS-rates. To further establish vaginal breech delivery and ECV as alternate options, the required knowledge and skill should be implemented in the revised curricula.
Background: Pathogenesis of portal hypertension is multifactorial and includes pathologic intrahepatic angiogenesis, whereby TIPS insertion is an effective therapy of portal hypertension associated complications. While angiogenin is a potent contributor to angiogenesis in general, little is known about its impact on TIPS function over time. Methods: In a total of 118 samples from 47 patients, angiogenin concentrations were measured in portal and inferior caval vein plasma at TIPS insertion (each blood compartment n = 23) or angiographic intervention after TIPS (each blood compartment n = 36) and its relationship with patient outcome was investigated. Results: Angiogenin levels in the inferior caval vein were significantly higher compared to the portal vein (P = 0.048). Ten to 14 days after TIPS, inferior caval vein angiogenin level correlated inversely with the portal systemic pressure gradient (P<0.001), measured invasively during control angiography. Moreover, patients with TIPS revision during this angiography, showed significantly lower angiogenin level in the inferior caval vein compared to patients without TIPS dysfunction (P = 0.01). Conclusion: In cirrhosis patients with complications of severe portal hypertension, circulating levels of angiogenin are derived from the injured liver. Moreover, angiogenin levels in the inferior caval vein after TIPS may predict TIPS dysfunction.
Introduction: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy. Methods and analysis: Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. Scope: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. Population: patients (≥18 years) with polypharmacy (≥5 prescriptions). Sample size: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. Intervention: complex intervention eMMa. Follow-up: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. Outcomes: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. Statistical analysis: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints.
DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma
(2021)
Background: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
The mammalian target of rapamycin and the integrated stress response are central cellular hubs regulating translation upon stress. The precise proteins and pathway specificity of translation targets of these pathways remained largely unclear. We recently described a new method for quantitative translation proteomics and found that both pathways control translation of the same sets of proteins.
Minimal residual disease (MRD) is the strongest predictor of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In BLAST study (NCT01207388), adults with BCP-ALL in remission with MRD after chemotherapy received blinatumomab, a CD19 BiTE® immuno-oncotherapy, 15 µg/m2/day for up to four 6-week cycles (4 weeks continuous infusion, 2 weeks off). Survival was evaluated for 110 patients, including 74 who received HSCT in continuous complete remission. With a median follow-up of 59·8 months, median survival (months) was 36·5 (95% CI: 22.0–not reached [NR]). Median survival was NR (29.5–NR) for complete MRD responders (n = 84) and 14.4 (3.8–32.3) for MRD non-responders (n = 23; p = 0.002); after blinatumomab and HSCT, median survival was NR (25.7–NR) (n = 61) and 16.5 (1.1–NR) (n = 10; p = 0.065), respectively. This final analysis suggests complete MRD response during blinatumomab treatment is curative. Post-hoc analysis of study data suggests while post blinatumomab HSCT may be beneficial in appropriate patients, long-term survival without HSCT is also possible.
Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
The influence and power of some OECD states is under threat but China appears to remain astonishingly flexible, economically potent, and politically strong. How accurate is this view? To answer this question, major aspects of Chinese economic regulation that were adopted in the country’s progress towards capitalist modernization are examined. The analysis requires a historical reconstruction of how China changed the way it intervenes economically and politically, especially with regard to the institutions of the central state. Such a reconstruction reveals that, since the 1990s, the central state has indeed increased its steering capacities. These capacities have a distinctive basis that includes acceptance of a state-centered approach, idiosyncratic innovation policies taking place in the "shadow" of the state’s hierarchy, and the ongoing influence of the communist party. An all-embracing controlling power is, however, not detectable. What does exist in China’s competition-driven system of “statecapitalist” regulation, is a set of limits on the state’s capacity to govern.
Young trees of deciduous Quercus robur and Q. petraea and evergreen Q. ilex were grown together in a competition lysimeter experiment to assess i) – whether the observed growth differences between evergreen Q. ilex and the deciduous Q. robur and Q. petraea on sandy soil in the field and ii) – whether the different natural distribution of Q. robur and Q. petraea could be attributed to physiological differences between the species under experimental drought stress (DS). Half of the plants were subjected to long-term DS in two consecutive years and monitored for physiological and growth parameters. In the first year, water withholding for more than three months did not lead to significant drought stress, probably because of a sufficient residual water volume in the lysimeter for the relatively small plants. However, in the second year, 2018, which was warmer, the bigger plants now competed for the residual water and clear drought stress symptoms developed for more than two months in all trees in the DS lysimeter basin. Growth was only moderately (and mostly not significantly) affected by the DS in the second year, except for a smaller total leaf area in DS Q. ilex as compared to DS Q. robur and Q. petraea and smaller root collar diameter in DS Q. ilex compared to DS Q. robur. Under DS, the deciduous species revealed significant decreases in ΔVIP, indicating a negative effect on electron transport through PS I. Pn, PIabs and water relations parameters (ΨPD and LWC) all decreased to various extents under DS in all three species, leading to clear separation of the deciduous from the evergreen species by PCA. However, PCA did not separate the two deciduous species from each other. It is concluded that longer root growth in the two deciduous species as compared to Q. ilex ameliorates DS effects in Q. robur and Q. petraea and may be the key to understand the better performance of deciduous oaks on sandy soil in the field.
Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.