SMAD2 is a member of the transforming growth factor ␤ and activin-signaling pathway. To examine the role of Smad2 in postgastrulation development, we independently generated mice with a null mutation in this gene. Smad2-deficient embryos die around day 7.5 of gestation because of failure of gastrulation and failure to establish an anterior-posterior (A-P) axis. Expression of the homeobox gene Hex (the earliest known marker of the A-P polarity and the prospective head organizer) was found to be missing in Smad2-deficient embryos. Homozygous mutant embryos and embryonic stem cells formed mesoderm derivatives revealing that mesoderm induction is SMAD2 independent. In the presence of wild-type extraembryonic tissues, Smad2-deficient embryos developed beyond 7.5 and up to 10.5 days postcoitum, demonstrating a requirement for SMAD2 in extraembryonic tissues for the generation of an A-P axis and gastrulation. The rescued postgastrulation embryos showed malformation of head structures, abnormal embryo turning, and cyclopia. Our results show that Smad2 expression is required at several stages during embryogenesis. T he transforming growth factor ␤ (TGF-␤) superfamily is a group of signaling molecules that play essential roles in development and tissue homeostasis in vertebrates and invertebrates (1-3). Members of this family include the TGF-␤s, activins, and bone morphogenetic proteins.A family of proteins known as SMADs has been shown to function downstream of TGF family type I receptors (reviewed in ref. 4). The TGF-␤ and activin type I receptors interact with SMAD2 and the closely related SMAD3 (5-9). After being phosphorylated by type I receptors, pathway-restricted SMADs associate with SMAD4 (10), translocate to the nucleus, and activate, in conjunction with several specific transcription factors, their respective target genes (4, 11).The SMAD2 protein consists of three domains (4), the Mad homology domain 1 (MH1) and the MH2 domain that harbors the DNA-binding site (12). The third linker region domain connects the MH1 and MH2 domains, is phosphorylated, and may serve as a molecular hinge. The MH2 domain interacts with the type I receptors and is phosphorylated on ligand activation. The SMAD2-type I receptor interaction is also regulated by a newly discovered protein named SARA (13). The MH2 domain also exhibits transactivation properties.The human SMAD2 gene is located on chromosome 18q21, in close proximity to the tumor suppressors DCC and SMAD4͞DPC4 (14-16). Mutations that disrupt the function of SMAD2 have been identified in colorectal cancers (16,17) and lung cancer (18), suggesting its role as a tumor suppressor.Smad2 is expressed almost ubiquitously and has an important role in early development (19)(20)(21)(22). Targeted inactivation of Smad2 resulted in early lethality before gastrulation. Though all these studies showed that Smad2-deficient embryos die because of gastrulation failure, two studies did not describe mesoderm formation (21,22), whereas the other reported transient mesoderm induction but failur...

Background Unnecessary healthcare utilization, non-adherence to current clinical guidelines, or insufficient personalized care are perpetual challenges and remain potential major cost-drivers for healthcare systems around the world. Implementing decision support systems into clinical care is promised to improve quality of care and thereby yield substantial effects on reducing healthcare expenditure. In this article, we evaluate the economic impact of clinical decision support (CDS) interventions based on electronic health records (EHR). Methods We searched for studies published after 2014 using MEDLINE, CENTRAL, WEB OF SCIENCE, EBSCO, and TUFTS CEA registry databases that encompass an economic evaluation or consider cost outcome measures of EHR based CDS interventions. Thereupon, we identified best practice application areas and categorized the investigated interventions according to an existing taxonomy of front-end CDS tools. Results and discussion Twenty-seven studies are investigated in this review. Of those, twenty-two studies indicate a reduction of healthcare expenditure after implementing an EHR based CDS system, especially towards prevalent application areas, such as unnecessary laboratory testing, duplicate order entry, efficient transfusion practice, or reduction of antibiotic prescriptions. On the contrary, order facilitators and undiscovered malfunctions revealed to be threats and could lead to new cost drivers in healthcare. While high upfront and maintenance costs of CDS systems are a worldwide implementation barrier, most studies do not consider implementation cost. Finally, four included economic evaluation studies report mixed monetary outcome results and thus highlight the importance of further high-quality economic evaluations for these CDS systems. Conclusion Current research studies lack consideration of comparative cost-outcome metrics as well as detailed cost components in their analyses. Nonetheless, the positive economic impact of EHR based CDS interventions is highly promising, especially with regard to reducing waste in healthcare.

Background: Data on patients with coronavirus disease 2019 (COVID-19) who return to hospital after discharge are scarce. Characterization of these patients may inform post-hospitalization care. Methods and Findings: Retrospective cohort study of patients with confirmed SARS-CoV-2 discharged alive from five hospitals in New York City with index hospitalization between February 27th-April 12th, 2020, with follow-up of ≥14 days. Significance was defined as P<0.05 after multiplying P by 125 study-wide comparisons. Of 2,864 discharged patients, 103 (3.6%) returned for emergency care after a median of 4.5 days, with 56 requiring inpatient readmission. The most common reason for return was respiratory distress (50%). Compared to patients who did not return, among those who returned there was a higher proportion of COPD (6.8% vs 2.9%) and hypertension (36% vs 22.1%). Patients who returned also had a shorter median length of stay (LOS) during index hospitalization (4.5 [2.9,9.1] vs. 6.7 [3.5, 11.5] days; Padjusted=0.006), and were less likely to have required intensive care on index hospitalization (5.8% vs 19%; Padjusted=0.001). A trend towards association between absence of in-hospital anticoagulation on index admission and return to hospital was also observed (20.9% vs 30.9%, Padjusted=0.064). On readmission, rates of intensive care and death were 5.8% and 3.6%, respectively. Conclusions: Return to hospital after admission for COVID-19 was infrequent within 14 days of discharge. The most common cause for return was respiratory distress. Patients who returned had higher proportion of COPD and hypertension with shorter LOS on index hospitalization, and a trend towards lower rates of in-hospital treatment-dose anticoagulation. Future studies should focus on whether these comorbid conditions, longer LOS and anticoagulation are associated with reduced readmissions.