Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial.

BACKGROUND: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. METHODS: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors. RESULTS: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]). CONCLUSIONS: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.

Inclusivity in Occupational Participation: Life Stories of Bangladeshi With Spinal Cord Injury.

This research aimed to describe the process of occupational participation among persons with spinal cord injury (SCI) discharged from the only SCI rehabilitation hospital in Bangladesh. We analyzed seven participants' interview transcripts and observations using the trajectory equifinality model. Study participants demonstrated the following occupational participation trajectories: (a) employing a strategy or difficulty in occupational participation; (b) performing solidarity or experiencing deprivation; (c) creating identity or divergence; and (d) being included in or excluded from everyday life. There are four pathways: (I) discouraging conditions that minimized daily performance; (II) reinforcing obligatory connections to optimization of daily performance; (III) reciprocity to facilitate social activities; and (IV) manipulating mastery in occupational participation. Occupational therapists can consider the trajectory phases and pathways of occupational participation when facilitating the inclusion of service users after discharge from the hospital.

Experience of Occupational Participation Among Persons With Spinal Cord Injury: Life Story Analysis With Trajectory Equifinality Model (TEM)Persons with spinal cord injury (SCI) in Bangladesh demonstrated inadequate skills in community integration because of limited access to health care follow-ups and unfavorable sociocultural conditions. This research focuses on occupational participation experiences among seven persons with SCI living in the community. We used trajectory equifinality model (TEM) to analyze semi-structured interview and observation data to understand human experiences in an irreversible timeline from a starting point to an endpoint. Data analysis revealed a conceptualization of four periods of occupational participation and four common types of non-linear pathways. Participants optimized shared occupational participation and used mastery over occupations to minimize the experience of occupational deprivation. These findings could assist in developing independent peer-led occupation-based health care programs with few skilled occupational therapists and limited financial resources. These 3 years of interviews and follow-up reports with participants who were selected purposively do not necessarily reflect how actual participation unfolded over time.

Discontinuation vs. continuation of renin-angiotensin system inhibition before non-cardiac surgery: the SPACE trial.

BACKGROUND AND AIMS: Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear. METHODS: From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy. RESULTS: Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]. CONCLUSIONS: Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies.

Development of a Triple-Negative Breast Cancer Leptomeningeal Disease Model in Zebrafish.

Leptomeningeal disease occurs when cancer cells migrate into the ventricles of the brain and spinal cord and then colonize the meninges of the central nervous system. The triple-negative subtype of breast cancer often progresses toward leptomeningeal disease and has a poor prognosis because of limited treatment options. This is due, in part, to a lack of animal models with which to study leptomeningeal disease. Here, we developed a translucent zebrafish casper (roy-/-; nacre-/-) xenograft model of leptomeningeal disease in which fluorescent labeled MDA-MB-231 human triple-negative breast cancer cells are microinjected into the ventricles of zebrafish embryos and then tracked and measured using fluorescent microscopy and multimodal plate reader technology. We then used these techniques to measure tumor area, cell proliferation, and cell death in samples treated with the breast cancer drug doxorubicin and a vehicle control. We monitored MDA-MB-231 cell localization and tumor area, and showed that samples treated with doxorubicin exhibited decreased tumor area and proliferation and increased apoptosis compared to control samples.

Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice.

The pregnant uterus is an immunologically rich organ, with dynamic changes in the inflammatory milieu and immune cell function underlying key stages of pregnancy. Recent studies have implicated dysregulated expression of the interleukin-1 (IL-1) family cytokine, IL-33, and its receptor, ST2, in poor pregnancy outcomes in women, including recurrent pregnancy loss, preeclampsia, and preterm labor. How IL-33 supports pregnancy progression in vivo is not well understood. Here, we demonstrate that maternal IL-33 signaling critically regulates uterine tissue remodeling and immune cell function during early pregnancy in mice. IL-33-deficient dams exhibit defects in implantation chamber formation and decidualization, and abnormal vascular remodeling during early pregnancy. These defects coincide with delays in early embryogenesis, increased resorptions, and impaired fetal and placental growth by late pregnancy. At a cellular level, myometrial fibroblasts, and decidual endothelial and stromal cells, are the main IL-33+ cell types in the uterus during decidualization and early placentation, whereas ST2 is expressed by uterine immune populations associated with type 2 immune responses, including ILC2s, Tregs, CD4+ T cells, M2- and cDC2-like myeloid cells, and mast cells. Early pregnancy defects in IL-33-deficient dams are associated with impaired type 2 cytokine responses by uterine lymphocytes and fewer Arginase-1+ macrophages in the uterine microenvironment. Collectively, our data highlight a regulatory network, involving crosstalk between IL-33-producing nonimmune cells and ST2+ immune cells at the maternal-fetal interface, that critically supports pregnancy progression in mice. This work has the potential to advance our understanding of how IL-33 signaling may support optimal pregnancy outcomes in women.

Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.

China Pakistan Economic Corridor Digital Transformation.

The China-Pakistan Economic Corridor (CPEC) vision and mission are to improve the people's living standards of Pakistan and China through bilateral investments, trade, cultural exchanges, and economic activities. To achieve this envisioned dream, Pakistan established the China-Pakistan Economic Corridor Authority (CPECA) to further its completion, but Covid-19 slowed it down. This situation compelled the digitalization of CPEC. This article reviews the best practices and success stories of various digitalization and e-governance programs and, in this light, advises the implementation of the Ajman Digital Governance (ADG) model as a theoretical framework for CPEC digitalization. This article concludes that the Pakistani government needs to transform CPEC digitalization by setting up the CPEC Digitalization and Transformation Center (DTC) at the CPECA office to attract more investors and businesses.

Design Strategies for Structurally Controlled Polymer Surfaces via Cyclophane-Based CVD Polymerization and Post-CVD Fabrication.

Molecular structuring of soft matter with precise arrangements over multiple hierarchical levels, especially on polymer surfaces, and enabling their post-synthetic modulation has tremendous potential for application in molecular engineering and interfacial science. Here, recent research and developments in design strategies for structurally controlled polymer surfaces via cyclophane-based chemical vapor deposition (CVD) polymerization with precise control over chemical functionalities and post-CVD fabrication via orthogonal surface functionalization that facilitates the formation of designable biointerfaces are summarized. Particular discussion about innovative approaches for the templated synthesis of shape-controlled CVD polymers, ranging from 1D to 3D architecture, including inside confined nanochannels, nanofibers/nanowires synthesis into an anisotropic media such as liquid crystals, and CVD polymer nanohelices via hierarchical chirality transfer across multiple length scales is provided. Aiming at multifunctional polymer surfaces via CVD copolymerization of multiple precursors, the structural and functional design of the fundamental [2.2]paracyclophane (PCP) precursor molecules, that is, functional CVD monomer chemistry is also described. Technologically advanced and innovative surface deposition techniques toward topological micro- and nanostructuring, including microcontact printing, photopatterning, photomask, and lithographic techniques such as dip-pen nanolithography, showcasing research from the authors' laboratories as well as other's relevant important findings in this evolving field are highlighted that have introduced new programmable CVD polymerization capabilities. Perspectives, current limitations, and future considerations are provided.

Dynamic Surface Modification of Metal-Organic Framework Nanoparticles via Alkoxyamine Functional Groups.

External surface engineering of metal-organic framework nanoparticles (MOF NPs) is emerging as an important design strategy, leading to optimized chemical and colloidal stability. To date, most of the MOF surface modifications have been performed either by physical adsorption or chemical association of small molecules or (preformed) polymers. However, most of the currently employed approaches cannot precisely control the polymer density, and dynamic modifications at the surfaces on demand have been a challenging task. Here, we introduce a general approach based on covalent modification employing alkoxyamines as a versatile tool to modify the outer surface of MOF nanoparticles (NPs). The alkoxyamines serve as initiators to grow polymers from the MOF surface via nitroxide-mediated polymerization (NMP) and allow dynamic attachment of small molecules via a nitroxide exchange reaction (NER). The successful surface modification and successive surface polymerization are confirmed via time-of-flight secondary ion mass spectrometry (ToF-SIMS), size exclusion chromatography (SEC), and nuclear magnetic resonance (NMR) spectroscopy. The functionalized MOF NPs exhibit high suspension stability and good dispersibility while retaining their chemical integrity and crystalline structure. In addition, electron paramagnetic resonance spectroscopy (EPR) studies prove the dynamic exchange of two different nitroxide species via NER and further allow us to quantify the surface modification with high sensitivity. Our results demonstrate that alkoxyamines serve as a versatile tool to dynamically modify the surface of MOF NPs with high precision, allowing us to tailor their properties for a wide range of potential applications, such as drug delivery or mixed matrix membranes.

Self-Management Embedded in Daily Activities: A Photoelicitation Focus Group Study among Persons with Spinal Cord Injury and Their Primary Caregivers in Bangladesh.

Purpose: This study explored how community-dwelling persons with spinal cord injury (SCI) and their primary caregivers execute self-management strategies in daily activities. These strategies were mapped to a preexisting self-management framework. Methods: Photoelicitation focus group discussions were conducted among 14 adults with SCI and their primary caregivers (in two groups). Moreover, a constant comparative framework was used to analyze the data. Results: This study identified nine groups of self-management strategies, some of which could not be categorized under the three main self-management components generally accepted in the literature. Accordingly, a new component is proposed based off of this analysis, entitled management of social complexities, which includes crucial strategies such as (1) relocating to another environment, (2) behaving in an assertive manner, and (3) advocating for social change. Conclusion: The results show that self-management, traditionally described as medical, emotional, and role management, should also include the management of social complexities. The identified strategies could be considered in the development of self-management enhancement programs in lower-middle-income countries.

Mental health of students amidst the COVID-19 pandemic: An empirical study.

Purpose: Considering the severity of the global outbreak of coronavirus (COVID-19) on the whole of humanity, particularly in this case on the physical and mental health of students, this study strives to explore the role of financial worries, employment anxiety and COVID-19 knowledge on depression and mental health among students in Bangladesh. Design/methodology/approach: In the study, a deductive reasoning approach was employed, together with a self-administered questionnaire survey. Questionnaires were sent to the respondents via different social media and by email by creating a Google form link. We finally received 387 responses students aged over 18 years who had internet access in order to complete the survey. To analyze the data, structural equation modeling via AMOS was used. Findings: The results showed that employment anxiety, financial worry, and knowledge on COVID-19 positively influence depression, and finally depression negatively influences the mental health of the students. Thus, our findings supported all of the proposed hypotheses. Originality/value: The research enriches the existing literature pool by contributing empirical substantiation on the role of employment anxiety, financial worries and knowledge of COVID-19 in depression, and the impact of depression on mental health.

Perioperative blood transfusion in major abdominal cancer surgery: a multi-centre service evaluation and national survey.

Background: Anaemia is associated with complications and death after surgery. Perioperative red-cell transfusion triggers are not well defined in patients having oncological surgery, or with cardiovascular disease. Methods: We carried out a prospective multicentre cohort study and a clinician survey of UK transfusion practice in adult patients undergoing surgery for abdominal malignancy. The primary outcome was red cell transfusion. Secondary outcomes were transfusion trigger haemoglobin, incidence of complications, length of hospital stay, and acute hospital mortality. Results: In this prospective cohort study, data were collected on 412 patients undergoing surgery for intrabdominal malignancy in 14 NHS hospitals. Twenty-two (5.2%) patients received preoperative, 42 (10.2%) intraoperative, and 52 (12.2%) postoperative red blood cell transfusion. The mean postoperative transfusion trigger was 75.3 g L-1, and the mean number of units of red blood cells transfused was 1.5 (standard deviation, 1.1). Seventeen (4.0%) patients had a documented postoperative troponin elevation. Five (1.2%) patients died within 30 days of surgery. In the survey, 117 clinicians submitted complete responses, of whom 62 (53%) indicated that a transfusion threshold of 70 g L-1 was appropriate: however, this decreased to six (5.1%) if there was evidence of recent cardiac ischaemia. There were 100 (86%) respondents who indicated equipoise for a trial of restrictive vs liberal transfusion, decreasing to 56% if there was coexisting cardiovascular disease. Conclusions: Many patients having oncological surgery receive red cell transfusion, the majority being given postoperatively. Restrictive transfusion practice is generally followed; however, variability exists especially in cardiovascular disease. Equipoise exists for a study of transfusion thresholds in this group.

Application of Machine Learning in Intensive Care Unit (ICU) Settings Using MIMIC Dataset: Systematic Review.

Modern Intensive Care Units (ICUs) provide continuous monitoring of critically ill patients susceptible to many complications affecting morbidity and mortality. ICU settings require a high staff-to-patient ratio and generates a sheer volume of data. For clinicians, the real-time interpretation of data and decision-making is a challenging task. Machine Learning (ML) techniques in ICUs are making headway in the early detection of high-risk events due to increased processing power and freely available datasets such as the Medical Information Mart for Intensive Care (MIMIC). We conducted a systematic literature review to evaluate the effectiveness of applying ML in the ICU settings using the MIMIC dataset. A total of 322 articles were reviewed and a quantitative descriptive analysis was performed on 61 qualified articles that applied ML techniques in ICU settings using MIMIC data. We assembled the qualified articles to provide insights into the areas of application, clinical variables used, and treatment outcomes that can pave the way for further adoption of this promising technology and possible use in routine clinical decision-making. The lessons learned from our review can provide guidance to researchers on application of ML techniques to increase their rate of adoption in healthcare.

Implications for preeclampsia: hypoxia-induced Notch promotes trophoblast migration.

In the first trimester of human pregnancy, low oxygen tension or hypoxia is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multiple cell types, the relationship between hypoxia and Notch in first trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human first trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a γ-secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed the second trimester chorionic villous sampling (CVS) samples and third trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.

API Driven On-Demand Participant ID Pseudonymization in Heterogeneous Multi-Study Research.

OBJECTIVES: To facilitate clinical and translational research, imaging and non-imaging clinical data from multiple disparate systems must be aggregated for analysis. Study participant records from various sources are linked together and to patient records when possible to address research questions while ensuring patient privacy. This paper presents a novel tool that pseudonymizes participant identifiers (PIDs) using a researcher-driven automated process that takes advantage of application-programming interface (API) and the Perl Open-Source Digital Imaging and Communications in Medicine Archive (POSDA) to further de-identify PIDs. The tool, on-demand cohort and API participant identifier pseudonymization (O-CAPP), employs a pseudonymization method based on the type of incoming research data. METHODS: For images, pseudonymization of PIDs is done using API calls that receive PIDs present in Digital Imaging and Communications in Medicine (DICOM) headers and returns the pseudonymized identifiers. For non-imaging clinical research data, PIDs provided by study principal investigators (PIs) are pseudonymized using a nightly automated process. The pseudonymized PIDs (P-PIDs) along with other protected health information is further de-identified using POSDA. RESULTS: A sample of 250 PIDs pseudonymized by O-CAPP were selected and successfully validated. Of those, 125 PIDs that were pseudonymized by the nightly automated process were validated by multiple clinical trial investigators (CTIs). For the other 125, CTIs validated radiologic image pseudonymization by API request based on the provided PID and P-PID mappings. CONCLUSIONS: We developed a novel approach of an ondemand pseudonymization process that will aide researchers in obtaining a comprehensive and holistic view of study participant data without compromising patient privacy.

Role of Machine Learning Techniques to Tackle the COVID-19 Crisis: Systematic Review.

BACKGROUND: SARS-CoV-2, the novel coronavirus responsible for COVID-19, has caused havoc worldwide, with patients presenting a spectrum of complications that have pushed health care experts to explore new technological solutions and treatment plans. Artificial Intelligence (AI)-based technologies have played a substantial role in solving complex problems, and several organizations have been swift to adopt and customize these technologies in response to the challenges posed by the COVID-19 pandemic. OBJECTIVE: The objective of this study was to conduct a systematic review of the literature on the role of AI as a comprehensive and decisive technology to fight the COVID-19 crisis in the fields of epidemiology, diagnosis, and disease progression. METHODS: A systematic search of PubMed, Web of Science, and CINAHL databases was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines to identify all potentially relevant studies published and made available online between December 1, 2019, and June 27, 2020. The search syntax was built using keywords specific to COVID-19 and AI. RESULTS: The search strategy resulted in 419 articles published and made available online during the aforementioned period. Of these, 130 publications were selected for further analyses. These publications were classified into 3 themes based on AI applications employed to combat the COVID-19 crisis: Computational Epidemiology, Early Detection and Diagnosis, and Disease Progression. Of the 130 studies, 71 (54.6%) focused on predicting the COVID-19 outbreak, the impact of containment policies, and potential drug discoveries, which were classified under the Computational Epidemiology theme. Next, 40 of 130 (30.8%) studies that applied AI techniques to detect COVID-19 by using patients' radiological images or laboratory test results were classified under the Early Detection and Diagnosis theme. Finally, 19 of the 130 studies (14.6%) that focused on predicting disease progression, outcomes (ie, recovery and mortality), length of hospital stay, and number of days spent in the intensive care unit for patients with COVID-19 were classified under the Disease Progression theme. CONCLUSIONS: In this systematic review, we assembled studies in the current COVID-19 literature that utilized AI-based methods to provide insights into different COVID-19 themes. Our findings highlight important variables, data types, and available COVID-19 resources that can assist in facilitating clinical and translational research.

Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy.

Maternal spiral arteries and newly formed decidual capillaries support embryonic development prior to placentation. Previous studies demonstrated that Notch signaling is active in endothelial cells of both decidual capillaries and spiral arteries, however the role of Notch signaling in physiologic decidual angiogenesis and maintenance of the decidual vasculature in early mouse pregnancy has not yet been fully elucidated. We used the Cdh5-CreERT2;Jagged1(Jag1)flox/flox (Jag1∆EC) mouse model to delete Notch ligand, Jag1, in maternal endothelial cells during post-implantation, pre-placentation mouse pregnancy. Loss of endothelial Jag1 leads to increased expression of Notch effectors, Hey2 and Nrarp, and increased endothelial Notch signaling activity in areas of the decidua with remodeling angiogenesis. This correlated with an increase in Dll4 expression in capillary endothelial cells, but not spiral artery endothelial cells. Consistent with increased Dll4/Notch signaling, we observed decreased VEGFR2 expression and endothelial cell proliferation in angiogenic decidual capillaries. Despite aberrant Dll4 expression and Notch activation in Jag1∆EC mutants, pregnancies were maintained and the decidual vasculature was not altered up to embryonic day 7.5. Thus, Jag1 functions in the newly formed decidual capillaries as an antagonist of endothelial Dll4/Notch signaling during angiogenesis, but Jag1 signaling is not necessary for early uterine angiogenesis.

Toolkit to Compute Time-Based Elixhauser Comorbidity Indices and Extension to Common Data Models.

OBJECTIVE: The time-dependent study of comorbidities provides insight into disease progression and trajectory. We hypothesize that understanding longitudinal disease characteristics can lead to more timely intervention and improve clinical outcomes. As a first step, we developed an efficient and easy-to-install toolkit, the Time-based Elixhauser Comorbidity Index (TECI), which pre-calculates time-based Elixhauser comorbidities and can be extended to common data models (CDMs). METHODS: A Structured Query Language (SQL)-based toolkit, TECI, was built to pre-calculate time-specific Elixhauser comorbidity indices using data from a clinical data repository (CDR). Then it was extended to the Informatics for Integrating Biology and the Bedside (I2B2) and Observational Medical Outcomes Partnership (OMOP) CDMs. RESULTS: At the University of Arkansas for Medical Sciences (UAMS), the TECI toolkit was successfully installed to compute the indices from CDR data, and the scores were integrated into the I2B2 and OMOP CDMs. Comorbidity scores calculated by TECI were validated against: scores available in the 2015 quarter 1-3 Nationwide Readmissions Database (NRD) and scores calculated using the comorbidities using a previously validated algorithm on the 2015 quarter 4 NRD. Furthermore, TECI identified 18,846 UAMS patients that had changes in comorbidity scores over time (year 2013 to 2019). Comorbidities for a random sample of patients were independently reviewed, and in all cases, the results were found to be 100% accurate. CONCLUSION: TECI facilitates the study of comorbidities within a time-dependent context, allowing better understanding of disease associations and trajectories, which has the potential to improve clinical outcomes.

Polymerization in MOF-Confined Nanospaces: Tailored Architectures, Functions, and Applications.

This feature article describes recent trends and advances in structuring network polymers using a coordination-driven metal-organic framework (MOF)-based template approach to demonstrate the concept of crystal-controlled polymerization in confined nanospaces, forming tailored architectures ranging from simple linear one-dimensional macromolecules to tunable three-dimensional cross-linked network polymers and interwoven molecular architectures. MOF-templated network polymers combine the characteristics and advantages of crystalline MOFs (high porosity, structural regularity, and designability) with the intrinsic behaviors of soft polymers (flexibility, processability, stability, or biocompatibility) with widespread application possibilities and tunable properties. The article ends with a summary of the remaining challenges to be addressed, and future research opportunities in this field are discussed.

An IFT20 mechanotrafficking axis is required for integrin recycling, focal adhesion dynamics, and polarized cell migration.

Directional cell migration drives embryonic development, cancer metastasis, and tissue repair and regeneration. Here, we examine the role of intraflagellar transport (IFT) 20 (Ift20) during polarized migration of epidermal cells. IFT20 is implicated in regulating cell migration independently of the primary cilium, but how IFT proteins integrate with the cell migration machinery is poorly understood. We show that genetic ablation of IFT20 in vitro slows keratinocyte migration during wound healing. We find that this phenotype is independent of the primary cilium and instead can be attributed to alterations in integrin-mediated mechanotransduction and focal adhesion (FA) dynamics. Loss of Ift20 resulted in smaller and less numerous FAs and reduced the levels of activated FA kinase. Studies of FA dynamics during microtubule-induced FA turnover demonstrated that Ift20 loss specifically impaired the reformation, but not the disassembly, of FAs. In the absence of Ift20 function, ß1 integrins endocytosed during FA disassembly are not transferred out of Rab5 (+) endosomes. This defective transit from the early endosome disrupts eventual recycling of ß1 integrins back to the cell surface, resulting in defective FA reformation. In vivo, conditional ablation of Ift20 in hair follicle stem cells (HF-SCs) similarly impairs their ability to invade and migrate during epidermal wound healing. Using explant studies, lineage tracing, and clonal analysis, we demonstrate that Ift20 is required for HF-SC migration and their contribution to epidermal regeneration. This work identifies a new Ift20 mechanotrafficking mechanism required for polarized cell migration and stem cell-driven tissue repair.