Selective mural cell recruitment of pericytes to networks of assembling endothelial cell-lined tubes.

Mural cells are critically important for the development, maturation, and maintenance of the blood vasculature. Pericytes are predominantly observed in capillaries and venules, while vascular smooth muscle cells (VSMCs) are found in arterioles, arteries, and veins. In this study, we have investigated functional differences between human pericytes and human coronary artery smooth muscle cells (CASMCs) as a model VSMC type. We compared the ability of these two mural cells to invade three-dimensional (3D) collagen matrices, recruit to developing human endothelial cell (EC)-lined tubes in 3D matrices and induce vascular basement membrane matrix assembly around these tubes. Here, we show that pericytes selectively invade, recruit, and induce basement membrane deposition on EC tubes under defined conditions, while CASMCs fail to respond equivalently. Pericytes dramatically invade 3D collagen matrices in response to the EC-derived factors, platelet-derived growth factor (PDGF)-BB, PDGF-DD, and endothelin-1, while minimal invasion occurs with CASMCs. Furthermore, pericytes recruit to EC tube networks, and induce basement membrane deposition around assembling EC tubes (narrow and elongated tubes) when these cells are co-cultured. In contrast, CASMCs are markedly less able to perform these functions showing minimal recruitment, little to no basement membrane deposition, with wider and shorter tubes. Our new findings suggest that pericytes demonstrate much greater functional ability to invade 3D matrix environments, recruit to EC-lined tubes and induce vascular basement membrane matrix deposition in response to and in conjunction with ECs.

SH2 domain protein E and ABL signaling regulate blood vessel size.

Blood vessels in different vascular beds vary in size, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow, eventually leading to the DA collapse. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA size in she mutants correlated with an increased endothelial expression of claudin 5a (cldn5a), which encodes a protein enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.

Defining the Functional Influence of Endothelial Cell-Expressed Oncogenic Activating Mutations on Vascular Morphogenesis and Capillary Assembly.

This study sought to define key molecules and signals controlling major steps in vascular morphogenesis, and how these signals regulate pericyte recruitment and pericyte-induced basement membrane deposition. The morphogenic impact of endothelial cell (EC) expression of activating mutants of Kirsten rat sarcoma virus (kRas), mitogen-activated protein kinase 1 (Mek1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Akt serine/threonine kinase 1 (Akt1), Ras homolog enriched in brain (Rheb) Janus kinase 2 (Jak2), or signal transducer and activator of transcription 3 (Stat3) expression versus controls was evaluated, along with EC signaling events, pharmacologic inhibitor assays, and siRNA suppression experiments. Primary stimulators of EC lumen formation included kRas, Akt1, and Mek1, whereas PIK3CA and Akt1 stimulated a specialized type of cystic lumen formation. In contrast, the key drivers of EC sprouting behavior were Jak2, Stat3, Mek1, PIK3CA, and mammalian target of rapamycin (mTor). These conclusions are further supported by pharmacologic inhibitor and siRNA suppression experiments. EC expression of active Akt1, kRas, and PIK3CA led to markedly dysregulated lumen formation coupled to strongly inhibited pericyte recruitment and basement membrane deposition. For example, activated Akt1 expression in ECs excessively stimulated lumen formation, decreased EC sprouting behavior, and showed minimal pericyte recruitment with reduced mRNA expression of platelet-derived growth factor-BB, platelet-derived growth factor-DD, and endothelin-1, critical EC-derived factors known to stimulate pericyte invasion. The study identified key signals controlling fundamental steps in capillary morphogenesis and maturation and provided mechanistic details on why EC activating mutations induced a capillary deficiency state with abnormal lumens, impaired pericyte recruitment, and basement deposition: predisposing stimuli for the development of vascular malformations.

Elucidating the Morphogenic and Signaling Roles of Defined Growth Factors Controlling Human Endothelial Cell Lumen Formation Versus Sprouting Behavior.

Five growth factors [ie, insulin, fibroblast growth factor-2 (FGF-2), stem cell factor, IL-3, and stromal-derived factor 1α] in combination are necessary for human endothelial cells (ECs) to undergo tube morphogenesis, a process requiring both lumen formation and sprouting behavior. This study investigated why these factors are required by subdividing the factors into 4 separate groups: insulin-only, insulin and FGF-2, no FGF-2 (all factors but without FGF-2), and all factors. The study found that the insulin-only condition failed to support EC morphogenesis or survival, the insulin and FGF-2 condition supported primarily EC lumen formation, and the no FGF-2 condition supported EC sprouting behavior. By comparison, the all-factors condition more strongly stimulated both EC lumen formation and sprouting behavior, and signaling analysis revealed prolonged stimulation of multiple promorphogenic signals coupled with inhibition of proregressive signals. Pharmacologic inhibition of Jak kinases more selectively blocked EC sprouting behavior, whereas inhibition of Raf, phosphatidylinositol 3-kinase, and Akt kinases showed selective blockade of lumen formation. Inhibition of Src family kinases and Notch led to increased sprouting coupled to decreased lumen formation, whereas inhibition of Pak, Mek, and mammalian target of rapamycin kinases blocked both sprouting and lumen formation. These findings reveal novel downstream biological and signaling activities of defined factors that are required for the assembly of human EC-lined capillary tube networks.

COVID-19-related financial scarcity is associated with greater delay discounting but not probability discounting.

Prior studies suggest that scarcity increases delay discounting (devaluation of delayed outcomes) and disturbs other decision-making processes. Evidence on the effect of COVID-19 on delay discounting is mixed. Also, no study has examined the effect of COVID-19-related scarcity on probability discounting (devaluation of probabilistic outcomes). The goal of the study was to examine cross-sectional associations between financial impact during the COVID-19 pandemic, delay discounting, and probability discounting. During April 2020, 1012 participants with low income were recruited on Amazon Mechanical Turk and completed measures of delay and probability discounting, perceived COVID-19-related financial impacts, and food security. Regression analyses indicate that compared to those with no COVID-19-related financial impacts, those with severe COVID-19-related financial impacts had greater delay discounting of money and greater delay discounting of a grocery gift card. Also, greater food insecurity in the past month was associated with greater delay discounting of a grocery gift card but not delay discounting of money. Perceived COVID-19 related financial impact was not associated with probability discounting. Combined with laboratory experiments, this study provides additional support for the idea that feelings of scarcity may increase delay discounting. However, as this study was observational, no assumptions of causality should be made about the specific effect of COVID-19 on delay discounting.

SH2 domain protein E (SHE) and ABL signaling regulate blood vessel size.

Blood vessels in different vascular beds vary in lumen diameter, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vascular lumen size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA lumen, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA lumen in she mutants correlated with an increased endothelial expression of claudin 5a and 5b (cldn5a / cldn5b), which encode proteins enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA lumen size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates lumen size during vascular tubulogenesis.

Extracellular Matrix Remodeling in Vascular Disease: Defining Its Regulators and Pathological Influence.

Because of structural and cellular differences (ie, degrees of matrix abundance and cross-linking, mural cell density, and adventitia), large and medium-sized vessels, in comparison to capillaries, react in a unique manner to stimuli that induce vascular disease. A stereotypical vascular injury response is ECM (extracellular matrix) remodeling that occurs particularly in larger vessels in response to injurious stimuli, such as elevated angiotensin II, hyperlipidemia, hyperglycemia, genetic deficiencies, inflammatory cell infiltration, or exposure to proinflammatory mediators. Even with substantial and prolonged vascular damage, large- and medium-sized arteries, persist, but become modified by (1) changes in vascular wall cellularity; (2) modifications in the differentiation status of endothelial cells, vascular smooth muscle cells, or adventitial stem cells (each can become activated); (3) infiltration of the vascular wall by various leukocyte types; (4) increased exposure to critical growth factors and proinflammatory mediators; and (5) marked changes in the vascular ECM, that remodels from a homeostatic, prodifferentiation ECM environment to matrices that instead promote tissue reparative responses. This latter ECM presents previously hidden matricryptic sites that bind integrins to signal vascular cells and infiltrating leukocytes (in coordination with other mediators) to proliferate, invade, secrete ECM-degrading proteinases, and deposit injury-induced matrices (predisposing to vessel wall fibrosis). In contrast, in response to similar stimuli, capillaries can undergo regression responses (rarefaction). In summary, we have described the molecular events controlling ECM remodeling in major vascular diseases as well as the differential responses of arteries versus capillaries to key mediators inducing vascular injury.

A "sludge audit" for health system colorectal cancer screening services.

OBJECTIVES: "Sludge," or the frictions or administrative burdens that make it difficult for people to attain what they want or need, is an unexplored health care delivery factor that may contribute to deficiencies in colorectal cancer (CRC) screening. We piloted a method to identify and quantify sludge in a southeastern US health system's delivery of CRC screening services. STUDY DESIGN: Mixed methods sludge audit. METHODS: We collected and analyzed quantitative (insurance claims, electronic health record, and administrative files) and qualitative (stakeholder interviews and process observations) data associated with CRC screening for instances of sludge. Because they contribute to sludge and reduce system capacity for high-value screening, we also evaluated low-value CRC screening processes. RESULTS: Although specific results were likely amplified by effects of the COVID-19 pandemic, the sludge audit revealed important areas for improvement. A 60.4% screening rate was observed. Approximately half of screening orders were not completed. The following categories of sludge were identified: communication, time, technology, administrative tasks, paperwork, and low-value care. For example, wait times for screening colonoscopy were substantial, duplicate orders were common, and some results were not accessible in the electronic health record. Of completed screenings, 32% were low-value and 38% were associated with low-value preoperative testing. There was evidence of a differential negative impact of sludge to vulnerable patients. CONCLUSIONS: Our sludge audit method identified and quantified multiple instances of sludge in a health system's CRC screening processes. Sludge audits can help organizations to systematically evaluate and reduce sludge for more effective and equitable CRC screening.

Triggering multiple sclerosis at conception and early gestation: The variation in ultraviolet radiation is as important as its intensity.

Background and objectives: Medical science needs to further elucidate the role of ultraviolet radiation (UVR), geographic latitude, and the role of vitamin D in the autoimmune disease multiple sclerosis (MS). We separated several papers into categories out of the thousands published and used their conclusions to explore the relationship between UVR and MS. Relevance: MS is increasing in incidence, particularly in women where MS is two to three times that in men and particularly severe in African Americans. Methods: We collected UVR data at our observatory in Central Maine and calculated the average coefficient of variation (CVUVR) for each month for 15 years (2007-2021, inclusive). Results: The month of conception (MOC) is more important than the month of birth (MOB) in explaining how UVR triggers the variable genetic predisposition to MS. We hypothesize that the rapidly increasing CVUVR is important in preventing an increase in the activity of the vitamin D receptor (VDR) from August to December, which then requires a higher intensity of UVR later in life to suppress the immune system, therefore predisposing to more MS. Limitations: One observatory at about 44° latitude. Conclusions: While variation in UVR is important at the MOC if UVR exceeds a threshold (e.g., if the sunspot number equals or is greater than 90, usually at a solar cycle MAX, or at elevations above approximately 3,000 feet above sea level), the MS mitigating vitamin D-VDR mechanism is overwhelmed and the genotoxic effects of higher-intensity UVR promote MS in those with a genetic predisposition. What is new in this research: This paper offers a new concept in MS research.

Increased Matrix Metalloproteinase-1 Activation Enhances Disruption and Regression of k-RasV12-Expressing Arteriovenous Malformation-Like Vessels.

This study sought to identify potential mechanisms by which k-RasV12-expressing endothelial cell (EC) tubes demonstrate an increased propensity to regress compared with controls. Activated k-Ras mutations play a role in a variety of pathological conditions, including arteriovenous malformations, which are prone to bleed, causing serious hemorrhagic complications. ECs expressing active k-RasV12 demonstrate markedly excessive lumen formation with widened and shortened tubes accompanied by reduced pericyte recruitment and basement membrane deposition, leading to deficient capillary network assembly. The current study showed that active k-Ras-expressing ECs secreted greater amounts of MMP-1 proenzyme compared with control ECs, and readily converted it to increased active MMP-1 levels through the action of plasmin or plasma kallikrein (generated from their added zymogens). Active MMP-1 degraded three-dimensional collagen matrices, leading to more rapid and extensive regression of the active k-Ras-expressing EC tubes, in conjunction with matrix contraction, compared with control ECs. Under conditions where pericytes protect control EC tubes from plasminogen- and MMP-1-dependent tube regression, this failed to occur with k-RasV12 ECs, due to reduced pericyte interactions. In summary, k-RasV12-expressing EC vessels showed an increased propensity to regress in response to serine proteinases through accentuated levels of active MMP-1, a novel pathogenic mechanism that may underlie hemorrhagic events associated with arteriovenous malformation lesions.

Acute Portal and Superior Mesenteric Vein Thrombosis with Topical Testosterone Therapy: An Adverse Drug Event Case Report.

This is a case report of a 55-year-old Caucasian male prescribed topical testosterone therapy for 12 months prior to admission, when he was diagnosed with acute thrombosis in the portal vein (PVT) and superior mesenteric vein (SMV). The patient had a negative thrombophilia workup, including Factor V Leiden, Prothrombin G20210A, and JAK2 V617F mutations. There were no other pertinent laboratory markers that raised concern for the cause of thrombus. No strong familial history of venous thromboembolism (VTE) was reported during the patient's initial workup. With this in mind, the patient's use of topical testosterone therapy was considered the most likely risk factor for the PVT and SMV thrombus. During hospitalization, the patient was initiated on therapeutic anticoagulation with a heparin drip and discharged to home on apixaban for 3 months with extended therapy to be determined by outpatient hematologist. With no other identified VTE risk factors, probability that this patient's VTE was attributed to testosterone was evaluated using the Naranjo scale with a calculated score of 6, which classifies the adverse reaction as "likely." Clinicians should be aware of the possibility that topical testosterone therapy may be a risk factor for venous thrombosis in unusual sites.

Extracellular Matrix Regulation of Vascular Morphogenesis, Maturation, and Stabilization.

The extracellular matrix represents a critical regulator of tissue vascularization during embryonic development and postnatal life. In this perspective, we present key information and concepts that focus on how the extracellular matrix controls capillary assembly, maturation, and stabilization, and, in addition, contributes to tissue stability and health. In particular, we present and discuss mechanistic details underlying (1) the role of the extracellular matrix in controlling different steps of vascular morphogenesis, (2) the ability of endothelial cells (ECs) and pericytes to coassemble into elongated and narrow capillary EC-lined tubes with associated pericytes and basement membrane matrices, and (3) the identification of specific growth factor combinations ("factors") and peptides as well as coordinated "factor" and extracellular matrix receptor signaling pathways that are required to form stabilized capillary networks.

Kailo: a systemic approach to addressing the social determinants of young people's mental health and wellbeing at the local level.

The mental health and wellbeing of children and young people is deteriorating. It is increasingly recognised that mental health is a systemic issue, with a wide range of contributing and interacting factors. However, the vast majority of attention and resources are focused on the identification and treatment of mental health disorders, with relatively scant attention on the social determinants of mental health and wellbeing and investment in preventative approaches. Furthermore, there is little attention on how the social determinants manifest or may be influenced at the local level, impeding the design of contextually nuanced preventative approaches. This paper describes a major research and design initiative called Kailo that aims to support the design and implementation of local and contextually nuanced preventative strategies to improve children's and young people's mental health and wellbeing. The Kailo Framework involves structured engagement with a wide range of local partners and stakeholders - including young people, community partners, practitioners and local system leaders - to better understand local systemic influences and support programmes of youth-centred and evidence-informed co-design, prototyping and testing. It is hypothesised that integrating different sources of knowledge, experience, insight and evidence will result in better embedded, more sustainable and more impactful strategies that address the social determinants of young people's mental health and wellbeing at the local level.

Molecular basis for pericyte-induced capillary tube network assembly and maturation.

Here we address the functional importance and role of pericytes in capillary tube network assembly, an essential process that is required for vascularized tissue development, maintenance, and health. Healthy capillaries may be directly capable of suppressing human disease. Considerable advances have occurred in our understanding of the molecular and signaling requirements controlling EC lumen and tube formation in 3D extracellular matrices. A combination of SCF, IL-3, SDF-1α, FGF-2 and insulin ("Factors") in conjunction with integrin- and MT1-MMP-induced signaling are required for EC sprouting behavior and tube formation under serum-free defined conditions. Pericyte recruitment to the abluminal EC tube surface results in elongated and narrow tube diameters and deposition of the vascular basement membrane. In contrast, EC tubes in the absence of pericytes continue to widen and shorten over time and fail to deposit basement membranes. Pericyte invasion, recruitment and proliferation in 3D matrices requires the presence of ECs. A detailed analysis identified that EC-derived PDGF-BB, PDGF-DD, ET-1, HB-EGF, and TGFß1 are necessary for pericyte recruitment, proliferation, and basement membrane deposition. Blockade of these individual factors causes significant pericyte inhibition, but combined blockade profoundly interferes with these events, resulting in markedly widened EC tubes without basement membranes, like when pericytes are absent.

Proinflammatory mediators, TNFα, IFNγ, and thrombin, directly induce lymphatic capillary tube regression.

In this work, we sought to investigate the direct effects of proinflammatory mediators on lymphatic endothelial cell (LEC) capillaries and whether they might induce regression. Our laboratory has developed novel in-vitro, serum-free, lymphatic tubulogenesis assay models whereby human LEC tube networks readily form in either three-dimensional collagen or fibrin matrices. These systems were initially conceptualized in the hopes of better understanding the influence of proinflammatory mediators on LEC capillaries. In this work, we have screened and identified proinflammatory mediators that cause regression of LEC tube networks, the most potent of which is TNFα (tumor necrosis factor alpha), followed by IFNγ (interferon gamma) and thrombin. When these mediators were combined, even greater and more rapid lymphatic capillary regression occurred. Surprisingly, IL-1ß (interleukin-1 beta), one of the most potent and pathologic cytokines known, had no regressive effect on these tube networks. Finally, we identified new pharmacological drug combinations capable of rescuing LEC capillaries from regression in response to the potent combination of TNFα, IFNγ, and thrombin. We speculate that protecting lymphatic capillaries from regression may be an important step toward mitigating a wide variety of acute and chronic disease states, as lymphatics are believed to clear both proinflammatory cells and mediators from inflamed and damaged tissue beds. Overall, these studies identify key proinflammatory mediators, including TNFα, IFNγ, and thrombin, that induce regression of LEC tube networks, as well as identify potential therapeutic agents to diminish LEC capillary regression responses.

Supplemental Nutrition Assistance Program (SNAP)-authorized retailers received a low score using the Business Impact Assessment for Obesity and population-level nutrition (BIA-Obesity) tool.

BACKGROUND: The Supplemental Nutrition Assistance Program (SNAP) supports Americans with lower income to purchase dietary products at authorized retailers. This research aimed to evaluate SNAP-authorized retailers' public commitments in support of nutrition security and to examine differences between traditional grocers and nontraditional (e.g., convenience, drug, dollar) SNAP-authorized retailers' public commitments. METHODS: Prominent United States (U.S.) SNAP-authorized retailers nationally and in two U.S. states (California and Virginia) were identified based on number of store locations (n = 61). Public information available in grey literature were reviewed and scored using the Business Impact Assessment for Obesity and population-level nutrition (BIA-Obesity) tool. SNAP-authorized retailers were classified as traditional (e.g., grocery) or nontraditional (e.g., non-grocery) retailers. Total BIA-Obesity from 0 to 615, representing low to optimal support) and category scores were calculated for corporate strategy, relationships with external organizations, product formulation, nutrition labeling, product and brand promotion, and product accessibility. Descriptive statistics were used to describe BIA-Obesity scores overall and by category. Mann-Whitney U was used to test for potential differences in median BIA-Obesity total scores between traditional and nontraditional SNAP-authorized retailers (a priori, p < 0.05). RESULTS: Average total BIA-Obesity scores for SNAP-authorized retailers ranged from 0 to 112 (16.5 ± 23.3). Total BIA-Obesity scores for traditional SNAP-authorized retailers (32.7 ± 33.6; median 25) were higher than nontraditional SNAP-authorized retailer scores (11.2 ± 16; median 5) (p = 0.008). For BIA-Obesity categories, average scores were highest for the category relationships with external organizations (8.3 ± 10.3) and lowest for promotion practices (0.6 ± 2.1). CONCLUSIONS: Results of this research underscore a dearth of available evidence and substantial opportunity for improvement regarding SNAP-authorized retailer strategies to support nutrition security among Americans with lower income.

Trends and Outcomes of Oral Anticoagulation With Direct Current Cardioversion for Atrial Fibrillation/Flutter at an Academic Medical Center.

Background: Increasing reports suggest the safe use of direct oral anticoagulants (DOACs) in electrical cardioversion. The aim of this study was to assess the trends and 30-day outcomes associated with anticoagulation for cardioversion. Methods: Patients who underwent electrical cardioversion from January 2015 to October 2020 with a 30-day follow-up were included; and outcomes including stroke, transient ischemic attack, intracranial hemorrhage (ICH), and major gastrointestinal bleeding were recorded. Results: Of the 515 patients, 351 (68%) were men and 164 (32%) were women, with a mean CHA2DS2VASc score of 2.6 ± 1.6. Outpatient apixaban use increased from 10% in 2015 to 46% in 2020 (P < 0.001) with a decline in the use of warfarin from 24% in 2015 to 10% in 2020 (P = 0.023). Apixaban use peri-procedurally for cardioversion increased from 32% in 2015 to 35% in 2020 (P = 0.317), while warfarin use decreased from 23% in 2015 to 14% in 2020 (P = 0.164). At discharge, apixaban prescriptions increased from 21% in 2015 to 61% in 2020 (P < 0.001), while warfarin prescriptions declined from 30% in 2015 to 13% in 2020 (P = 0.009). No ICH was recorded in the 30 days after cardioversion. Ischemic stroke occurred in four (0.7%) patients with one (0.29%) of the 338 patients on a DOAC, one (0.8%) of the 124 patients on warfarin and two (5.5%) of the 36 patients not receiving anticoagulation post cardioversion. There were seven (1%) major gastrointestinal bleeding events in patients on oral anticoagulation, of which four (3%) were on warfarin and three (0.8%) were on DOACs. Conclusions: Our study shows the increasing and safe use of DOACs for the purpose of cardioversion. The rates of 30-day ischemic stroke post cardioversion were low and only occurred in patients admitted in the intensive care unit.

The effect of ultraviolet radiation on the incidence and severity of major mental illness using birth month, birth year, and sunspot data.

Background and objectives: The evaluation of the severity of patients afflicted with major mental illness (MMI) has been problematic because of confounding variables and genetic variability. There have been multiple studies that suggest several human diseases, especially schizophrenia, are predisposed to be born in certain months or seasons. This observation implied an epigenetic effect of sunlight, likely ultraviolet radiation (UVR), which is damaging to DNA, especially in an embryo. This paper outlines a method to evaluate the severity of schizophrenia (SZ), bipolar disorder (BPD), and schizoaffective disorder (SZ-AFF) using the month/year of birth of those affected compared to the month/year of birth of the general population (GP). Relevance: Our previous research found that more intense UVR (equal to or greater than 90 sunspot number (SSN)) had a negative effect on the average human lifespan. Also, human birth rates vary in frequency by month of birth reflecting variables like availability of food, sunlight, and other unknown epigenetic factors. We wanted to see if the patient month of birth varied from the average birth months of the general population and if UVR has an epigenetic effect promoting these diseases. Methods: We obtained the month and year of birth of 1,233 patients admitted over a 15-year period to Maine's largest state psychiatric hospital and counted the months of birth for each diagnosis of SZ, BPD, and SZ-AFF, and compared these results to the general population's birth months of 4,265,555 persons from U. S. Census Year 2006. The number of patients in each month was normalized to August and compared with the normalized birth months of the general population (GP). Plots of the normalized months were considered rates of change (e.g., derivatives) and their respective integrals gave domains of each mental illness relative to the GP. Normalizing the GP to unity was then related to the factor 1.28, e.g., 28% more entropy, deduced from the Sun's fractal dimension imprinted on biological organisms. Results: The percent of patients meeting our criterion for severity: SZ = 27%; BPD = 26%; SZ-AFF = 100%. Conclusions: High UVR intensity or a rapid increase in UVR in early gestation are likely epigenetic triggers of major mental illness. BPD is more epigenetically affected than SZ or SZ-AFF disorders. We found that 52% of 1,233 patients comprised the core function of a tertiary-care psychiatric hospital. Also, mental illness exacerbated when the median SSN doubled. This work also validates the Kraeplinian dichotomy. What is new in this research: This paper offers a new paradigm for evaluating the severity of MMI and supports significant epigenetic effects from UVR.

Modes of Failure in Venous Thromboembolism Prophylaxis.

Venous thromboembolism (VTE) is associated with potentially preventable in-hospital morbidity and mortality. Although evidence-based guidelines are widely available, their application in clinical practice varies markedly. VTE prophylaxis involves a multistep dynamic process that can fail at various points during hospital stay. Our aim was to identify defects in VTE prophylaxis. Upon admission, our patients undergo VTE risk stratification and orders for prophylaxis are entered. All patients that fulfill the criteria for the Patient Safety Indicator (PSI)-12, as defined by the Agency for Healthcare Research and Quality, are prospectively entered in a database. From a review of 138 PSI-12 patients, only 21 had correct risk stratification and appropriate chemoprophylaxis during their hospital stay; 70 had been incorrectly stratified, with 28 of these patients receiving incorrect prophylaxis due to incorrect stratification, thus delaying the correct administration of chemoprophylaxis for >24 h. Inadequate application of mechanical prophylaxis was noted in 114 patients. VTE prophylaxis relies on correct risk stratification, ordering appropriate pharmacomechanical measures and, finally, the delivery of this treatment throughout the hospital stay. A large percentage of patients who had a thromboembolic complication received inadequate prophylaxis. This study identifies potential areas for intervention to improve VTE prophylaxis.