An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

4D intravital imaging identifies platelets as the predominant cellular procoagulant surface in a mouse hemostasis model.

Interplay between platelets, coagulation factors, endothelial cells (ECs) and fibrinolytic factors is necessary for effective hemostatic plug formation. This study describes a four-dimensional (4D) imaging platform to visualize and quantify hemostatic plug components in mice with high spatiotemporal resolution. Fibrin accumulation following laser-induced vascular injury was observed at the platelet plug-EC interface, controlled by the antagonistic balance between fibrin generation and breakdown. We observed less fibrin accumulation in mice expressing low levels of tissue factor (TFlow) or F12-/- mice compared to controls, whereas increased fibrin accumulation, including on the vasculature adjacent to the platelet plug, was observed in plasminogen-deficient mice or wild-type mice treated with tranexamic acid (TXA). Phosphatidylserine (PS), a membrane lipid critical for the assembly of coagulation factors, was first detected at the platelet plug-EC interface, followed by exposure across the endothelium. Impaired PS exposure resulted in a significant reduction in fibrin accumulation in cyclophilin D-/- mice. Adoptive transfer studies demonstrated a key role for PS exposure on platelets, and to a lesser degree on ECs, in fibrin accumulation during hemostatic plug formation. Together, these studies suggest that (1) platelets are the functionally dominant procoagulant cellular surface, and (2) plasmin is critical for limiting fibrin accumulation at the site of a forming hemostatic plug.

Mice expressing nonpolymerizable fibrinogen have reduced arterial and venous thrombosis with preserved hemostasis.

ABSTRACT: Elevated circulating fibrinogen levels correlate with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% ferric chloride (FeCl3) challenges compared with wild-type (FgaWT/WT) mice, but this protection was lost, with injuries driven by higher concentrations of FeCl3. In contrast, fibrinogen-deficient (Fga-/-) mice showed no evidence of occlusion, even with high-concentration FeCl3 challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in FgaWT/WT, FgaWT/EK, and FgaEK/EK mice, consistent with preserved fibrinogen-platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, FgaWT/EK and FgaEK/EK mice had preserved hemostasis in multiple models as well as normal wound healing times after skin incision, unlike Fga-/- mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.

Fibrin(ogen) engagement of S. aureus promotes the host antimicrobial response and suppression of microbe dissemination following peritoneal infection.

The blood-clotting protein fibrin(ogen) plays a critical role in host defense against invading pathogens, particularly against peritoneal infection by the Gram-positive microbe Staphylococcus aureus. Here, we tested the hypothesis that direct binding between fibrin(ogen) and S. aureus is a component of the primary host antimicrobial response mechanism and prevention of secondary microbe dissemination from the peritoneal cavity. To establish a model system, we showed that fibrinogen isolated from FibγΔ5 mice, which express a mutant form lacking the final 5 amino acids of the fibrinogen γ chain (termed fibrinogenγΔ5), did not support S. aureus adherence when immobilized and clumping when in suspension. In contrast, purified wildtype fibrinogen supported robust adhesion and clumping that was largely dependent on S. aureus expression of the receptor clumping factor A (ClfA). Following peritoneal infection with S. aureus USA300, FibγΔ5 mice displayed worse survival compared to WT mice coupled to reduced bacterial killing within the peritoneal cavity and increased dissemination of the microbes into circulation and distant organs. The failure of acute bacterial killing, but not enhanced dissemination, was partially recapitulated by mice infected with S. aureus USA300 lacking ClfA. Fibrin polymer formation and coagulation transglutaminase Factor XIII each contributed to killing of the microbes within the peritoneal cavity, but only elimination of polymer formation enhanced systemic dissemination. Host macrophage depletion or selective elimination of the fibrin(ogen) ß2-integrin binding motif both compromised local bacterial killing and enhanced S. aureus systemic dissemination, suggesting fibrin polymer formation in and of itself was not sufficient to retain S. aureus within the peritoneal cavity. Collectively, these findings suggest that following peritoneal infection, the binding of S. aureus to stabilized fibrin matrices promotes a local, macrophage-mediated antimicrobial response essential for prevention of microbe dissemination and downstream host mortality.

Integrated genetic and metabolic characterization of Latin American cassava (Manihot esculenta) germplasm.

Cassava (Manihot esculenta Crantz) is an important staple crop for food security in Africa and South America. The present study describes an integrated genomic and metabolomic approach to the characterization of Latin American cassava germplasm. Classification based on genotyping correlated with the leaf metabolome and indicated a key finding of adaption to specific eco-geographical environments. In contrast, the root metabolome did not relate to genotypic clustering, suggesting the different spatial regulation of this tissue's metabolome. The data were used to generate pan-metabolomes for specific tissues, and the inclusion of phenotypic data enabled the identification of metabolic sectors underlying traits of interest. For example, tolerance to whiteflies (Aleurotrachelus socialis) was not linked directly to cyanide content but to cell wall-related phenylpropanoid or apocarotenoid content. Collectively, these data advance the community resources and provide valuable insight into new candidate parental breeding materials with traits of interest directly related to combating food security.

Both G protein-coupled and immunoreceptor tyrosine-based activation motif receptors mediate venous thrombosis in mice.

Platelets are critical in hemostasis and a major contributor to arterial thrombosis (AT). (Pre)clinical studies suggest platelets also contribute to venous thrombosis (VT), but the mechanisms are largely unknown. We hypothesized that in VT, platelets use signaling machinery distinct from AT. Here we aimed to characterize the contributions of platelet G protein-coupled (GPCR) and immunoreceptor tyrosine-based activation motif (ITAM) receptor signaling to VT. Wild-type (WT) and transgenic mice were treated with inhibitors to selectively inhibit platelet-signaling pathways: ITAM-CLEC2 (Clec2mKO), glycoprotein VI (JAQ1 antibody), and Bruton's tyrosine kinase (ibrutinib); GPCR-cyclooxygenase 1 (aspirin); and P2Y12 (clopidogrel). VT was induced by inferior vena cava stenosis. Thrombin generation in platelet-rich plasma and whole-blood clot formation were studied ex vivo. Intravital microscopy was used to study platelet-leukocyte interactions after flow restriction. Thrombus weights were reduced in WT mice treated with high-dose aspirin + clopidogrel (dual antiplatelet therapy [DAPT]) but not in mice treated with either inhibitor alone or low-dose DAPT. Similarly, thrombus weights were reduced in mice with impaired ITAM signaling (Clec2mKO + JAQ1; WT + ibrutinib) but not in Clec2mKO or WT + JAQ1 mice. Both aspirin and clopidogrel, but not ibrutinib, protected mice from FeCl3-induced AT. Thrombin generation and clot formation were normal in blood from high-dose DAPT- or ibrutinib-treated mice; however, platelet adhesion and platelet-neutrophil aggregate formation at the vein wall were reduced in mice treated with high-dose DAPT or ibrutinib. In summary, VT initiation requires platelet activation via GPCRs and ITAM receptors. Strong inhibition of either signaling pathway reduces VT in mice.

Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with an Fga truncation mutation.

Genetic variants within the fibrinogen Aα chain encoding the αC-region commonly result in hypodysfibrinogenemia in patients. However, the (patho)physiological consequences and underlying mechanisms of such mutations remain undefined. Here, we generated Fga270 mice carrying a premature termination codon within the Fga gene at residue 271. The Fga270 mutation was compatible with Mendelian inheritance for offspring of heterozygous crosses. Adult Fga270/270 mice were hypofibrinogenemic with ∼10% plasma fibrinogen levels relative to FgaWT/WT mice, linked to 90% reduction in hepatic Fga messenger RNA (mRNA) because of nonsense-mediated decay of the mutant mRNA. Fga270/270 mice had preserved hemostatic potential in vitro and in vivo in models of tail bleeding and laser-induced saphenous vein injury, whereas Fga-/- mice had continuous bleeding. Platelets from FgaWT/WT and Fga270/270 mice displayed comparable initial aggregation following adenosine 5'-diphosphate stimulation, but Fga270/270 platelets quickly disaggregated. Despite ∼10% plasma fibrinogen, the fibrinogen level in Fga270/270 platelets was ∼30% of FgaWT/WT platelets with a compensatory increase in fibronectin. Notably, Fga270/270 mice showed complete protection from thrombosis in the inferior vena cava stasis model. In a model of Staphylococcus aureus peritonitis, Fga270/270 mice supported local, fibrinogen-mediated bacterial clearance and host survival comparable to FgaWT/WT, unlike Fga-/- mice. Decreasing the normal fibrinogen levels to ∼10% with small interfering RNA in mice also provided significant protection from venous thrombosis without compromising hemostatic potential and antimicrobial function. These findings both reveal novel molecular mechanisms underpinning fibrinogen αC-region truncation mutations and highlight the concept that selective fibrinogen reduction may be efficacious for limiting thrombosis while preserving hemostatic and immune protective functions.

Recreating the future-Indigenous research paradigms in health professional education research.

INTRODUCTION: Health and self-determination are recognised as universal human rights. Health professional education research and practice hold the capacity to prioritise values, worldviews and agendas that envisage sustainable and equitable futures for the entire community served. This paper explores the need for the co-location of Indigenous research paradigms in health professional education research and teaching. Indigenous communities have a long history of science, research and sustainable living and are holders of ways of knowing, being and doing that can shape actions and priorities in health research that value equity and sustainability. DISCUSSION: Knowledge construction in health professional education research does not occur in isolation nor is it value neutral. A continued dominance of the biomedical approach to health creates a system of innovation that is unbalanced and unable to deliver health outcomes demanded by contemporary society. As power and hierarchies are embedded in health professional education research and praxis, transformative action is required to bring forth marginalised voices in research processes. Critical reflexivity regarding the ontological, epistemological, axiological and methodological positioning of researchers is an important step towards creating and sustaining research structures that effectively value and co-locate different perspectives in knowledge production and translation. CONCLUSION: Working towards more equitable and sustainable futures for Indigenous and non-Indigenous communities requires health care systems to be informed and guided by different knowledge paradigms. This can work to avoid the ongoing reproduction of inefficient biomedical structures and purposefully disrupt the status quo of health inequities. Realising this requires the effective co-location of Indigenous research paradigms and ways of working into health professional education research that centre relationality, wholism, interconnectedness and self-determination. This calls for a raising of the critical consciousness of health professional education research academies.

Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread.

Hyperacute T Wave in the Early Diagnosis of Acute Myocardial Infarction.

STUDY OBJECTIVE: The diagnostic performance of T-wave amplitudes for the detection of myocardial infarction is largely unknown. We aimed to address this knowledge gap. METHODS: T-wave amplitudes were automatically measured in 12-lead ECGs of patients presenting with acute chest discomfort to the emergency department within a prospective diagnostic multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists. Patients with left ventricular hypertrophy, complete left bundle branch block, or paced ventricular depolarization were excluded. The performance for lead-specific 95th-percentile thresholds were reported as likelihood ratios (lr), specificity, and sensitivity. RESULTS: Myocardial infarction was the final diagnosis in 445 (18%) of 2457 patients. In most leads, T-wave amplitudes tended to be greater in patients without myocardial infarction than those with myocardial infarction, and T-wave amplitude exceeding the 95th percentile had positive and negative lr close to 1 or with confidence intervals (CIs) crossing 1. The exceptions were leads III, aVR, and V1, which had positive lrs of 3.8 (95% CI, 2.7 to 5.3), 4.3 (95% CI, 3.1 to 6.0) and 2.0 (95% CI, 1.4 to 2.9), respectively. These leads normally have inverted T waves, so T-wave amplitude exceeding the 95th percentile reflects upright rather than increased-amplitude hyperacute T waves. CONCLUSION: Hyperacute T waves, when defined as increased T-wave amplitude exceeding the 95th percentile, did not provide useful information in diagnosing myocardial infarction in this sample.

Hepatitis B in Africa Collaborative Network: cohort profile and analysis of baseline data.

Approximately 80 million people live with chronic hepatitis B virus (HBV) infection in the WHO Africa Region. The natural history of HBV infection in this population is poorly characterised, and may differ from patterns observed elsewhere due to differences in prevailing genotypes, environmental exposures, co-infections, and host genetics. Existing research is largely drawn from small, single-centre cohorts, with limited follow-up time. The Hepatitis B in Africa Collaborative Network (HEPSANET) was established in 2022 to harmonise the process of ongoing data collection, analysis, and dissemination from 13 collaborating HBV cohorts in eight African countries. Research priorities for the next 5 years were agreed upon through a modified Delphi survey prior to baseline data analysis being conducted. Baseline data on 4,173 participants with chronic HBV mono-infection were collected, of whom 38.3% were women and the median age was 34 years (interquartile range 28-42). In total, 81.3% of cases were identified through testing of asymptomatic individuals. HBeAg-positivity was seen in 9.6% of participants. Follow-up of HEPSANET participants will generate evidence to improve the diagnosis and management of HBV in this region.

The impact of the baby friendly hospital initiative on healthcare utilization among newborns insured by Medicaid in Delaware.

BACKGROUND: The Baby Friendly Hospital Initiative was created to enhance breastfeeding, although its impact on infant healthcare utilization is unclear. Breast feeding infants are vulnerable to readmission soon after birth secondary to dehydration and hyperbilirubinemia. Breastfeeding can also protect infants from unnecessary health care utilization later in life by preventing infection. The objective of this study was to examine the impact of the Baby Friendly Hospital Initiative on readmissions and emergency department utilization among Medicaid births in Delaware. METHODS: The study was a quasi-experimental design. Medicaid claims files were used to study births at five hospitals in Delaware born between January 1, 2014, and December 31, 2018, and covered under Medicaid at time of birth. Three hospitals were designated Baby Friendly, two were not and served as controls. Outcomes included Emergency Department (ED) utilization and readmissions within 30 days and one-year of birth hospitalization. Exposure to the Baby Friendly Hospital Initiative was determined by year and hospital of birth. Logistic regression and interrupted time series segmented regression analysis with controls were used to assess the effect of Baby Friendly Hospital Initiative on healthcare utilization. RESULTS: In total, 19,695 infants were born at five hospitals with 80% (15,939) born at hospitals that were designated Baby Friendly. ED utilization and readmissions over the 1st year of life for breastfeeding related diagnosis at the Baby Friendly hospitals occurred in 240 (1.5%) and 226 (1.4%) of infants, respectively. Exposure to the Baby Friendly Hospital Initiative was associated with increased odds of all cause 30-day readmission (AOR: 1.15; 95% CI: 1.03-1.28) but not readmissions over the 1st year of life. While 30-day ED visits did not change after BFHI, one-year ED visits were reduced (0.91, 95% CI 0.86-0.97). A significant negative trend was seen over time for ED utilization post BFHI compared to controls (B: -5.90, p < 0.01). CONCLUSION: There was a small observed increase in the odds of all cause 30-day readmissions with no change in one-year readmissions after BFHI in Delaware. Although there were no observed changes in 30-day ED utilization, there was a reduction in one-year ED utilization following the implementation of the Baby Friendly Hospital Initiative in Delaware birth hospitals. Our data help to inform policy and decision making for statewide systems of care that may be used to support breast feeding.

The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: (1) To evaluate the direct (un-mediated) and indirect (mediated) relationship between antenatal exposure to opioid agonist medication as treatment for opioid use disorder (MOUD) and the severity of neonatal opioid withdrawal syndrome (NOWS), and (2) to understand the degree to which mediating factors influence the direct relationship between MOUD exposure and NOWS severity. METHODS: This cross-sectional study includes data abstracted from the medical records of 1294 opioid-exposed infants (859 MOUD exposed and 435 non-MOUD exposed) born at or admitted to one of 30 US hospitals from July 1, 2016, to June 30, 2017. Regression models and mediation analyses were used to evaluate the relationship between MOUD exposure and NOWS severity (i.e., infant pharmacologic treatment and length of newborn hospital stay (LOS)) to identify potential mediators of this relationship in analyses adjusted for confounding factors. RESULTS: A direct (un-mediated) association was found between antenatal exposure to MOUD and both pharmacologic treatment for NOWS (aOR 2.34; 95%CI 1.74, 3.14) and an increase in LOS (1.73 days; 95%CI 0.49, 2.98). Delivery of adequate prenatal care and a reduction in polysubstance exposure were mediators of the relationship between MOUD and NOWS severity and as thus, were indirectly associated with a decrease in both pharmacologic treatment for NOWS and LOS. CONCLUSIONS FOR PRACTICE: MOUD exposure is directly associated with NOWS severity. Prenatal care and polysubstance exposure are potential mediators in this relationship. These mediating factors may be targeted to reduce the severity of NOWS while maintaining the important benefits of MOUD during pregnancy.

Laparoscopic Video Analysis Using Temporal, Attention, and Multi-Feature Fusion Based-Approaches.

Adapting intelligent context-aware systems (CAS) to future operating rooms (OR) aims to improve situational awareness and provide surgical decision support systems to medical teams. CAS analyzes data streams from available devices during surgery and communicates real-time knowledge to clinicians. Indeed, recent advances in computer vision and machine learning, particularly deep learning, paved the way for extensive research to develop CAS. In this work, a deep learning approach for analyzing laparoscopic videos for surgical phase recognition, tool classification, and weakly-supervised tool localization in laparoscopic videos was proposed. The ResNet-50 convolutional neural network (CNN) architecture was adapted by adding attention modules and fusing features from multiple stages to generate better-focused, generalized, and well-representative features. Then, a multi-map convolutional layer followed by tool-wise and spatial pooling operations was utilized to perform tool localization and generate tool presence confidences. Finally, the long short-term memory (LSTM) network was employed to model temporal information and perform tool classification and phase recognition. The proposed approach was evaluated on the Cholec80 dataset. The experimental results (i.e., 88.5% and 89.0% mean precision and recall for phase recognition, respectively, 95.6% mean average precision for tool presence detection, and a 70.1% F1-score for tool localization) demonstrated the ability of the model to learn discriminative features for all tasks. The performances revealed the importance of integrating attention modules and multi-stage feature fusion for more robust and precise detection of surgical phases and tools.

A qualitative evaluation of remote training to develop a fitness surveillance system.

Objectives: In the USA, 18% of school-aged young people are classified as obese, and rural populations appear to be particularly at risk. Achieving high levels of fitness reduces the risk of obesity and underlying health conditions. To better understand youth obesity trends and fitness levels, annual fitness testing ([FT], that is, surveillance) in schools has been recommended. Although many K-12 schools conduct FT, surveillance programmes that compile unified standardised test results are rare. Design: Qualitative design. Setting: Physical education teachers from 11 schools (n = 13; n = 4 men) participated in remote training about conducting FitnessGram FT. Methods: Data included two semi-structured interviews per teacher on experiences with distance fitness training, implementing FitnessGram, and data entry for annual surveillance. Results: Inductive analysis using axial and open coding identified four themes: (1) barriers prior to study, (2) study training, (3) implementation challenges and suggestions and (4) teacher feedback. Teachers had an interest in FT but lacked the recommended training and equipment needed to implement it annually. Conclusion: Teachers believed the training they received (as part of this study) prepared them to collect reliable and valid data, and that FT had benefits for their students and programmes. Every teacher expressed interest in reporting annual surveillance data. Efforts to train teachers for FT through virtual professional development may be a viable means of establishing a unified surveillance system.

Opposition-based sine cosine optimizer utilizing refraction learning and variable neighborhood search for feature selection.

This paper proposes new improved binary versions of the Sine Cosine Algorithm (SCA) for the Feature Selection (FS) problem. FS is an essential machine learning and data mining task of choosing a subset of highly discriminating features from noisy, irrelevant, high-dimensional, and redundant features to best represent a dataset. SCA is a recent metaheuristic algorithm established to emulate a model based on sine and cosine trigonometric functions. It was initially proposed to tackle problems in the continuous domain. The SCA has been modified to Binary SCA (BSCA) to deal with the binary domain of the FS problem. To improve the performance of BSCA, three accumulative improved variations are proposed (i.e., IBSCA1, IBSCA2, and IBSCA3) where the last version has the best performance. IBSCA1 employs Opposition Based Learning (OBL) to help ensure a diverse population of candidate solutions. IBSCA2 improves IBSCA1 by adding Variable Neighborhood Search (VNS) and Laplace distribution to support several mutation methods. IBSCA3 improves IBSCA2 by optimizing the best candidate solution using Refraction Learning (RL), a novel OBL approach based on light refraction. For performance evaluation, 19 real-wold datasets, including a COVID-19 dataset, were selected with different numbers of features, classes, and instances. Three performance measurements have been used to test the IBSCA versions: classification accuracy, number of features, and fitness values. Furthermore, the performance of the last variation of IBSCA3 is compared against 28 existing popular algorithms. Interestingly, IBCSA3 outperformed almost all comparative methods in terms of classification accuracy and fitness values. At the same time, it was ranked 15 out of 19 in terms of number of features. The overall simulation and statistical results indicate that IBSCA3 performs better than the other algorithms.

Novel Criteria for the Observe-Zone of the ESC 0/1h-hs-cTnT Algorithm.

BACKGROUND: The non-ST-segment-elevation myocardial infarction (NSTEMI) guidelines of the European Society of Cardiology (ESC) recommend a 3h cardiac troponin determination in patients triaged to the observe-zone of the ESC 0/1h-algorithm; however, no specific cutoff for further triage is endorsed. Recently, a specific cutoff for 0/3h high-sensitivity cardiac troponin T (hs-cTnT) change (7 ng/L) was proposed, warranting external validation. METHODS: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction, on the basis of complete cardiac workup, cardiac imaging, and serial hs-cTnT. Hs-cTnT concentrations were measured at presentation, after 1 hour, and after 3 hours. The objective was to externally validate the proposed cutoff, and if necessary, derive and internally as well as externally validate novel 0/3h-criteria for the observe-zone of the ESC 0/1h-hs-cTnT-algorithm in an independent multicenter cohort. RESULTS: Among 2076 eligible patients, application of the ESC 0/1h-hs-cTnT-algorithm triaged 1512 patients (72.8%) to either rule out or rule in NSTEMI, leaving 564 patients (27.2%) in the observe-zone (adjudicated NSTEMI prevalence, 120/564 patients, 21.3%). The suggested 0/3h-hs-cTnT-change of <7 ng/L triaged 517 patients (91.7%) toward rule-out, resulting in a sensitivity of 33.3% (95% CI, 25.5-42.2), missing 80 patients with NSTEMI, and ≥7 ng/L triaged 47 patients toward rule-in (8.3%), resulting in a specificity of 98.4% (95% CI, 96.8-99.2). Novel derived 0/3h-criteria for the observe-zone patients ruled out NSTEMI with a 3h hs-cTnT concentration <15 ng/L and a 0/3h-hs-cTnT absolute change <4 ng/L, triaging 138 patients (25%) toward rule-out, resulting in a sensitivity of 99.2% (95% CI, 96.0-99.9), missing 1 patient with NSTEMI. A 0/3h-hs-cTnT absolute change ≥6 ng/L triaged 63 patients (11.2%) toward rule-in, resulting in a specificity of 98% (95% CI, 96.2-98.9) Thereby, the novel 0/3h-criteria reduced the number of patients in the observe zone by 36%s and the number of type 1 myocardial infarction by 50%. Findings were confirmed in both internal and external validation. CONCLUSIONS: A combination of a 3h-hs-cTnT concentration (<15 ng/L) and a 0/3h absolute change (<4 ng/L) is necessary to safely rule out NSTEMI in patients remaining in the observe-zone of the ESC 0/1h-hs-cTnT-algorithm. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT00470587.

Talin-1 is the principal platelet Rap1 effector of integrin activation.

Ras-related protein 1 (Rap1) is a major convergence point of the platelet-signaling pathways that result in talin-1 binding to the integrin ß cytoplasmic domain and consequent integrin activation, platelet aggregation, and effective hemostasis. The nature of the connection between Rap1 and talin-1 in integrin activation is an important remaining gap in our understanding of this process. Previous work identified a low-affinity Rap1-binding site in the talin-1 F0 domain that makes a small contribution to integrin activation in platelets. We recently identified an additional Rap1-binding site in the talin-1 F1 domain that makes a greater contribution than F0 in model systems. Here we generated mice bearing point mutations, which block Rap1 binding without affecting talin-1 expression, in either the talin-1 F1 domain (R118E) alone, which were viable, or in both the F0 and F1 domains (R35E,R118E), which were embryonic lethal. Loss of the Rap1-talin-1 F1 interaction in platelets markedly decreases talin-1-mediated activation of platelet ß1- and ß3-integrins. Integrin activation and platelet aggregation in mice whose platelets express only talin-1(R35E, R118E) are even more impaired, resembling the defect seen in platelets lacking both Rap1a and Rap1b. Although Rap1 is important in thrombopoiesis, platelet secretion, and surface exposure of phosphatidylserine, loss of the Rap1-talin-1 interaction in talin-1(R35E, R118E) platelets had little effect on these processes. These findings show that talin-1 is the principal direct effector of Rap1 GTPases that regulates platelet integrin activation in hemostasis.

State-Level Social and Economic Policies and Their Association With Perinatal and Infant Outcomes.

Policy Points State-level social and economic policies that expand tax credits, increase paid parental leave, raise the minimum wage, and increase tobacco taxes have been demonstrated to reduce adverse perinatal and infant health outcomes. These findings can help prioritize evidence-based legislated policies to improve perinatal and infant outcomes in the United States. CONTEXT: Rates of preterm birth and infant mortality are alarmingly high in the United States. Legislated efforts may directly or indirectly reduce adverse perinatal and infant outcomes through the enactment of certain economic and social policies. METHODS: We conducted a narrative review to summarize the associations between perinatal and infant outcomes and four state-level US policies. We then used a latent profile analysis to create a social and economic policy profile for each state based on the observed policy indicators. FINDINGS: Of 27 articles identified, nine focused on tax credits, eight on paid parental leave, four on minimum wages, and six on tobacco taxes. In all but three studies, these policies were associated with improved perinatal or infant outcomes. Thirty-three states had tax credit laws, most commonly the earned income tax credit (n = 28, 56%). Eighteen states had parental leave laws. Two states had minimum wage laws lower than the federal minimum; 14 were equal to the federal minimum; 29 were above the federal minimum; and 5 did not have a state law. The average state tobacco tax was $1.76 (standard deviation = $1.08). The latent profile analysis revealed three policy profiles, with the most expansive policies in Western and Northeastern US states, and the least expansive policies in the US South. CONCLUSIONS: State-level social and economic policies have the potential to reduce adverse perinatal and infant health outcomes in the United States. Those states with the least expansive policies should therefore consider enacting these evidence-based policies, as they have shown a demonstratable benefit in other states.