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Hypoglycemia is a common occurrence in critically ill patients and is associated with significant mortality and morbidity. We developed a machine learning model to predict hypoglycemia by using a multicenter intensive care unit (ICU) electronic health record dataset. Machine learning algorithms were trained and tested on patient data from the publicly available eICU Collaborative Research Database. Forty-four features including patient demographics, laboratory test results, medications, and vitals sign recordings were considered. The outcome of interest was the occurrence of a hypoglycemic event (blood glucose

Thyrotropin stimulating hormone (TSH) suppression in patients with differentiated thyroid cancer (DTC) aims to decrease the growth and proliferation of thyroid cancer cells. However, the effect of TSH-suppressive therapy on bone microarchitecture remains undefined. Cross-sectional study including 43 women with DTC undergoing TSH-suppressive therapy (sTSH) compared to 20 women also on levothyroxine (LT4) therapy but with TSH in the low-normal range (nTSH) since the thyroid surgery. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA), and trabecular bone score (TBS) was evaluated using the TBS iNsigth software. Fracture risk assessed by FRAX, with and without TBS, was calculated. The relationship between suppressive therapy-related parameters and bone parameters was investigated. The TBS mean values were not significantly different in the sTSH and nTSH groups (1.273 ± 0.12 vs 1.307 ± 0.14, p = 0.7197). In both groups, postmenopausal women had degraded microarchitecture (TBS 1.216 ± 0.11 vs 1.213 ± 0.09, p = 0.9333), while premenopausal women had normal microarchitecture (1.328 ± 0.11 vs 1.401 ± 0.12, p = 0.195). The percentage of all postmenopausal women with degraded TBS was 54.7%, while the percentage of osteoporosis diagnoses was 16.1%. The TBS-adjusted FRAX-probability of fracture was similar in sTSH and nTSH groups. Body mass index (BMI) and menopausal status were the only variables associated with TBS and BMD. Trabecular microarchitecture assessed by TBS was similar between women on long-term suppressive therapy in DTC and those on LT4 replacement therapy aiming at a TSH level within the low-normal reference range. Low TBS values were observed in postmenopausal women of both groups, suggesting that not only suppressed TSH levels but also a low-normal TSH is associated with deteriorated bone microarchitecture in postmenopausal women following total thyroidectomy.

Objective To validate the use of Seegene Allplex™ Vaginitis assay in the diagnosis of candidiasis, bacterial vaginosis (BV) and trichomoniasis. Design Cross-sectional, prospective study conducted in a single centre. Setting Outpatient clinic of a gynaecology department. Population Consecutive symptomatic and asymptomatic women (18-60 years of age). Methods Comparison of the assay test with the reference standards for the diagnosis of vaginitis (cultures for yeasts, Nugent for BV and nucleic acid amplification test for trichomoniasis). Main outcome measures Performance of the investigational assay, in comparison with the reference standards for the diagnosis of the presence of Candida spp., Trichomonas vaginalis and BV. Secondary objectives are the evaluation of the performance of the test in postmenopausal women and in symptomatic women. Results A diagnosis of vaginitis was established in 14.0%. The global prevalences of BV, Candida spp. and T. vaginalis were 22.3%, 13.2% and 2.4%, respectively. The sensitivity and specificity of the assay test for those three causes of vaginitis were as follows: BV 91.7% and 86.6%; any Candida spp. 91.1% and 95.6%; Candida albicans 88.1% and 98.2%, non-albicans Candida 100% and 97.5%, and T. vaginalis 94.4 and 99.9%. The performance of the test was identical in the subgroup of women that reported vulvovaginal symptoms. The presence of multiple infections did not interfere with the performance of the test. Conclusions The Seegene Allplex™ Vaginitis assay has an excellent performance in the diagnosis of the BV and presence of Candida; the results were good for trichomoniasis, but the study was underpowered for this outcome. Tweetable abstract Seegene Allplex™ Vaginitis is an excellent option for screening and diagnosis of vaginitis.

Ischemic stroke is one of the leading causes of death and disability worldwide. This acute vascular event interferes with blood supply to the brain and induces a burst of free radicals such as nitric oxide and superoxide, producing peroxynitrite, a precursor of strong nitrating agents. Fibrinogen is one of the most abundant plasma proteins; it plays a role in the hemostatic system, mediating clot formation, which can be affected by nitrotyrosine formation. We hypothesized that nitration of fibrinogen by ONOOH and ONOOCO radical products could be one of the early events of the ischemic stroke, and protein-bound 3-nitrotyrosine could be a potential biomarker for diagnosis and/or prognosis of this condition. A targeted mass spectrometry approach was developed to analyze the nitration of fibrinogen and its association with ischemic stroke. First, a comprehensive mapping of 3-nitrotyrosine locations and their relative quantification was performed by LC-MS/MS, using in vitro nitrated fibrinogen samples. Twenty different 3-nitrotyrosine residues were identified on fibrinogen nitrated in vitro, varying with the peroxynitrite tofibrinogen molar ratio used. Nine tyrosine residues that were consistently modified at different treatment ratios were chosen to perform a targeted LC-MS/MS analysis in clinical samples. Enriched fibrinogen fractions from clinical samples from 24 ischemic stroke and 12 patients with non-inflammatory conditions were analysed with this method. Three of the nine tyrosine residues analysed (βY452, βY475 and γY380) showed a significant difference between the ischemic stroke and non-inflammatory disease groups. ROC curve analysis suggested an association of these residues either individually or in combination with ischemic stroke. Different tyrosine nitration patterns were also observed in fibrinogen modified in vitro and in vivo, suggesting differences in the nitration process in these situations. This is the first study showing a putative association between the nitration profile of specific tyrosine residues in human fibrinogen and ischemic stroke. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting human populations, yet CL remains largely ignored in drug discovery programs. CL causes disfiguring skin lesions and often relapses after "clinical cure" using existing therapeutics. To expand the pool of anti-CL lead candidates, we implemented an integrated screening platform comprising three progressive Leishmania parasite life cycle forms. We identified tretazicar (CB1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide) as a potent inhibitor of Leishmania parasite viability across multiple Leishmania species, which translated into complete and prolonged in vivo suppression of CL lesion formation in BALB/c mice when used as a monotherapy and which was superior to liposomal amphotericin B. In addition, oral twice a day administration of tretazicar healed the majority of existing Leishmania major (L. major) cutaneous lesions. In drug combination studies, there was a strong potentiation when subtherapeutic doses of liposomal amphotericin B and tretazicar were simultaneously administered. This drug combination decreased L. major lesion size in mice earlier than individual monotherapy drug treatments and maintained all animals lesion free for up to 64 days after treatment cessation. In contrast, administration of subtherapeutic doses of tretazicar or amphotericin B as monotherapies resulted in no or partial lesion cures, respectively. We propose that tretazicar should be explored as a component of a systemic CL combination therapy and potentially for other diseases where amphotericin B is a first line therapy.

This paper aims to investigate, for the first time, physicochemical characteristics and antioxidant capacity of Psidium myrtoides ripe and unripe fruit. In addition, essential oil was extracted fro...

Background Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. Methods In this open label study, 18 healthy volunteers, aged 18–50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. Results All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28–41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. Conclusion Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808

Federal University of Par?. Geoscience Institute. Bel?m, PA, Brazil. Federal University of Par?. Geoscience Institute. Bel?m, PA, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Federal University of Par?. Geoscience Institute. Bel?m, PA, Brazil. The distribution, seasonal variation and sources of 16 polycyclic aromatic hydrocarbons (PAH) from suspended particulate matter (SPM) of the Aur? River, a small amazon typical river located in Northern Brazil, were determined. Gas chromatography?mass spectrometry analysis of SPM revealed a mixture of PAH from different origins and a seasonal variation of PAH primary source for the studied area. Pyrene was the dominant PAH in both studied periods. Total PAH content (?PAH) ranged from lower than quantification limit (LOQ) to 2498.2 ng g?1 dw during the dry season and?

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. Here, we used naïve mice to investigate the effects of acute systemic administration of IRL790 on protein levels and phosphorylation states of proteins relevant for synaptic plasticity and transmission. IRL790 increased pro-brain-derived neurotrophic factor protein levels and phosphorylation at Ser1303 of the N-methyl-D-aspartate (NMDA) subtype 2B glutamate receptor (NR2B) in prefrontal cortex. IRL790 also increased the phosphorylation states at Ser19, Ser31, and Ser40, respectively, of tyrosine hydroxylase in striatum. IRL790 reduced protein levels of the NR2B receptor in striatum but not in prefrontal cortex. Taken together, we report that systemically administered IRL790 rapidly elicits changes in protein level and phosphorylation state of proteins associated with a beneficial effect on synaptic markers and neurotransmission. SIGNIFICANCE STATEMENT: The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. In this study, we report that systemically administered IRL790 rapidly elicits changes in protein level and phosphorylation state of proteins associated with a beneficial effect on synaptic markers and neurotransmission.

Throughout development, neurons are capable of integrating external and internal signals leading to the morphological changes required for neuronal polarization and axon growth. The first phase of axon elongation occurs during neuronal polarization. At this stage, membrane remodeling and cytoskeleton dynamics are crucial for the growth cone to advance and guide axon elongation. When a target is recognized, the growth cone collapses to form the presynaptic terminal. Once a synapse is established, the growth of the organism results in an increased distance between the neuronal cell bodies and their targets. In this second phase of axon elongation, growth cone-independent molecular mechanisms and cytoskeleton changes must occur to enable axon growth to accompany the increase in body size. While the field has mainly focused on growth-cone mediated axon elongation during development, tension driven axon growth remains largely unexplored. In this review, we will discuss in a critical perspective the current knowledge on the mechanisms guiding axon growth following synaptogenesis, with a particular focus on the putative role played by the axonal cytoskeleton.

Objective Infection as sequelae to explosion-related injury is an enduring threat to our troops. There are limited data on the effects of blast on antibiotic pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. The observational study presented here is our Institute’s first attempt to address this issue by combining our existing interdepartmental blast, infection modeling, and in vivo PK/PD capabilities and was designed to determine the PK effects of blast on the first-line antibiotic, cefazolin, in an in vivo mouse model. Methods A total of 160 male BALB/c mice were divided to sham and blast (exposed to blast overpressure of 19 psi) in two biological replicates. At 1 hour after blast/sham exposure, the animals received IV injection of cefazolin (328 mg/kg). Animals were euthanized at 3 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, or 10 hours after the injection. Plasma and liver were analyzed for concentration of cefazolin using mass-spectrometry. Results We observed increases in the concentration of cefazolin in the plasma and liver of blast exposed animals at later time points and increase in elimination half-life. Conclusion Our results indicate that blast-induced physiologic changes significantly influence cefazolin PK and suggest that efficacy could be affected in the context of the blast; assessment of efficacy and PD effects require further investigation. Metabolic changes resulting from blast may influence other classes of antibiotics and other therapeutics used with these injuries. Therefore, this may have important treatment considerations in other areas of military medicine.

OBJECTIVES: Leftover opioids can contribute to misuse and abuse. Recommended dosing quantities in the electronic medical record can guide prescribing patterns. We hypothesized that decreasing the default from 30 doses to 12 doses would decrease the overall number of opioids prescribed without increasing second opioid prescriptions or additional health utilization. METHODS: We performed a single-center retrospective study of children with forearm and elbow fractures who presented to the emergency department for evaluation and subsequent orthopedic follow-up between January 15, and September 19, 2017. The default dispensing quantity was decreased on June 1, 2016 from 30 doses to 12 doses. Patients were categorized to preintervention and postintervention groups. We compared the number of opioids prescribed, second opioid prescriptions, emergency department visits, and pain-related telephone calls and orthopedic visits with χ(2) and logistic regression analyses. RESULTS: There were 1107 patients included. Rates of opioid prescribing were similar preintervention and postintervention (61% vs 56%, P = 0.13). After the change to the default quantity, the median number of doses decreased from 18 to 12 doses, with opioid prescriptions of 30 or more doses dropping from 35% to 11%. No significant association was found between preintervention versus postintervention, opioid prescription at discharge, and having 1 or more pain-related or unexpected follow-up visits. CONCLUSIONS: Lowering the default dispensing quantity of opioids in the electronic medical record decreases the number of opioids prescribed without increasing second prescriptions or additional health care utilization. These findings suggest that a further reduction in the number of opioids prescribed for upper-extremity fractures may be possible.

Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors ("PvW1") was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.

Objectives Evaluate the epidemiological aspects of patients with endometrial cancer, based on statistics from the Oncology Gynecology Center of Santa Marcelina Hospital in Sao Paulo, Brazil between 2011 to 2018. Methods Evaluate the epidemiological aspects of patients with endometrial cancer (EC), based on statistics from the Oncology Gynecology Center of Santa Marcelina Hospital in Sao Paulo, Brazil between 2011 to 2018. Results The median age at diagnosis was 63 years and the diagnosed cases were predominantly white ethnicity (51%). Bleeding after menopause was the most frequent symptom reported (77.8%). Among the cases analyzed, 36 nulliparous patients presented endometrial cancer (15%). The most prevalent histological type was endometrioid adenocarcinoma (66.1%). The most frequent tumor staging was IA with 30.9%, followed by IB 18.83%, II 2%, IIIA 8%, IIIB 9.2% IIIC1 4.6%, IIIC2 6.69%, IVA 0.42% and IVB 16.74%. Surgical staging with hysterectomy and bilateral adnexectomy represented 76.9% and the most frequent adjuvant treatment was brachytherapy (53.1%). Seventy patients underwent brachytherapy and pelvic radiotherapy (29.9%) and 38 patients underwent adjuvant brachytherapy, radiotherapy and chemotherapy as an adjuvant (15.9%). An overall survival rate of 65% and a mortality rate of 29% over the 5-year period have been identified. Conclusions EC is the eighth most frequent gynecological tumor in Brazil. Data analysis allowed to corroborate the most common clinical symptom and the frequent histological type in the literature. This neoplasm classically presents early symptoms and curative treatment, however the data analysis shows a high death rate and diagnosis of advanced disease. So, the endometrioid type, doesn´t have the best prognosis always and needs a better molecular analysis to optimize therapy,to reduce mortality.

Introduction Coronary Heart Disease (CAD) is a multifactorial disease, including environmental and genetic risk factors. Current smoking, dyslipidemia and diabetes have a significant impact in long- term mortality and morbidity. However, several genetic variants associated with CAD but not with traditional risk factors (TRFs) has been reported to improve prediction of events and extended mortality, in younger CAD people. Aim To evaluate the clinical utility of a GRS composed by variants from GWAS associated to CAD but not with TRF to predict life-long residual risk in patients under 55 years old and a low level of TRFs. Methods We conducted a prospective study with 573 consecutive patients aged 150 mg/ml). We analysed several biochemical markers and performed a GRS with variants not associated with TRFs (TCF21 rs12190287, CDKN2B-AS1 rs1333049, CDKN2B rs4977574, PHACTR1 rs1332844, MIA3 rs17465637, ADAMTS7 rs3825807, ZC3HC1 rs11556924, SMAD3 rs17228212 and GJA4 rs618675). We studied the GRS association with a primary composite endpoint of all-cause vascular morbidity and mortality including recurrent acute coronary syndrome (myocardial infarct and unstable angina), coronary revascularization (coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), re-hospitalization for heart failure, ischemic stroke and cardiovascular dead. Results A total of 573 patients were studied and followed up for a mean of 4.7±4.0 years. There were 169 recurrent cardiovascular events. The GRS was sub-divided into terciles, verifying that patients in the third tercile (high risk) had a higher number of risk alleles. Compared with the low-risk GRS tercile, the multivariate-adjusted HR for recurrences was 1.520 (95% CI 1.011–2.286); p=0.044 for the intermediate-risk group and was 2.051 (95% CI 1.382–3.044); p Conclusions A multilocus GRS may identify young coronary disease patients with a low level of TRFs but at significant risk of long-term events recurrence. The genetic information may improve prediction discrimination, and reclassification over the conventional risk factors alone, providing better cost-effective therapeutic strategies. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Epicardial adipose tissue (EAT) volume can be noninvasively detected by CT and has been suggested to predict major adverse cardiovascular events (MACE). Framingham Risk Score is one of a number of scoring systems used to determine an individual's chances of developing cardiovascular disease, hence identifying who is most likely to benefit from prevention. Objectives The purpose of this study was to determine net reclassification improvement (NRI) and improved risk prediction based on EAT volume, in comparison to a traditionally known cardiovascular risk score, such as the Framingham. Methods 895 asymptomatic volunteers were prospectively enrolled in a single Portuguese center (mean age 51.9±7.7, 78.5% male) and underwent a median follow-up time of 3.7 years (IQR 5.0). EAT volume was measured by Cardiac Computed Tomography (CCT) using a modified simplified method. For NRI assessment, EAT volume as a continuous variable was added to the Framingham Risk Score. Results After 3.7 median years of follow-up, 27 patients developed a MACE. Using NRI, the net proportion of events (netNRIe) that assigned a higher risk was 33.3% (better reclassified), and the net ratio of non-events (netNRIne) was 24.7%, resulting in a net reclassification index (netNRI) of 58.0%. When the new marker was included in the model, 58.0% of patients were better reclassified. In our work, a total of 33.3% of patients who suffered events (n=27) were correctly reclassified and assigned a higher risk. Conclusion EAT volume results in a high reclassification rate in an asymptomatic, low-risk population, demonstrating the benefit of this marker beyond traditional risk assessment models. Our study supports its application, especially in carefully selected individuals. Funding Acknowledgement Type of funding sources: None. Figure 1

Introduction Epicardial adipose tissue (EAT) is an emerging cardiovascular risk marker. It has been suggested to be an inflammatory mediator with a role in subclinical atherosclerosis and coronary artery disease. However, its prognostic relevance in hard clinical outcomes remains thoroughly unexplored in the literature. Purpose Evaluate the prognostic relevance of EAT, regarding the occurrence of major adverse cardiovascular events (MACE) in an asymptomatic population. Methods 895 asymptomatic volunteers were prospectively enrolled in a single Portuguese center (mean age 51.9±7.7, 78.5% male) and underwent a median follow-up time of 3.7 years (IQR 5.0). EAT volume was measured by Cardiac Computed Tomography (CCT) using a modified simplified method. Participants were distributed into two groups, above and below the EAT-volume median. We compared both groups regarding the occurrence of MACE through univariate analysis, Kaplan-Meier Survival curves and log-rank test. Association to subclinical atherosclerosis was addressed using correlation between EAT volume and calcium score (Agatson). Results There is a strong correlation between EAT volume and calcium score (r=0.205, p Conclusion In an asymptomatic population, EAT volume seems to be related to subclinical atherosclerosis and to the occurrence of adverse cardiovascular events on long-term follow-up. Our study addresses some unanswered questions, such as the prognostic relevance of EAT as an emerging cardiovascular risk marker. Funding Acknowledgement Type of funding sources: None.

Background Atrial fibrillation (AF) is frequent in patients admitted with acute coronary syndromes (ACS). The development of this arrhythmia occurs in 2–21% of patients with non ST-elevation ACS and 21% of ST-elevation ACS. According with the most recent European guidelines, a short period up to 1 week of triple antithrombotic therapy (TAT) is recommended, followed by dual antithrombotic therapy (DAT) using a NOAC and a single antiplatelet agent, preferably clopidogrel. Objective To compare the antithrombotic strategy (DAT vs TAT) used and its prognostic value in patients with AF and ACS. Methods Retrospective analysis of patients' data admitted with ACS in a multicentric registry between 10/2010–09/2019. TAT was defined as the prescription of dual antiplatelet therapy and one anticoagulant and DAT as one antiplatelet and one anticoagulant. Survival and rehospitalization were evaluated through Kaplan-Meier curve. Results 1067 patients were included, mean age 67±14 years, 72.3% male. Patients who developed de novo AF during hospitalization due to ACS were older (75±12 vs 66±14 years, p Conclusions In patients with ACS and de novo AF, a low percentage of patients was discharged with oral anticoagulation (51.8%). In those whose anticoagulation was initiated, DAT was the preferred strategy. 1-year outcomes were not different between the antithrombotic strategy, except for all cause re-admission. Funding Acknowledgement Type of funding sources: None.

Background Hepatocyte nuclear factor4 A (HNF4A) gene was considered by GWAS associated with atherosclerosis and CAD susceptibility. Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α), a transcriptor factor encoded by the HNF4A gene, are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. Aim We propose identifying the genetic predisposition to atherosclerosis progression and events occurrence or regression and better prognosis, through a cohort study from GENEMACOR population. Methods We investigated a cohort of 1,712 patients who underwent coronary angiography with more than 70% stenosis of at least one main coronary vessel. 33 SNPs associated with the risk of CAD in previous GWAS were genotyped by TaqMan assays methodology. We evaluated the best genetic model associated with CAD prognosis (events) with a 95% CI in bivariate analysis. The hazard function was performed by a Cox survival regression model adjusted for age, sex, type 2 diabetes, hypertension, and hypercholesterolemia, to evaluate their relationship with the event's incidence. Finally, we constructed Kaplan–Meier cumulative-event curves for the significant genetic variants. Results Our evaluation revealed a SNP paradoxically associated with protection from atherosclerosis progression and events occurrence: rs1884613 C>G in the HNF4A gene on chromosome 20 dominant model [OR=0.653; 95% CI (0.522–0.817); p=0.0002]. Cox survival regression model showed a CAD protective effect of HNF4A with a Hazard ratio (HR) of 0.771; p=0.007. The Kaplan-Meier cumulative event analysis disclosed that the CG+GG vs CC genotype of rs1884613 HNF4α was associated with a better prognosis (Breslow test, p=0.004) at the end of the follow-up. Conclusion We identified, in this study, one SNPs paradoxically associated with a better CAD prognosis rs1884613 in HNF4A. The HNF4A gene variants could induce loss of HNF4α function, modifying and modulating hepatic lipase and lipid metabolism conferring a beneficial effect on atherosclerosis progression and events occurrence. Funding Acknowledgement Type of funding sources: None.

Background Metabolic syndrome (MetS) is a clinical condition composed of metabolic and cardiovascular risk factors, such as abdominal obesity, hyperglycemia, dyslipidemia and hypertension. Many patients with MetS suffer major adverse cardiovascular events (MACE) that are not adequately identified by traditional risk assessment, suggesting the need for early detection of subclinical coronary heart disease to identify those at high-risk. Coronary artery calcification (CAC) screening has added utility in categorizing patients with low, intermediate and high cardiovascular risk. Purpose Evaluate the prognostic role of CAC score in asymptomatic population patients with metabolic syndrome in cardiovascular events risk prediction. Methods A total of 1,122 asymptomatic individuals without known coronary heart disease, enrolled from GENEMACOR study, were followed for a mean of 5.3±3.4 years for the primary endpoint of all-cause of cardiovascular events. All were referred for computed tomography for the CAC scoring assessment. According to the Hoff's nomogram, 3 categories were created: low CAC (0≤CAC75). In a subgroup of 507 individuals with MetS and 615 controls, CAC values were compared by T-student and association of CAC severity with events occurrence was evaluated. Finally, a logistic regression model adjusted for CAC severity was performed in patients with MetS. Results Among our population, the extent of CAC differs significantly between men and women in the same age group. Patients with Mets (23.2%, n=115) had higher CAC scores than controls (219.0±486.0 vs 115.8±370.8, p Conclusion Our results point to the importance of the inclusion of CAC screening in patients with MetS to further stratify those patients that, despite tight control of cardiovascular risk factors, may benefit from more intensive therapies. This tool is a useful and straightforward method that could have a significant impact on the prognosis of future cardiovascular disease in patients with MetS. Funding Acknowledgement Type of funding sources: None.

Introduction In patients (P) with non-ST segment elevation acute coronary syndromes (NSTE-ACS), an invasive strategy is recommended to reduce adverse outcomes. The optimal timing to perform coronary angiography (CA) remains undetermined, particularly in our era attending to the new European guidelines restricting pre-treatment (PT). Objective To evaluate the prognostic value of an early strategy (ES; 24h) when no loading dose of a P2Y12 antagonist was given as PT in NSTE-ACS. Material and methods Retrospective analysis of P data admitted with NSTE-ACS at multicentric national registry between 2015–19. Compared demographic and clinical characteristics of P with an ES versus DS. A multivariate logistic regression was performed to evaluate predictor factors of in-hospital and 1-year endpoints. Survival was evaluated through Kaplan-Meier curve and Cox multivariate regression. Results 691P were included, mean age 64±11 years, 77.4% male. 59.2% performed CA as an ES. P proposed to a DS presented higher KK class, higher levels of creatinine and lower of hemoglobin. They also needed more frequently invasive (1.1 vs 0.7%, p=0.692) or non-invasive ventilation (1.8 vs 0.7%, p=282). A higher proportion of DS patients used the transfemoral access (5.5 vs 9.3%, p=0.058). On CA, 6.2% had normal coronary arteries, 49.2% 1-vessel disease and 45.1% multivessel disease. Revascularization was performed in 88.2%: PCI in 86.2%, CABG in 1.7% and both in 0.3%, with no significant differences. Pending CA, 98.4% were medicated with aspirin, 64.8% ticagrelor and 44% clopidogrel, with no differences. P proposed to an ES were more medicated with glycoprotein inhibitor (36.3 vs 26.4%, p=0.015) and non-fractioned heparin (6.4 vs 2.1%, p=0.01) and less with fondaparinux (56.2 vs 65.2%, p=0.017). A higher percentage of calcium-channel blockers (25.2 vs 11.7%, pI (p=0.002) and nitrate prescription at discharge (p=0.001). A DS was not a predictor factor (p=0.812). Conclusion Our results are in accordance with available data. In P with higher-risk NSTE-ACS in the absence of P2Y12 antagonist PT, an ES was not associated with a reduction in the composite of global mortality and rehospitalization for cardiovascular causes. Funding Acknowledgement Type of funding sources: None.

Introduction TCF21 is expressed in cells that migrate into the developing plaque facilitating the repair of the vessel wall. However, the rs12190287 risk allele (C) of TCF21 can lead to reduced TCF21 expression being a risk factor for CAD. Purpose Investigate whether the variant rs12190287 G>C of TCF21 gene represents a risk factor for CAD in a Southern European population. Methods Case-control with 3139 individuals, 1723 CAD patients and 1416 controls, adjusted for age and gender. Genotyping of TCF21 rs12190287 G>C was performed by TaqMan Real-Time PCR. CAD association of each genetic model was evaluated. Multivariate logistic regression analysis adjusted for confound variables: smoking status, dyslipidemia, diabetes, physical inactivity, and hypertension, was made. Results TCF21 rs12190287 G>C has shown significant genotypic differences between cases and controls: GG 9.5% vs 11.9%; GC 43.2% vs 46.5% and CC 47.3% vs 41.6%. CAD risk was significant in all models: dominant (OR 1.28; 95% CI: 1.02–1.61; p=0.033); recessive (OR 1.26; 95% CI: 1.09–1.45; p=0.001); additive (OR 1.20; 95% CI: 1.08–1.34; p=0.001). After multivariate analysis, TCF21 variant was independently associated with CAD. Conclusion TCF21 variant rs12190287 G>C may be a risk factor for CAD. It is plausible that TCF21 loci exert its protective effect by promoting infiltration of fibromyocytes in the coronary wall lesion and fibrous layer and loss of TCF21 expression can result in fewer fibromyocytes to fibrous cap increasing vulnerability of the plaque. Funding Acknowledgement Type of funding sources: None. Variables associated with CAD risk

Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors (“PvW1”) was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.

ObjectiveGastrointestinal (GI) bleeding commonly requires intensive care unit (ICU) in cases of potentialhaemodynamiccompromise or likely urgent intervention. However, manypatientsadmitted to the ICU stop bleeding and do not require further intervention, including blood transfusion. The present work proposes an artificial intelligence (AI) solution for the prediction of rebleeding in patients with GI bleeding admitted to ICU.MethodsA machine learning algorithm was trained and tested using two publicly available ICU databases, the Medical Information Mart for Intensive Care V.1.4 database and eICU Collaborative Research Database using freedom from transfusion as a proxy for patients who potentially did not require ICU-level care. Multiple initial observation time frames were explored using readily available data including labs, demographics and clinical parameters for a total of 20 covariates.ResultsThe optimal model used a 5-hour observation period to achieve an area under the curve of the receiving operating curve (ROC-AUC) of greater than 0.80. The model was robust when tested against both ICU databases with a similar ROC-AUC for all.ConclusionsThe potential disruptive impact of AI in healthcare innovation is acknowledge, but awareness of AI-related risk on healthcare applications and current limitations should be considered before implementation and deployment. The proposed algorithm is not meant to replace but to inform clinical decision making. Prospective clinical trial validation as a triage tool is warranted.

Sousa, AC, Gomes, TM, Sousa, MS, Saraiva, AR, Araujo, GS, Figueiredo, T, and Novaes, JS. Static stretch performed after strength training session induces hypotensive response in trained men. J Strength Cond Res 33(11): 2981-2990, 2019-The purpose of this study was to compare the acute effect of 3 different combinations between passive static stretching exercises (SE) with resistance training (RT) on blood pressure (BP) response in normotensive trained men. Twenty-six volunteer subjects (age: 26.1 ± 5.4 years; body mass: 86.5 ± 10.5 kg; height: 1.78 ± 0.6 cm) participated in this study. After assessing 10 repetition maximum loads for the bench press, lat pulldown, shoulder press, leg press, leg extension, and leg curl, the subjects were randomly assigned on 3 experimental conditions: (a) static SE were performed before the RT session (SE + RT); (b) static SE were performed after the RT session (RT + SE); and (c) static SE were performed between the RT session (RTSE). The BP was measured for 60 minutes after the RT session. The 2-way analysis of variance for repeated measures showed no significant difference (p > 0.05) between the experimental conditions. In within comparisons, only the RT + SE experimental condition did not cause significant increases (p = 0.07) on systolic blood pressure (SBP) when compared the baseline and post-test moments (132.2 ± 10.7 vs. 141.3 ± 18.1 mm Hg). In addition, hypotensive effects were found in SBP only in the RT + SE experimental condition when compared SBP baseline (132.2 ± 10.7 mm Hg) vs. SBP30 minutes (121.7 ± 11.8 mm Hg; p = 0.04), SBP45 minutes (120.6 ± 9.8 mm Hg; p = 0.03), and SBP60 minutes (120.0 ± 7.9 mm Hg; p = 0.00). These findings suggest that performing static SE after the RT session provide an ideal combination for a postexercise hypotensive response from 30 minutes after exercise (and this change was enhanced up to 60 minutes). In conclusion, strength and conditioning professionals can prescribe static SE after RT if the goal is to reduce blood pressure after training.

BackgroundPlasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite.MethodsCYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry.ResultsSeventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype.ConclusionThe plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure.Clinical Trials RegistrationNCT02960568.

Universidade do Estado do Par?. Programa de P?s Gradua??o em Biologia Parasit?ria da Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa de P?s Gradua??o em Virologia. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa de P?s Gradua??o em Virologia. Ananindeua, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa de P?s Gradua??o em Virologia. Ananindeua, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa Institucional de Bolsas de Inicia??o Cient?fica. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa de P?s Gradua??o em Virologia. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Programa de P?s Gradua??o em Virologia. Ananindeua, PA, Brasil Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil University of Leuven. Rega Institute for Medical Research. Department of Microbiology and Immunology. aboratory of Clinical and Epidemiological Virology. Leuven, Belgium. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Worldwide rotaviruses A (RVA) are responsible for approximately 215,000 deaths annually among children aged 50% of gastroenteritis cases in this age group. The aim of this study was to assess the genetic variability of G1P[8] strains detected in children with severe diarrhea in Bel?m, Par?, Brazil, during the post-rotavirus vaccine introduction era. Phylogenetic analysis clustered the VP4 and VP7 genes of 40 samples selected between 2009 and 2011 into lineages found to be different from the Rotarix? vaccine strain. A detailed investigation of their complete genotype constellations identified 2 reassortant viruses (5%), resulting from reassortments between the genogroups Wa-like and DS-1-like (G1-P[8]-I1-R2-C1-M1-A1-N1-T2-E1-H1) and Wa-like and AU-1-like (G1-P[8]-I1-R3-C1-M1-A1-N1-T1-E1-H1) genotype constellations. A comparison of the amino acid residues presents in the antigenic epitopes of VP7 and VP4, showed differences in the electrostatic charges distribution, between wild type Brazilian strains and the Rotarix? and RotaTeq? vaccine strains. These findings reflect the structural analyses of the antigenic regions of VP7 and VP4 of the RVA G1P[8] in children with gastroenteritis in Northern Brazil raising the hypothesis that structural modifications at these sites over time may account for the emergence of new strains that could possibly pose a challenge to current vaccines.

Funding Acknowledgements Type of funding sources: None. OnBehalf Portuguese Registry of Acute Coronary Syndromes Background Acute coronary syndromes (ACS) are common and several scores were proposed to identify high-risk patients that presented worse prognosis in short and long-term follow up. CHA2DS2-VASc score is the score used to decide the initiation of anticoagulation therapy in atrial fibrillation (AF) patients. It is an easy and convenient score, used by physicians in clinical practice, which is helpful to apply in ACS predicting the high-risk patients. Objective CHA2DS2-VASc score as a prognosis method in ACS. Methods Multicenter retrospective study, based on the Portuguese Registry of ACS between 1/10/2010-4/09/2019. CHA2DS2-VASc test as a predictor of AF with a receiver operating characteristic curve. Logistic regression to access if the score was a predictor of AF. According with a punctuation of CHA2DS2-VASc as 0, 1 and ≥2, was performed a Kaplan-Meier test to establish the survival rates and cardiovascular admission at one year of follow-up. Results 25271 patients had ACS, 1023 patients (4.2%) presented de novo AF. CHA2DS2-VASc score was a median predictor of de novo AF (Area Under Curve: 0.642, confidence interval (CI) 0.625-0.659), with a 66.7% sensibility and 55.1% specificity. Logistic regression revealed that the CHA2DS2-VASc score was a predictor of de novo AF in ACS (odds ratio (OR) 2.07, p Conclusions CHA2DS2-VASc score was a predictor of de novo AF in ACS and can be used as a prognostic method for all causes of re-admission and, in special, for cardiovascular cause of re-admission.