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COVID-19, caused by the SARS-CoV-2 virus, is spreading rapidly worldwide, with devastating consequences for patients, healthcare workers, health systems, and economies. As it reaches low- and middle-income countries, the pandemic puts healthcare workers at high risk and challenges the abilities of healthcare systems to respond to the crisis. This study measured levels of knowledge and preparedness regarding COVID-19 among physicians and nurses. A cross-sectional survey was conducted among healthcare workers in Libya between February 26 and March 10, 2020. We obtained 1,572 valid responses of a possible 2,000 (78.6%) participants from 21 hospitals, of which 65.1% were from physicians and 34.9% from nurses. The majority of participants (70%) used social media as a source of information. A total of 47.3% of doctors and 54.7% of nurses received adequate training on how to effectively use personal protective equipment. Low confidence in managing suspected COVID-19 patients was reported by 83.8% of participants. Furthermore, 43.2% of healthcare workers were aware of proper hand hygiene techniques. Less than 7% of participants received training on how to manage COVID-19 cases, whereas 20.6% of doctors and 26.3% of nurses felt that they were personally prepared for the outbreak. Awareness and preparedness for the pandemic were low among frontline workers during the study. Therefore, an effective educational training program should be implemented to ensure maintenance of appropriate practices during the COVID-19 pandemic.

Purpose: To report the clinical and electrophysiological features of cone dystrophy with supernormal rod response (CDSRR)., Methods: Retrospective cohort study of 15 unrelated patients (nine males and six females, median age 16, range 5-47 years) diagnosed with CDSRR by clinical examination, full-field electroretinography (ERG) and genetic testing., Observations: History, ophthalmic examination including near vision, color vision and contrast sensitivity assessment, multimodal retinal imaging and ERG. Genetic testing was done for all patients using next-generation sequencing., Results: The rate of consanguinity was 86.7%. Color vision was defective in 56.3%. Near vision was defective in all patients (mean 20/160). Contrast sensitivity was affected in all patients at low contrast of 2.5%. A parafoveal ring of increased autofluorescence imaging was seen in most patients (75%). Supernormal mixed maximal response b-wave was seen bilaterally in 63% of patients (and high normal in 37%). Rod dysfunction with prolonged rod b-wave latency was detected in all. The 30-Hz flicker response was more reduced and delayed compared to the single-flash cone response. A novel homozygous missense variant c.530G>C (p.Cys177Ser) in KCNV2 was detected in one patient, the nonsense homozygous mutation c.427G>T (p.Glu143*) was found in 13 patients, and the nonsense c.159C>G (p.Tyr53*) was found in one patient., Conclusion: This is the largest cohort of CDSRR from a single ethnic background. Rod dysfunction and reduced 30-Hz flicker response were demonstrated in all patients. In contrast to previous descriptions in the literature, a supernormal combined dark-adapted rod-cone ERG was present in the majority of the patients at standard stimulus intensity. Considering the consistent genotype and the demonstration of likely pathogenic genetic variants in all the patients, we argue that the combination of delayed rod b-wave and subnormal flicker response strongly suggests the diagnosis of CDSRR.

Traffic air pollution is a major health problem and is recognized as an important risk factor for cardiovascular (CV) diseases. In a previous experimental study, we showed that diesel exhaust (DE) exposures induced cardiac mitochondrial and CV dysfunctions associated with the gaseous phase. Here, we hypothesized that NO 2 exposures to levels close to those found in DE induce a mitochondrial reactive oxygen species (ROS) production, which contribute to an endothelial dysfunction, an early indicator for numerous CV diseases. For this, we studied the effects of NO 2 on ROS production and its impacts on the mitochondrial, coronary endothelial and cardiac functions, after acute (one single exposure) and repeated (three h/day, five days/week for three weeks) exposures in Wistar rats. Acute NO 2 exposure induced an early but reversible mitochondrial ROS production. This event was isolated since neither mitochondrial function nor endothelial function were impaired, whereas cardiac function assessment showed a reversible left ventricular dysfunction. Conversely, after three weeks of exposure this alteration was accompanied by a cardiac mitochondrial dysfunction highlighted by an alteration of adenosine triphosphate (ATP) synthesis and oxidative phosphorylation and an increase in mitochondrial ROS production. Moreover, repeated NO 2 exposures promoted endothelial dysfunction of the coronary arteries, as shown by reduced acetylcholine-induced vasodilatation, which was due, at least partially, to a superoxide-dependent decrease of nitric oxide (NO) bioavailability. This study shows that NO 2 exposures impair cardiac mitochondrial function, which, in conjunction with coronary endothelial dysfunction, contributes to cardiac dysfunction. Together, these results clearly identify NO 2 as a probable risk factor in ischemic heart diseases.

Over the past decade, advances in digital trends and technology have greatly impacted the medical field with rapid delivery of and access to information. The field of cardiovascular medicine in particular has seen major technological advances and is well versed in the use of digital platforms and social media. In these unprecedented times of the COVID-19 pandemic, social media and other digital platforms are essential tools for communication, education, and delivery of information. In this review, we discuss the ways virtual learning and social media are changing medical education and research., Competing Interests: Conflict of Interest Disclosure: The author has completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported., (© 2020 Houston Methodist Hospital Houston, Texas.)

Recurrent pregnancy loss (RPL) is a common disease, which presents as two, three or more failed pregnancies. It is attributed to many risk factors, yet half of the cases are idiopathic. In this report, we present a case of a 44-year-old woman with a complaint of secondary infertility for 10 years and a history of three spontaneous abortions. Blood tests and images showed no abnormalities, except for hysteroscopy which showed a polyp-like mass. Pathology revealed an endometrial stroma showing severe decidualization with a lot of gestational villi showing fibrosis and hyaline degeneration, features of old gestational product death, with no glands crowding or cellular atypia. In this case, the conception products were not preceded with a miscarriage and did not cause any symptoms indicating its existing. The asymptomatic endometrial polyp filled with fibrotic gestational villi without a prior miscarriage is an unprecedented case in the medical literature., (© The Author(s) 2020. Published by Oxford University Press.)

What Is Known and Objective: Limited sampling strategies (LSS), using few sampling times after dosing, have been used to reliably predict the isoniazid area under the 24-hour concentration-time curve (AUC). Experience with isoniazid is very limited, and no LSS has been developed in south-Mediterranean populations. Hence, we aimed to develop an accurate and convenient LSS for predicting isoniazid AUC in Tunisian patients with extrapulmonary tuberculosis., Methods: Pharmacokinetic profiles consisting of six blood samples each, collected during the 24-hour dosing interval, were obtained from 25 (6 men and 19 women) Tunisian patients with extrapulmonary tuberculosis. The AUC was calculated according to the linear trapezoidal rule. The isoniazid concentrations at each sampling time were correlated by a linear regression analysis with the measured AUC. We analysed all the developed models for their ability to estimate the isoniazid AUC. Error indices including the percentage of Mean Absolute Prediction Error (%MAE) and the percentage of Root Mean Squared Prediction Error (%RMSE) were used to evaluate the predictive performance. The agreement between predicted and measured AUCs was investigated using Bland and Altman and mountain plot analyses., Results and Discussion: Among the 1-time-point estimations, the C 3 -predicted AUC showed the highest correlation with the measured one (r 2  = .906, %MAE = 10.45% and %RMSE = 2.69%). For the 2-time-point estimations, the model including the C 2 and C 6 provided the highest correlation between predicted and measured isoniazid AUC (r 2  = .960, %MAE = 8.02% and %RMSE = 1.75%). The C 0 /C 3 LSS model provided satisfactory correlation and agreement (r 2  = .930, %MAE = 10.19% and %RMSE = 2.32%). The best multilinear regression model for predicting the full isoniazid AUC was found to be the combination of 3 time points: C 0 , C 1 and C 6 (r 2  = .992, %MAE = 4.06% and %RMSE = 0.80%). The use of a 2-time-point LSS to predict AUC in our population could be sufficient. C 2 /C 6 combination has shown the best correlation but the use of the C 0 /C 3 combination could be more practical with an accurate prediction. Therapeutic drug monitoring of isoniazid based on the C 3 can be used also in daily clinical practice in view of its reliability and practicality., What Is New and Conclusion: The LSS using C 0 and C 3 is reliable, accurate and practical to estimate the AUC of isoniazid. A 1-time-point LSS including C 3 had acceptable correlation coefficient and prediction error indicators could be used alternatively., (© 2019 John Wiley & Sons Ltd.)

The pharmacokinetics of Tacrolimus is characterized by a high interindividual variability that is mainly explained by pharmacogenetics biomarkers. The aims were to develop a population pharmacokinetic model (Pk pop) taking into account post-transplant phases (PTP), CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms on Tac pharmacokinetics in adult kidney transplant patients. The Pk pop study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (age, weight, sex, hematocrit and CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. A one-compartment model (Vd: volume of distribution, CL: Tac Clearance) was found to correctly describe the evolution of the C0/D regardless of the PTP. The influence of the covariates has shown that only the CYP3A4*1B and CYP3A4*22 polymorphisms were significantly associated only with CL, regardless of PTP (p = .04 and 0.02, respectively). Only the CYP3A4*22 polymorphism influenced CL during early PTP (P1: the first three months, p = .02). During the late PTP (P2: >3 months), only CYP3A4 polymorphisms were found to affect CL (p = .03 for both). The external validation of the final model, including both CYP3A4 polymorphisms, showed an acceptable predictive performance during P1 and P2. We developed and validated a tac Pk pop model including both CYP3A4*22 and CYP3A4*1B polymorphisms, taking into account PTP. This model was very useful in the Tac dose proposal in this population on any PT day but could not be used in other organ transplants due to pharmacokinetic differences., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the current preclinical models. Therefore, we sought to develop an adult human primary cardiomyocyte contractility model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic effect (sarcomere shortening) and generating multi-parameter data to profile different mechanisms of action based on cluster analysis of a set of 12 contractility parameters. We report that 17 positive and 9 negative inotropes covering diverse mechanisms of action exerted concentration-dependent increases and decreases in sarcomere shortening, respectively. Interestingly, the multiparametric readout allowed for the differentiation of inotropes operating via distinct mechanisms. Hierarchical clustering of contractility transient parameters, coupled with principal component analysis, enabled the classification of subsets of both positive as well as negative inotropes, in a mechanism-related mode. Thus, human cardiomyocyte contractility model could accurately facilitate informed mechanistic-based decision making, risk management and discovery of molecules with the most desirable pharmacological profile for the correction of heart failure.

Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action. However, the pro-arrhythmic mechanisms in PCs are not entirely understood, particularly in humans, as most investigations are conducted in animals. The aims of this study are to present a novel human PCs electrophysiology biophysically-detailed computational model, and to disentangle ionic mechanisms of human Purkinje-related electrophysiology, pacemaker activity and arrhythmogenicity. The new Trovato2020 model incorporates detailed Purkinje-specific ionic currents and Ca 2+ handling, and was developed, calibrated and validated using human experimental data acquired at multiple frequencies, both in control conditions and following drug application. Multiscale investigations were performed in a Purkinje cell, in fibre and using an experimentally-calibrated population of PCs to evaluate biological variability. Simulations demonstrate the human Purkinje Trovato2020 model is the first one to yield: (i) all key AP features consistent with human Purkinje recordings; (ii) Automaticity with funny current up-regulation (iii) EADs at slow pacing and with 85% hERG block; (iv) DADs following fast pacing; (v) conduction velocity of 160 cm/s in a Purkinje fibre, as reported in human. The human in silico PCs population highlights that: (1) EADs are caused by I CaL reactivation in PCs with large inward currents; (2) DADs and triggered APs occur in PCs experiencing Ca 2+ accumulation, at fast pacing, caused by large L-type calcium current and small Na + /Ca 2+ exchanger. The novel human Purkinje model unlocks further investigations into the role of cardiac Purkinje in ventricular arrhythmias through computer modeling and multiscale simulations., Competing Interests: Declaration of Competing Interest CT, EP, NN, AV, SS and BR declare no conflicts of interest. NAG is an employee of AnaBios Corporation., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC 50 ∼ 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v in complex with tubulin and confirmed their direct binding at the colchicine site. 4v inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that 4v represents a promising new generation of tubulin inhibitors.

The phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. The primary aim of the study was to characterize and qualify this biomarker for therapeutic trials of LRRK2 inhibitors in Parkinson's disease (PD). To this end, analytically validated assays were used to monitor levels of pS935 LRRK2 and total LRRK2 in peripheral blood mononuclear cells (PBMCs) from the following donor groups: healthy controls, idiopathic PD, and G2019S carriers with and without PD. Neither analyte correlated with age, gender, or disease severity. While total LRRK2 levels were similar across the four groups, there was a significant reduction in pS935 LRRK2 levels in disease-manifesting G2019S carriers compared to idiopathic PD. In aggregate, these data indicate that phosphorylation of LRRK2 at S935 may reflect a state marker for G2019S LRRK2-driven PD, the underlying biology for which requires investigation in future studies. This study also provides critical foundational data to inform the integration of pS935 and total LRRK2 levels as biomarkers in therapeutic trials of LRRK2 kinase inhibitors.

In preclinical drug development, accurate prediction of drug effects on the human heart is critically important, whether in the context of cardiovascular safety or for the purpose of modulating cardiac function to treat heart disease. Current strategies have significant limitations, whereby, cardiotoxic drugs can escape detection or potential life-saving therapies are abandoned due to false positive toxicity signals. Thus, new and more reliable translational approaches are urgently needed to help accelerate the rate of new therapy development. Renewed efforts in the recovery of human donor hearts for research and in cardiomyocyte isolation methods, are providing new opportunities for preclinical studies in adult primary cardiomyocytes. These cells exhibit the native physiological and pharmacological properties, overcoming the limitations presented by artificial cellular models, animal models and have great potential for providing an excellent tool for preclinical drug testing. Adult human primary cardiomyocytes have already shown utility in assessing drug-induced cardiotoxicity risk and helping in the identification of new treatments for cardiac diseases, such as heart failure and atrial fibrillation. Finally, strategies with actionable decision-making trees that rely on data derived from adult human primary cardiomyocytes will provide the holistic insights necessary to accurately predict human heart effects of drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Fixed drug eruption (FDE) represents a drug-related cutaneous reaction. Many drugs been associated with this clinical entity, with continually evolving documentation of implicated agents and clinical presentations. A bullous form can occur although it is rare., Objectives: To assess the epidemiological and clinical characteristics of FDE., Methods: We retrospectively analysed all FDE cases who presented to the Clinical Pharmacology Department at the University Hospital, Monastir, Tunisia, for allergy workup., Results: The mean age of the 41 confirmed FDE cases was 43.8 ± 15.5 years. The time between first lesion onset and FDE diagnosis was less than 1 month for 13 patients (31.7%). Fifteen patients had bullous lesions. The upper limbs were the most common location (65.9% of cases). The patch tests were positive in 27 cases; a provocation test yielded a positive response in the four cases tested. Nonsteroidal anti-inflammatory drugs (NSAIDs) were involved in 51.2%, antibiotics in 24.4%, and other analgesics in 19.5%. The most common offending drug was mefenamic acid in 24.4% of cases. Bullous lesions were significantly associated with paracetamol intake (P = .014; odds ratio 16.7; 95% confidence interval: 1.76-158)., Conclusions: NSAIDs and antibiotics were the most implicated in inducing FDE; paracetamol was associated with bullous lesions., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recent FDA approval of an allopregnanolone-based treatment specifically for postpartum depression, brexanolone, now commercially called Zulresso®, is an exciting development for patients and families impacted by postpartum depression and allows us to start asking questions about why and how this compound is so effective. Allopregnanolone is a neuroactive steroid, or neurosteroid, which can be synthesized from steroid hormone precursors, such as progesterone, or synthesized de novo from cholesterol. Neurosteroids are positive allosteric modulators at GABA A receptors (GABA A Rs), a property which is thought to mediate the therapeutic effects of these compounds. However, the durability of effect of brexanolone in clinical trials questions the mechanism of action mediating the remarkable antidepressant effects, leading us to ask why and how does this drug work. Asking why this drug is effective may provide insight into the underlying neurobiology of postpartum depression. Exploring how this drug works will potentially elucidate a novel antidepressant mechanism of action and may provide useful information for next generation drug development. In this review, we examine the clinical and preclinical evidence supporting a role for allopregnanolone in the underlying neurobiology of postpartum depression as well as foundational evidence supporting the therapeutic effects of allopregnanolone for treatment of postpartum depression., (© 2019 The Author(s).)

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

Cadmium (Cd), poisoning has been reported from all around the World, causing many deaths annually. Cd is a toxic heavy metal, and is widely present in environment. It has been reported that chronic Cd exposure is associated with kidney disease, osteoporosis, cardiovascular diseases and cancer. Smoking causes exposure to significantly higher Cd levels in humans. Tobacco smoke transports Cd into the lungs. Blood then transport it to the rest of the body where it increases effects by potentiating Cd that is already present from Cd-rich food. Other high exposures of Cd can occur with people, who live near hazardous waste sites, or factories that release Cd into the air and people who work in the metal refinery industry. Breathing of Cd can severely damage the lungs and may even cause death. Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of Cd exposure on obesity and diabetes are contradictory. On the converse, results of epidemiologic studies linking Cd exposure and Osteoporosis, overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels. In turn, laboratory studies demonstrated that Cd adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with human diseases are still to be adequately investigated. Therefore, the aim of the present review was to explore the impact of Cd exposure and status on the risk of Cd in human diseases., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Association of Clinical Biochemists of India 2019.)

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck (H&N) cancers with an increasing worldwide incidence and a worsening prognosis. The abundance of tumour infiltrating lymphocytes (TILs) has been shown to be a key prognostic indicator in a range of cancers with emerging evidence of its role in OSCC progression and treatment response. However, the current methods of TIL analysis are subjective and open to variability in interpretation. An automated method for quantification of TIL abundance has the potential to facilitate better stratification and prognostication of oral cancer patients. We propose a novel method for objective quantification of TIL abundance in OSCC histology images. The proposed TIL abundance (TILAb) score is calculated by first segmenting the whole slide images (WSIs) into underlying tissue types (tumour, lymphocytes, etc.) and then quantifying the co-localization of lymphocytes and tumour areas in a novel fashion. We investigate the prognostic significance of TILAb score on digitized WSIs of Hematoxylin and Eosin (H&E) stained slides of OSCC patients. Our deep learning based tissue segmentation achieves high accuracy of 96.31%, which paves the way for reliable downstream analysis. We show that the TILAb score is a strong prognostic indicator (p = 0.0006) of disease free survival (DFS) on our OSCC test cohort. The automated TILAb score has a significantly higher prognostic value than the manual TIL score (p = 0.0024). In summary, the proposed TILAb score is a digital biomarker which is based on more accurate classification of tumour and lymphocytic regions, is motivated by the biological definition of TILs as tumour infiltrating lymphocytes, with the added advantages of objective and reproducible quantification.

Introduction : Hypoxia is one of the intrinsic features of solid tumors, and it is always associated with aggressive phenotypes, including resistance to radiation and chemotherapy, metastasis, and poor patient prognosis. Hypoxia manifests these unfavorable effects through activation of a family of transcription factors, Hypoxia-inducible factors (HIFs) play a pivotal role in the adaptation of tumor cells to hypoxic and nutrient-deprived conditions by upregulating the transcription of several pro-oncogenic genes. Several advanced human cancers share HIFs activation as a final common pathway. Areas covered : This review highlights the role and regulation of the HIF-1/2 in cancers and alludes on the biological complexity and redundancy of HIF-1/2 regulation. Moreover, this review summarizes recent insights into the therapeutic approaches targeting the HIF-1/2 pathway. Expert opinion : More studies are needed to unravel the extensive complexity of HIFs regulation and to develop more precise anticancer treatments. Inclusion of HIF-1/2 inhibitors to the current chemotherapy regimens has been proven advantageous in numerous reported preclinical studies. The combination therapy ideally should be personalized based on the type of mutations involved in the specific cancers, and it might be better to include two drugs that inhibit HIF-1/2 activity by synergistic molecular mechanisms.

The Safety Pharmacology Society (SPS) held a West Coast Regional Meeting in Foster City, CA on November 14, 2018 at the Gilead Sciences Inc. site. The meeting was attended by scientists from the pharmaceutical and biotechnology industry, contract research organizations (CROs) and academia. A variety of scientific topics were presented by speakers, covering a broad variety of topics in the fields of safety risk assessment; from pro-arrhythmia and contractility risk evaluation, to models of heart failure and seizure in-a-dish; and discovery sciences; from stem cells and precision medicine, to models of inherited cardiomyopathy and precision cut tissue slices. The present review summarizes the highlights of the presentations and provides an overview of the high level of innovation currently underlying many frontiers in safety pharmacology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Several studies have highlighted the negative impact of maternal obesity on ultrasound accuracy for fetal weight estimation (EFW). However, the evidence is conflicting. We aimed in our study to find if the ultrasound accuracy for EFW would differ or decrease in obese and morbid obesity classes. We also studied the mode of delivery within the same cohort., Methods: It is a retrospective study of obese patients with recorded BMI ≥30 kg/m 2 , class I and II (BMI: 30-39.9 kg/m 2 ) compared with extreme obese class III (BMI ≥40 kg/m 2 ), who gave birth after 28-week gestation of viable singleton, who had an ultrasound within 7 d of delivery with reported normal amniotic fluid and no major fetal anomaly; the EFW was consistently measured through Hadlock regression formula in the period of 2014-2015 inclusive. Differences between the EFW and actual birth weight (ABW) were assessed by percentage error, accuracy in predictions within ±10% of error and the Pearson correlation coefficient were used to correlate EFW with the ABW. The study's secondary outcome was to study the mode of delivery and the rate of cesarean section in obese and morbid obese patients., Results: Total 106 cases fulfilled our criteria. Class I and II as the first group (n = 53). Class III as the second group (n = 53). Maternal and birth characteristics were similar. The Pearson correlation coefficient equal 1 in both groups. The overall mean absolute difference (MAD) in grams of the whole obese cohort was 242 ± 213. The MAD was 242 ± 202 and 242 ± 226 g for the first and second group, respectively (p = 1.0). The overall mean absolute percentage error (MAPE) in this obese cohort was 8%. The MAPE for the first and second group, respectively were 8 and 7% (p = 0.4). The overall rate of cesarean delivery was 60% (64/106) with no differences between the obese and morbid obese BMI classes. Sixty-six percentage (42/64) of these cesarean cases was for repeat cesarean section., Conclusion: Despite what has been previously reported about the negative impact of maternal obesity on EFW accuracy, we could not demonstrate this relationship in our obese cohort (MAPE <10%). In addition, we could not illustrate a significant difference in ultrasound accuracy across various obesity classes. However, we found a significantly increased rate of delivery by repeated cesarean section in this obese cohort.

Background: Every year about three million Muslims visit the Holy City of Makkah in Saudi Arabia to perform the Hajj. Because of the large number of people present during this period, pilgrims can be subjected to many health hazards. An adequate system to minimize these health hazards is needed to support the pilgrims who attend the Hajj. This study justifies the need for developing a large data-based m-Health application to identify the health hazards encountered during the Hajj., Materials and Methods: In developing a big data-based m-Health application, this study follows the framework suggested by Hevner. The design of the science framework allows the development of a technological solution (i.e., design artifact) of the problem through a series of actions. The design involves rigorous knowledge of the environmental factors, including knowledge of the construction and evaluation of technological solutions, that are important and relevant to an existing problem., Results: Based on the design science framework, the process of artifact development can be classified into Artifact Design, Artifact Implementation, and Artifact Evaluation. This paper presents the Artifact Design step for the design of the big data-based m-Health application, which has an Environmental Relevance Cycle, a Knowledge-based rigor Cycle, and an Artifice development and design cycle. The big data-based m-Health application is a prototype and must be evaluated using the evaluation-and-feedback loop process until the optimum artifact is completely built and integrated into the system., Conclusion: Development of a big data-based m-Health application using a design science framework can support the effective and comprehensive plan of the government of Saudi Arabia for preventing and managing Hajj-related health issues. Our proposed model for developing and designing a big data-based m-Health application could provide direction for developing the most advanced solution for dealing with the Hajj-related health issues in the future.

Purpose: This study measured levels of compassion fatigue, burnout and satisfaction among critical care and emergency nurses. It investigated coping strategies as moderating factors and as predictors to levels of compassion fatigue., Methods: Using a cross-sectional design, this study was conducted on 228 (84.4%) out of 270 from four Jordanian hospitals. Nurses worked in different types of critical care units and emergency departments. Nurses completed a demographic questionnaire on the professional quality of life and coping strategies indicator scales., Results: Nurses had low to average compassion satisfaction, burnout and secondary stress syndrome. Problem-solving and avoidance ranged between very low and average levels. Nurses reported having very low to average levels on seeking social support scale. Female nurses had better compassion satisfaction compared with their male colleagues, and the type of unit had a significant impact on the secondary stress syndrome, problem-solving, and seeking social support. Nurses from the surgical cardiovascular ICU scored the highest mean scores on the secondary stress syndrome. Better coping strategies were associated with higher compassion satisfaction and lower levels of secondary stress syndrome. Problem-solving significantly predicted compassion satisfaction, avoidance significantly predicted secondary traumatic syndrome., Conclusions: Coping strategies are moderating factors that could improve compassion satisfaction among critical care nurses. Managers could use findings to create healthier and supportive work environments. We recommend focusing on activities that promote better coping strategies, including improving the social support system. We also recommend replicating this study using a qualitative approach to identify further causes of compassion fatigue., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

The sapRH gene, which encodes the serine alkaline protease SAPRH, from Bacillus safensis RH12, was isolated and its DNA sequence was determined. The deduced amino-acid sequence showed strong homology with other Bacillus proteases. The highest sequence identity value (97%) was obtained with SAPB from B. pumilus CBS, with only 9 amino-acids of difference. The region, encoding SAPRH was heterologously expressed in E. coli BL21-AI™ cells using GATEWAY™ pDEST™17 expression-vector. The recombinant (His) 6 -tag enzyme (His 6 -rSAPRH) was purified in a single affinity chromatography step and its biochemical properties were determined and compared to those of SAPRH and rSAPB. Interestingly, His 6 -rSAPRH showed improved thermostability compared to SAPRH and rSAPB. The molecular dynamics of SAPRH compared to SAPB revealed a more thermostable structure, thus confirming the in vitro results showing that His 6 -rSAPRH has a t 1/2 of 120 min against 90 and 30 min for SAPRH and rSAPB, respectively, at 70 °C and different kinetic parameters to synthetic peptides. The docking simulations data allow in getting an insight into the involvement of some key amino-acids in substrate binding and account for the selectivity. Overall, this is the first report of a sapRH gene cloned from B. safensis which can be a promising potential candidate for future applications in detergent formulations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A novel extracellular protease (SAPRH) was hyper-produced (9000 U/mL) from Bacillus safensis RH12, a newly isolated enzyme from a Tunisian offshore oil field. The enzyme was purified to homogeneity, using salt-precipitation, heat-treatment and FPLC anion-exchange chromatography. The purified enzyme was a monomer of molecular mass of ~28 kDa. The NH 2 -terminal 23 amino-acid sequence of SAPRH showed high homology with those of Bacillus-proteases. SAPRH displayed optimal activity at pH 9 and 60 °C. It was strongly inhibited by phenylmethanesulfonyl fluoride (PMSF) and diiodopropyl fluorophosphates (DFP), indicating that it belongs to the serine-proteases family. Moreover, SAPRH was extremely stable at a broad range of temperature and pH retaining 85% of its activity at 50 °C and 75% at pH 11. The enzyme exhibited excellent stability and compatibility with surfactants and commercial detergents, revealing 90% stability with SDS and 100% stability with Class commercial laundry detergent. One of the most distinctive properties is its catalytic efficiency, which is higher than that of Alcalase 2.5 L, typeDX (commercial enzyme) and SAPB from B. pumilus CBS. Interestingly, the results of the wash performance analysis demonstrated considerably good de-staining at 40 °C for 30 min with low supplementation (500 U/mL). Accordingly, such a protease could be considered as a good detergent-additive in detergent industry., (Copyright © 2018. Published by Elsevier B.V.)

Background: Lamotrigine (LAM), an antiepileptic, with panoply of indications and uses in neurology, is FDA approved, in psychiatry, for bipolar prophylaxis. Apart from this indication, trend of its use in psychiatry is on the rise addressing a multitude of disorders., Study Question: LAM remains one of only few psychotropic drugs with antiglutamate activity. This might render LAM a potential therapeutic option in treatment-resistant major psychiatric disorders. We reviewed LAM pharmacology and its diverse indications while examining the extant evidence., Methods: EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies up to date of June 2016., Results: Sound evidence supports use of LAM for acute bipolar depression and prophylaxis, treatment-resistant schizophrenia, treatment-resistant obsessive-compulsive disorder, posttraumatic stress disorder, depersonalization disorder, and affective dysregulation and behavioral dyscontrol domains of borderline personality disorder. Less compelling evidence is present for use in behavioral and psychological symptoms of dementia and neuropsychiatric sequelae of traumatic brain injury. No evidence supports use in autism spectrum disorder or acute unipolar depression., Conclusions: LAM is an important addition to the psychopharmacological armamentarium. Level of evidence supporting the use of LAM in off-label indications is highly variable, and hence, sound clinical judgment is necessary for its proper use and placement in real-life psychiatric practice and psychopharmacotherapy algorithms.

Objective To review the obstetric impact and natural history of anencephalic pregnancies beyond the age of viability. Study design A retrospective chart review of all cases with a prenatal diagnosis of anencephaly who delivered after 24 weeks' gestation during the period 1990 until 2016. Obstetric outcomes including mode of delivery, live births, shoulder dystocia, antepartum haemorrhage (APH), postpartum haemorrhage (PPH) and uterine rupture were studied. Results A total of 42 cases were studied. The average gestational age at diagnosis was 22 weeks (range 10-41). The average gestational age at birth was 36 weeks (range 25-44 weeks). Induction of labour was performed in 55% (23/42) of the cases. Livebirths were documented in 40% (17/42) of the cases. The average birth weight was 1597±746 g. The rate of vaginal birth was 69% (29/42), the overall rate of caesarean section was 31% (13/42), with a primary caesarean section in 31% (4/13) and a repeat caesarean section in 69% (9/13) of the patients. There were two cases of shoulder dystocia. No other complications were encountered. Conclusion Overall, anencephaly is not associated with an increased risk of obstetric complications; however, there is a tendency towards delivery via repeated caesarean section in women with a previous uterine scar and anencephaly. The prenatal counselling of potential obstetric outcomes could be of robust value for parents who opt to continue with anencephalic pregnancies.

The structural, mechanical, electronic and optical properties of SrTMO₃ (TM = Rh, Zr) compounds are investigated by using first principle calculations based on density functional theory (DFT). The exchange-correlation potential was treated with the generalized gradient approximation (GGA) for the structural properties. Moreover, the modified Becke-Johnson (mBJ) approximation was also employed for the electronic properties. The calculated lattice constants are in good agreement with the available experimental and theoretical results. The elastic constants and their derived moduli reveal that SrRhO₃ is ductile and SrZrO₃ is brittle in nature. The band structure and the density of states calculations with mBJ-GGA predict a metallic nature for SrRhO₃ and an insulating behavior for SrZrO₃. The optical properties reveal that both SrRhO₃ and SrZrO₃ are suitable as wave reflectance compounds in the whole spectrum for SrRhO₃ and in the far ultraviolet region (FUV) for SrZrO₃.

Hypoxic-ischemic (HI) encephalopathy is a devastating injury that occurs when the fetal brain is deprived of oxygen and blood to a degree that may lead to neurological damage, seizing and cerebral palsy. In rodents, early environmental enrichment that promotes maternal care-taking behavior (mCTB) can improve neurobehavioral outcomes and protect against neurological decline. We hypothesized that an enhanced nesting environment would improve mCTB as measured by pup weight gain, and support greater HI recovery in developing rats. Pregnant dams (E15-16) were introduced to either control Standard Facility (SF) housing or closed nestbox (CN) conditions and maintained in larger cages through pup weaning. On postnatal day (PND) 7, male and female Long-Evans rat pups ( N = 73) were randomly sorted into one of two surgical conditions: control and HI. HI pups received isoflurane anesthesia and right carotid artery ligation, a 2-h rest followed by 90 min exposure to a moist hypoxic (92% N, 8% O2) chamber. Pups (PND 8) were weighed daily, and tested on the Morris Water Maze (MWM) task (PND 35-50). Results demonstrate significant differences afforded to male and female pups based on weight measure, where CN-rearing modifies pre-weaning adolescent weights in females and increases post-weaning weights in males and females by an average of 10 g. Following successful MWM training and acquisition (PND 35-37), both male and female CN-raised animals demonstrated faster latency to find the hidden platform (HP) during HP trials (PND 38-42) and appeared to freely explore the MWM pool during an additional probe trial (PND 43). Moreover, after sacrifice (PND 60), CN rearing created sex-specific alterations in brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) immunopositive cell staining of the dorsomedial striatum and CA1 of the hippocampus. CN-rearing afforded HI males higher BDNF levels in the striatum and produced greater GDNF levels in the hippocampus of HI-injured females. These results suggest that early life environmental enrichment positively modifies nesting environment, increases weight gain, as well as spatial learning and memory in a sex-specific directionality. Our findings also implicate correlative changes in corticolimbic neurotrophin protein levels in the CN-reared animals that may contribute to these benefits.

Background: Our study objective was to examine the feasibility of implementing a culturally congruent mentorship pilot program, Youth-First (YF), that targets behavior modification among elementary school-aged children with disruptive behavior and a history of school suspension. We hypothesize that it is feasible to implement the YF program to reduce disruptive behaviors and recidivism of level III/IV infractions in school settings among at-risk African American students., Methods: We assessed program feasibility based on the success of program acceptance by parents/guardians, study enrollment, and intervention compliance by students. A pre/posttest study design was used to examine whether the YF program reduced recidivism of disruptive behavior among enrolled at-risk African American elementary school children between September 2016 and January 2017. Generalized linear mixed models examined whether student behavioral scores improved over time and varied by program mentor. A McNemar test examined the reduction in cumulative incidence of level III/IV infractions pre-post YF program intervention., Results: Intervention acceptance, enrollment, and compliance were 100% (95% confidence interval [CI] 86 to 100%), 100% (95% CI 86 to 100%), and 67% (95% CI 45 to 84%), respectively ( N  = 24). Overall, student behavioral scores improved and plateaued over time (Time 2 effect: b  = - 0.01, 95% CI - 0.02, < 0.01); a two-week period was associated with a seven-point improvement (effect size: Cohen's d  = 0.47, 95% CI 0.03, 0.94) in behavioral scores. Behavioral score improvements were class-specific, based on respectfulness behavior ( b  = 0.11, 95% CI < 0.01, 0.26). No recidivism of level III/IV infractions was reported during and post YF intervention., Conclusion: The integration of culturally congruent mentorship in elementary school-settings is feasible and can reduce risk of disruptive behaviors among at-risk African American students. Future studies should use randomized clinical trials to determine the effectiveness of culturally congruent mentorship interventions (void of potential selection and confounding biases) in reducing disruptive behavior, level III/IV infractions, and school suspensions among at-risk children., Competing Interests: Syracuse University Institutional Review Board granted ethical approval for all study procedures and activities.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cysticercus tenuicollis is the metacestode of canine tapeworm Taenia hydatigena, which has been reported in domestic and wild ruminants and is causing veterinary and economic losses in the meat industry. This study was conducted to determine the sequence variation in the mitochondrial cytochrome c oxidase subunit 1 (coxl) gene in 20 isolates of T. hydatigena metacestodes (cysticercus tenuicollis) collected from northern West Bank in Palestine. Nine haplotypes were detected, with one prevailing (55%). The total haplotype diversity (0.705) and the total nucleotide diversity (0.0045) displayed low genetic diversity among our isolates. Haplotype analysis showed a star-shaped network with a centrally positioned common haplotype. The Tajima's D, and Fu and Li's statistics in cysticercus tenuicollis population of this region showed a negative value, indicating deviations from neutrality and both suggested recent population expansion for the population. The findings of this study would greatly help to implement control and preventive measures for T. hydatigena larvae infection in Palestine.

Background: A family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking., Methods: A whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein-protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk., Results: Sequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and protein-protein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6., Conclusions: In this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.

Research has shown the effectiveness of observational practice for motor learning, but there continues to be debate about the mechanisms underlying effectiveness. Although cortical processes can be moderated during observation, after both physical and observational practice, how these processes change with respect to behavioural measures of learning has not been studied. Here we compared short-term physical and observational practice during the acquisition and retention of a novel motor task to evaluate how each type of practice modulates EEG mu rhythm (8-13 Hz). Thirty healthy individuals were randomly assigned to one of three groups: (1) physical practice (PP), (2) observational practice (OP), and (3) no practice (NP) control. There were four testing stages: baseline EEG, practice, postpractice observation, and delayed retention. There was significant bilateral suppression of mu rhythm during PP but only left lateralized mu suppression during OP. In the postpractice observation phase, mu suppression was bilateral and larger after PP compared to that after OP. NP control showed no evidence of suppression and was significantly different to both the OP and PP groups. When comparing the three groups in retention, the groups did not differ with respect to tracing times, but the PP group showed fewer errors, especially in comparison to the NP group. Therefore, although the neurophysiological measures index changes in the OP group, which are similar but moderated in comparison to PP, changes in these processes are not manifest in observational practice outcomes when assessed in a delayed retention test.

A transcultural clinical nurse specialist narrates how nursing has provided ways to exercise her passion for the clinical intellect as it intersects with the compassion of the heart. She encourages nurses to become social justice entrepreneurs, or what she terms Nurse Philanthropists, devoting time, talent, and energy to social justice issues as activists, advocates, and ambassadors. Florence Nightingale was the first Nurse Philanthropist, using wealth she inherited to establish St. Thomas Hospital in London. However, nurses do not have to be wealthy in order to enter the world of philanthropy. Inspired by the work of Madeleine Leininger, the author has established several non-profits that have grown into Zaman International, an organization with more than 4000 volunteers, 220 partner organizations, a baby cemetery, a fresh food program that delivers hot meals to homes, well and water projects in several countries, a vocational training and literacy program, and a one-stop center providing food, clothing, and essential needs for female-headed households living on less than $12,000 a year, helping negotiate a better future for them and re-pattern the cycle of intergenerational poverty.

Human toxocariasis is a cosmopolitan parasitic zoonosis caused by Toxocara canis and Toxocara cati which are roundworms of dogs and cats. It is mostly a benign condition. We here report a case of acute pancreatitis secondary to toxocariasis.

Background: Patients' suffering has been increasingly investigated by health-care researchers especially in the chronically ill. Suffering is viewed as a progressive negative consequence that associated with pain, impaired self-esteem, and social alienation. This qualitative evidence synthesis aimed to provide further insights into the application of phenomenology in explaining suffering among patients with chronic illnesses., Methods: Studies included in this qualitative evidence synthesis study were retrieved by searching from the following electronic databases: CINAHL, PubMed Central, and EBSCO., Findings: Phenomenology is regarded as influential to generate in-depth evidence about suffering that are grounded in chronically ill patients' perspectives. The philosophical constructs of suffering suggested fundamental dimensions such as stress, distress, hopelessness, and depression along with pain. Evidence encompasses the entire manifestation of suffering in which all interrelated meanings are understood and referred to a unique structure. Hermeneutic phenomenology was adopted as an effective strategy to elucidate human experience leading to the discovery of the embedded meanings of life experience., Conclusion: The phenomenological approach provides nursing research with the pathway to explore patients' suffering experiences in the chronically ill., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Doxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use. Beyond its anticoagulant action, enoxaparin (ENX), a low molecular weight heparin, has been shown to exert multiple pharmacological actions including antioxidant, anti-inflammatory and antiapoptotic effects. Therefore, the current study aimed to assess if ENX could ameliorate cardiotoxicity induced by DOX., Methods: Twenty-one adult male Wistar albino rats were randomly allocated into three groups (n = 7 each) of control, receiving 0.9% saline (i.p.), DOX, receiving 2.5 mg/kg of DOX (i.p.) thrice weekly; and DOX + ENX, receiving ENX (250 IU/kg/day i.p.) and a DOX dose equivalent to that of the DOX only group., Results: DOX-induced cardiotoxicity was indicated by marked increases in cardiac troponin I (cTnI) and severe histological lesions, which significantly correlated with cardiotoxicity, oxidative stress, inflammation and apoptosis markers, compared to controls. DOX group also showed elevations in malondialdehyde (MDA), a marker of oxidative stress, and reductions in total antioxidant capacity (TAC). Cardiac inflammatory markers including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) and caspase-3, an apoptotic marker, were also elevated in the DOX group. DOX, however, did not significantly alter brain natriuretic peptide (BNP) levels. ENX significantly attenuated, but not completely reversed, DOX-induced cardiotoxicity through lowering cTnI and improving cardiomyopathy histopathological scores as compared to the DOX group. ENX also decreased MDA, increased TAC of rats' heart to levels relatively comparable to control. Significant reductions in TNF-α, IL-1β and caspase-3 were also observed following ENX treatment relative to the DOX only group., Conclusions: Collectively, these results describe a cardioprotective effect for ENX against DOX-induced cardiotoxicity which is likely facilitated via suppression of oxidative stress, inflammation and apoptosis.

To assess drug-induced pro-arrhythmic risk, especially Torsades de Pointe (TdP), new models have been proposed, such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs). Previously we evaluated the electrophysiological profile of 15 reference drugs in hESC-CMs and hiPSC-CMs for their effects on intracellular AP and extracellular field potential, respectively. Our findings indicated that SC-CMs exhibited immature phenotype and had the propensity to generate false positives in predicting TdP risk. To expand our knowledge with mature human cardiac tissues for drug-induced pro-arrhythmic risk assessment, human ventricular trabeculae (hVT) from ethically consented organ donors were used to evaluate the effects of the same 15 drugs (8 torsadogenic, 5 non-torsadogenic, and 2 discovery molecules) on AP parameters at 1 and 2 Hz. Each drug was tested blindly with 4 concentrations in duplicate trabeculae from 2 hearts. To identify the pro-arrhythmic risk of each drug, a pro-arrhythmic score was calculated as the weighted sum of percent drug-induced changes compared to baseline in various AP parameters, including AP duration and recognized pro-arrhythmia predictors such as triangulation, beat-to-beat variability and incidence of early-afterdepolarizations, at each concentration. In addition, to understand the translation of this preclinical hVT AP-based model to clinical studies, a ratio that relates each testing concentration to the human therapeutic unbound Cmax (Cmax) was calculated. At a ratio of 10, for the 8 torsadogenic drugs, 7 were correctly identified by the pro-arrhythmic score; 1 was mislabeled. For the 5 non-torsadogenic drugs, 4 were correctly identified as safe; 1 was mislabeled. Calculation of sensitivity, specificity, positive predictive value, and negative predictive value indicated excellent performance. For example, at a ratio of 10, scores for sensitivity, specificity, positive predictive value and negative predictive values were 0.88, 0.8, 0.88 and 0.8, respectively. Thus, the hVT AP-based model combined with the integrated analysis of pro-arrhythmic score can differentiate between torsadogenic and non-torsadogenic drugs, and has a greater predictive performance when compared to human SC-CM models.

The association of indirect exposure to firearm-related violence and standardized test scores among third grade elementary school children were analyzed using geospatial mapping of police department data for all gunshots in Syracuse, NY (n = 2, 127) and state standardized test scores from 2009-2015. Confirmed gunshots were geocoded and mapped across the city and neighborhood school catchment areas. Third grade standardized New York State test scores for English Language Arts (ELA) and math were coded as dichotomous variables of proficient and below proficient scores. State standardized test scores for ELA and math were found to be 50% lower in the elementary schools located within higher concentration gunshot areas, than in elementary schools in lower gunshot areas. Higher levels of gun violence within school catchment areas were significantly associated with higher rates of ELA and math failure ( p ≤ .05). These findings suggest that community violence may be an important, though under recognized, social determinant of poor school performance.

Cardiac safety remains the leading cause of drug development discontinuation. We developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk. Methods: Adult human primary cardiomyocytes from ethically consented organ donors were used to measure contractility transients. We used measures of changes in contractility parameters as markers to infer both drug-induced inotropic effect (sarcomere shortening) and pro-arrhythmia (aftercontraction, AC); contractility escape (CE); time to 90% relaxation (TR90). We addressed the clinical relevance of this approach by evaluating the effects of 23 torsadogenic and 10 non-torsadogenic drugs. Each drug was tested separately at four multiples of the free effective therapeutic plasma concentration (fETPC). Results: Human cardiomyocyte-based model differentiated between torsadogenic and non-torsadogenic drugs. For example, dofetilide, a torsadogenic drug, caused ACs and increased TR90 starting at 10-fold the fETPC, while CE events were observed at the highest multiple of fETPC (100-fold). Verapamil, a non-torsadogenic drug, did not change TR90 and induced no AC or CE up to the highest multiple of fETPCs tested in this study (222-fold). When drug pro-arrhythmic activity was evaluated at 10-fold of the fETPC, AC parameter had excellent assay sensitivity and specificity values of 96 and 100%, respectively. This high predictivity supports the translational safety potential of this preparation and of the selected marker. The data demonstrate that human cardiomyocytes could also identify drugs associated with inotropic effects. hERG channel blockers, like dofetilide, had no effects on sarcomere shortening, while multi-ion channel blockers, like verapamil, inhibited sarcomere shortening. Conclusions: Isolated adult human primary cardiomyocytes can simultaneously predict risks associated with inotropic activity and pro-arrhythmia and may enable the generation of reliable and predictive data for assessing human cardiotoxicity at an early stage in drug discovery.

Context: Diabetes is a growing global metabolic epidemic. Current research is focussing on exploring how the biological processes and clinical outcomes of diabetes are related and developing novel biomarkers to measure these relationships, as this can subsequently improve diagnostic, therapeutic and management capacity., Objective: The objective of this study is to identify the most recent advances in molecular biomarkers of diabetes and directions that warrant further research., Methods: Using a systematic search strategy, the MEDLINE, CINAHL and OVID MEDLINE databases were canvassed for articles that investigated molecular biomarkers for diabetes. Initial selections were made based on article title, whilst final inclusion was informed by a critical appraisal of the full text of each article., Results: The systematic search returned 246 records, of which 113 were unique. Following screening, 29 records were included in the final review. Three main research strategies (the development of novel technologies, broad biomarker panels, and targeted approaches) identified a number of potential biomarkers for diabetes including miR-126, C-reactive protein, 2-aminoadipic acid and betatrophin., Conclusion: The most promising research avenue identified is the detection and quantification of micro RNA. Further, the utilisation of functionalised electrodes as a means to detect biomarker compounds also warrants attention.

On March 24 and 25, 2017 researchers and clinicians from around the world met at Temple University in Philadelphia to discuss the current knowledge of Mycobacterium avium ssp. paratuberculosis (MAP) and its relationship to human disease. The conference was held because of shared concern that MAP is a zoonotic bacterium that poses a threat not only to animal health but also human health. In order to further study this problem, the conferees discussed ways to improve MAP diagnostic tests and discussed potential future anti-MAP clinical trials. The conference proceedings may be viewed on the www.Humanpara.org website. A summary of the salient work in this field is followed by recommendations from a majority of the conferees.

Introduction: The Comprehensive in vitro Proarrhythmic Assay (CiPA) aims to update current cardiac safety testing to better evaluate arrhythmic risk. A central theme of CiPA is the use of in silico approaches to risk prediction incorporating models of drug binding to hERG. To parameterize these models, accurate in vitro measurement of potency and kinetics of block is required. The Ion Channel Working Group was tasked with: i) selecting a protocol that could measure kinetics of block and was easily implementable on automated platforms for future rollout in industry and ii) acquiring a reference dataset using the standardized protocol., Methods: Data were acquired using a 'step depolarisation' protocol using manual patch-clamp at ambient temperature., Results: Potency, kinetics and trapping characteristics of hERG block for the CiPA training panel of twelve drugs were measured. Timecourse of block and trapping characteristics could be reliably measured if the time constant for onset of block was between ~500ms and ~15s. Seven drugs, however had time courses of block faster than this cut-off., Discussion: Here we describe the implementation of the standardized protocol for measurement of kinetics and potency of hERG block for CiPA. The results highlight the challenges in identifying a single protocol to measure hERG block over a range of kinetics. The dataset from this study is being used by the In Silico Working Group to develop models of drug binding for risk prediction and is freely available as a 'gold standard' ambient temperature dataset to evaluate variability across high throughput platforms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study reports preclinical data showing that the interleukin (IL)-1β modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1β antibody gevokizumab improves 'surrogate' markers of survival (i.e., left ventricular remodeling, hemodynamics, and function as well as coronary function). However, whether IL-1β modulation per se or in combination with standard treatments of heart failure improves long-term outcome in human heart failure remains to be determined.

Background: In silico modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae. Methods and Results: Ex vivo recordings from human ventricular trabeculae in control conditions were used to develop populations of in silico human ventricular cell models that integrated intra- and inter-individual variability in action potential (AP) biomarker values. Models were based on the O'Hara-Rudy ventricular cardiomyocyte model, but integrated experimental AP variability through variation in underlying ionic conductances. Changes to AP duration, triangulation and early after-depolarization occurrence from application of the four drugs at multiple concentrations and pacing frequencies were compared between simulations and experiments. To assess the impact of variability in IC50 measurements, and the effects of including state-dependent drug binding dynamics, each drug simulation was repeated with two different IC50 datasets, and with both the original O'Hara-Rudy hERG model and a recently published state-dependent model of hERG and hERG block. For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments. However, for multichannel blockers quinidine and verapamil, simulations were not in agreement with experiments across all IC50 datasets and I Kr block models tested. Quinidine simulations resulted in overprolonged APs and high incidence of repolarization abnormalities, which were not observed in experiments. Verapamil simulations showed substantial AP prolongation while experiments showed mild AP shortening. Conclusions: Results for dofetilide and sotalol show good agreement between experiments and simulations for selective compounds, however lack of agreement from simulations of quinidine and verapamil suggest further work is needed to understand the more complex electrophysiological effects of these multichannel blocking drugs.