Staphylococcus aureus isolates from children with clinically differentiated osteomyelitis exhibit distinct transcriptomic signatures.

There is substantial genomic heterogeneity among Staphylococcus aureus isolates of children with acute hematogenous osteomyelitis (AHO) but transcriptional behavior of clinically differentiated strains has not been previously described. This study evaluates transcriptional activity of S. aureus isolates of children with AHO that may regulate metabolism, biosynthesis, or virulence during bacterial growth and pathogenesis. In vitro growth kinetics were compared between three S. aureus clinical isolates from children with AHO who had mild, moderate, and severe illness. Total RNA sequencing was performed for each isolate at six separate time points throughout the logarithmic phase of growth. The NASA RNA-Sequencing Consensus Pipeline was used to identify differentially expressed genes allowing for 54 comparisons between the three isolates during growth. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways were used to evaluate transcriptional variation in metabolism, biosynthesis pathways and virulence potential of the isolates. The S. aureus isolates demonstrated differing growth kinetics under standardized conditions with the mild isolate having higher optical densities with earlier and higher peak rates of growth than that of the other isolates (p<0.001). Enrichment pathway analysis established distinct transcriptional signatures according to both sampling time and clinical severity. Moderate and severe isolates demonstrated pathways of bacterial invasion, S. aureus infection, quorum sensing and two component systems. In comparison, the mild strain favored biosynthesis and metabolism. These findings suggest that transcriptional regulation during the growth of S. aureus may impact the pathogenetic mechanisms involved in the progression of severity of illness in childhood osteomyelitis. The clinical isolates studied demonstrated a tradeoff between growth and virulence. Further investigation is needed to evaluate these transcriptional pathways in an animal model or during active clinical infections of children with AHO.

What's New in Pediatric Septic Arthritis? A Review of Pertinent Clinical Questions.

BACKGROUND: The evaluation and treatment of children with septic arthritis (SA) is challenging and requires an organized approach to address the spectrum of pathogens which appear to aggregate in age-specific groups. Although evidence-based guidelines have recently been published for the evaluation and treatment of children with acute hematogenous osteomyelitis, there is a relative dearth of literature devoted exclusively to SA. METHODS: Recently published guidance for the evaluation and treatment of children with SA was reviewed and evaluated with respect to pertinent clinical questions to summarize what is new in this area of practice for pediatric orthopaedic surgeons. RESULTS: Evidence suggests that there is a profound difference between children with primary SA and those who have contiguous osteomyelitis. This disruption of the commonly accepted paradigm of a continuum of osteoarticular infections has important implications in the evaluation and treatment of children with primary SA. Clinical prediction algorithms have been established to help determine the applicability of magnetic resonance imaging during the evaluation of children suspected to have SA. Antibiotic duration for SA has been recently studied with some evidence in favor of short-course parenteral followed by short-course oral therapy may be successful if the pathogen is not methicillin-resistant Staphylococcus aureus . CONCLUSION: Recent studies of children with SA have provided better guidance for evaluation and treatment to improve diagnostic accuracy, processes of evaluation, and clinical outcomes. LEVEL OF EVIDENCE: Level 4.

COVID-19 Therapeutics for Low- and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact.

Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States (US), European Union (EU), and World Health Organization (WHO) clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism and with at least five registered trials. The search yielded 1,001, 203, and 1,128 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 13 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics with established safety profiles. The available evidence regarding proposed mechanisms of action, potential limitations, and trial status is summarized. The results of the search demonstrate few published studies of high quality, a low proportion of trials completed, and the vast majority with negative results. These findings reflect limited investment in COVID-19 therapeutics development compared with vaccines. We also identified the need for better coordination of trials of accessible agents and their combinations in LMICs. To prevent COVID-19 from becoming a neglected tropical disease, there is a critical need for rapid and coordinated efforts in the evaluation and deployment of those agents found to be efficacious.

Evaluation of prophylactic dosages of Enoxaparin in non-surgical elderly patients with renal impairment.

BACKGROUND: Thromboprophylaxis dosing strategies using enoxaparin in elderly patients with renal disease are limited, while dose adjustments or monitoring of anti-Xa levels are recommended. We sought to evaluate the efficacy and safety of enoxaparin 20 mg versus 30 mg subcutaneously daily by comparing anti-Xa levels, thrombosis and bleeding. METHODS: We conducted a prospective, single-blinded, single-center randomized clinical trial including non-surgical patients, 70 years of age or older, with renal disease requiring thromboprophylaxis. Patients were randomized to receive either 20 mg or 30 mg of enoxaparin. The primary endpoint was peak anti-Xa levels on day 3. Secondary endpoints included trough anti-Xa levels on day 3, achievement of within range prophylactic target peak anti-Xa levels and the occurrence of hemorrhage, thrombosis, thrombocytopenia or hyperkalemia during hospitalization. RESULTS: Thirty-two patients were recruited and sixteen patients were randomized to each arm. Mean peak anti-Xa level was significantly higher in 30 mg arm (n = 13) compared to the 20 mg arm (n = 11) 0.26 ± 0.11, 95%CI (0.18-0.34), versus 0.14 ± 0.09, 95CI (0.08-0.19) UI/ml, respectively; p = 0.004. Mean trough anti-Xa level was higher in 30 mg arm (n = 10) compared to the 20 mg arm (n = 16), 0.06 ± 0.03, 95CI (0.04-0.08) versus 0.03 ± 0.03, 95CI (0.01-0.05) UI/ml, respectively; p = 0.044. Bleeding events reported in the 30 mg arm were one retroperitoneal bleed requiring multiple transfusions, and in the 20 mg arm one hematuria. No thrombotic events were reported. CONCLUSION: Peak anti-Xa levels provided by enoxaparin 20 mg were lower than the desired range for thromboprophylaxis in comparison to enoxaparin 30 mg. TRIAL REGISTRATION: The trial was retrospectively registered on ClinicalTrials.gov identifier: NCT03158792 . Registered: May 18, 2017.

The first Fetal Echocardiography experience for Prenatal diagnosis of Congenital Heart Disease in Lebanon: Successes and challenges.

OBJECTIVES: To describe the first Lebanese fetal echocardiography experience for prenatal diagnosis of congenital heart diseases (CHD), showcase successes, and hurdles. METHODS: This was a retrospective study from January 2014 to December 2017. A total of 350 fetal echocardiograms for 299 fetuses were performed at the Children's Heart Center at the American University of Beirut, the only fetal center in Lebanon. Data were collected regarding diagnosis, reasons for referral, and timing of referral. RESULTS: The mean gestational age at presentation was 25.3 weeks (standard deviation 4.9 weeks). The primary reasons for referral were abnormal anomaly scan (81 27%), history of previous child with CHD (48 16%), and pre-existing maternal congenital heart disease (15 5%). A total of 144 fetal echocardiograms were normal and 155 patients were diagnosed prenatally with CHD giving a detection rate of 44%. The most identified cardiac lesions were ventricular septal defects (31, 20%), atrial septal defects (15, 9.7%). Significant CHD defined as major abnormalities which would impact pregnancy and future quality of life of the baby were identified in 78 fetuses, with a detection rate of 22%. CONCLUSION: High rates of detection are mainly due to low rates of referral when indicated and possibly parental anxiety regarding CHD diagnosis.

The Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Cardiovascular Homeostasis: A Non-Systematic Literature Review.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been gaining major attention recently after the emergence of data showing the promising role of these proteins in lipid homeostasis and atherosclerosis process, glucose and blood pressure regulation. MATERIALS AND METHODS: PubMed, EMBASE, Scholar and Scopus databases were searched to identify randomized controlled trials, observational studies, in-vitro trials and reviews about the role of PCSK9 in cardiovascular homeostasis. RESULTS: PCSK9 was found to have major impact on lipid homeostasis and inflammatory process through regulation of low-density lipoprotein receptors. Furthermore, inflammation was found to stimulate the expression of PCSK9 in various cells. As for glomerular proteinuria, a positive correlation was determined between PCSK9 levels and the degree of proteinuria. Hypertension, a major cardiovascular risk factor, is likely affected by PCSK9 levels through their role on epithelial sodium channel (ENaC) surface expression. Likewise, some studies show that PCSK9 is associated with higher fasting blood glucose and plasma insulin, demonstrating a potential role of PCSK9 in glucose homeostasis. The role of PCSK9 in cardiovascular homeostasis is one that is still not completely unraveled. CONCLUSION: Studies have clearly shown the implication of PCSK9 in the cardiovascular risk factors: the higher the PCSK9 levels, the higher the risk of atherosclerosis, fasting plasma glucose and insulin resistance. Inhibiting PCSK9 may therefore theoretically prove to present great benefits in diabetic patients with high cardiovascular risk.

Transfusion Therapy in Children With Sickle Cell Disease.

Hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation represent the 3 disease-modifying therapies in children with sickle cell disease (SCD). Blood transfusions play an increasingly important role in both prevention and management of SCD complications in this age group. This review will focus on the indications of blood transfusion in children with SCD and modalities of its administration. It will also highlight the complications of this life-saving therapy and ways of optimizing transfusion to minimize its associated risks.

Optimal Duration of Monitoring for Atrial Fibrillation in Cryptogenic Stroke: A Nonsystematic Review.

Atrial fibrillation (AF) is the most common form of cardiac arrhythmias and an independent risk factor for stroke. Despite major advances in monitoring strategies, clinicians tend to miss the diagnoses of AF and especially paroxysmal AF due mainly to its asymptomatic presentation and the rather limited duration dedicated for monitoring for AF after a stroke, which is 24 hours as per the current recommended guidelines. Hence, determining the optimal duration of monitoring for paroxysmal atrial fibrillation after acute ischemic stroke remains a matter of debate. Multiple trials were published in regard to this matter using both invasive and noninvasive monitoring strategies for different monitoring periods. The data provided by these trials showcase strong evidence suggesting a longer monitoring strategy beyond 24 hours is associated with higher detection rates of AF, with the higher percentage of patients detected consequently receiving proper secondary stroke prevention with anticoagulation and thus justifying the cost-effectiveness of such measures. Overall, we thus conclude that increasing the monitoring duration for AF after a cryptogenic stroke to at least 72 hours will indeed enhance the detection rates, but the cost-effectiveness of this monitoring strategy compared to longer monitoring durations is yet to be established.