Observational study of intracranial compliance analysis in neurologically healthy pediatric patients using a non-invasive device.

Information about the morphology of the intracranial pressure waveform, as well as the variations in intracranial pressure (ICP) and compliance in pediatric patients are essential to diagnose and predict the progression of various neurological conditions. However, there is no information on the morphology of the IP waveform in neurologically healthy pediatric patients. In the present study, intracranial compliance was therefore analyzed in neurologically healthy patients with the aid of a noninvasive device. The study was an observational, cross-sectional study. Fifty-five neurologically healthy participants were included. Data on intracranial compliance with the patient in two positions, lying down (0°) and seated (45°), were collected with a noninvasive extracranial sensor, which allowed the intracranial pressure waveforms to be recorded. The values of the ratio P2/P1 were then analyzed. A questionnaire (with a scale from zero to ten, where ten corresponds to the highest level of satisfaction) was applied for patients to evaluate their satisfaction with the sensor. Patients were 10 years old (average), and most of them were (58%). Mean P2/P1 ratio was 0.94 (sd = 0.14) in the supine position and 0.91 (sd = 0.15) in the seated position. Participants were satisfied with the length of time for which the equipment was used (9.8, sd = 0.71). The device did not cause any discomfort. The noninvasive method used was well accepted by the patients. Intracranial compliance values were determined by analysis of the P2/P1 ratio in neurologically healthy pediatric population.Trial registration: Brazilian Registry of Clinical Trials Identifier: RBR-5j74ddg.

Doxycycline for Multidrug-Resistant Gram-Negative Bacterial Infection Treatment: A Scoping Review.

Introduction: Multidrug-resistant bacterial infections limit available therapeutic options. Doxycycline is an old antibiotic from the tetracycline class that exhibits a wide antibacterial action, including Gram-negative bacteria (GNB), and could be an alternative for the treatment of multidrug-resistant (MDR) Enterobacteriaceae. The study aimed to systematically identify, evaluate, and summarize the results of studies related to outcomes of treatments for MDR-GNB infections in patients treated with doxycycline. Methods: This review was conducted in four databases during weeks 41-52 of 2022: PubMed, Medline, Scopus, and Web of Science, from the earliest year available on each database to December 2022. Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines were followed in conducting this study, and PICO was used for the research question of this review. Results: This scoping review found 8 retrospective studies that included 59 patients. Of these, 69% were treated for ventilator-associated pneumonia (VAP), 27% for urinary tract infections, 2% for bloodstream infections, and 2% for wound infections, both of which were associated with VAP. The usual dosage of doxycycline was 100 mg intravenously or orally. Clinical and microbiologic improvements were achieved in 81.3% and 87% of all patients, respectively. The mortality rate was 17.3% and was exclusively due to VAP. Conclusions: Doxycycline showed promising results in this review; however, randomized clinical trials or prospective cohorts are recommended to demonstrate the efficacy of doxycycline in the treatment of MDR infections with GNB.

Chylothorax After Heart Surgery in Children.

Chylothorax is a consequence of a thoracic duct injury that can occur during surgical procedures in patients with congenital heart disease. It is associated with high rates of morbimortality and increased use of clinical and hospital resources. The aim of this study was to evaluate the risk factors, distribution, manifestations, complications, and treatments for chylothorax in patients undergoing cardiac surgery in a tertiary pediatric hospital in southern Brazil. This is a retrospective, quantitative study, in which all medical records (n = 166) of patients with chylothorax after pediatric cardiac surgery between January 2014 and December of 2020 and a matched control group (n = 166) were analyzed. Over the study period, there was an increase in incidence of chylothorax from 4.5% in 2014 to 7.6% in 2020, a trend that has been reported in the literature. After multivariate analysis, the following were identified as risk factors for the diagnosis of chylothorax: genetic syndrome (OR 2.298); prolonged cardiopulmonary bypass time (greater than 120 min) (OR 2.410); fluid overload in the immediate postoperative period (OR 1.110); and SIRS (OR 2.527). Mortality was two times greater (p = 0.021) and there was a higher rate (34.4%) of infection (p < 0.001) in patients who developed chylothorax. In addition, a sensitivity analysis was performed comparing patients with low- and high-output chylothorax (> 20 mL/kg), which confirmed unfavorable outcomes for the latter group. Herein, we show that hemodynamic alterations were important factors for diagnosis. Understanding the risk factors, outcomes, and complications helps early identification and enables the reduction of morbidity and mortality.

Naringenin-4'-glucuronide as a new drug candidate against the COVID-19 Omicron variant: a study based on molecular docking, molecular dynamics, MM/PBSA and MM/GBSA.

This study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (in silico). NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and -15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. In vitro and preclinical studies are needed to confirm these findings.Communicated by Ramaswamy H. Sarma.

Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis.

BACKGROUND: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. METHODS: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. RESULTS: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. CONCLUSIONS: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Assessment of Pediatric Telemedicine Using Remote Physical Examinations With a Mobile Medical Device: A Nonrandomized Controlled Trial.

Importance: The number of innovations in health care based on the use of platforms, digital devices, apps, and artificial intelligence has grown exponentially in recent years. When used correctly, these technologies allow inequities in access to health care to be addressed by optimizing care and reducing social and geographic barriers. However, most of the technological health care solutions proposed have not undergone rigorous clinical studies. Objective: To assess the concordance between measurements from a remote physical examination using a mobile medical device and measurements from a conventional in-person physical examination. Design, Setting, and Participants: This nonrandomized controlled trial was conducted from January 1 to December 31, 2020. The clinical parameters compared were heart rate; body temperature; heart, lung, and abdominal auscultation; otoscopy; throat and oral examination; and skin examination. A total of 690 patients with clinical stability and various symptoms who were seen in the emergency department of 2 Brazilian pediatric hospitals were eligible to enter this study. Main Outcomes and Measures: The primary outcome was concordance between measurements from a telemedicine physical examination using a mobile medical device and measurements from a conventional in-person physical examination. The secondary outcome was the specificity and sensitivity of the digital device, considering the conventional in-person consultation as the gold standard. Results: Among 690 patients, the median (IQR) age at study entry was 5 (1-9) years; 348 (50.4%) were female, and 331 (48.0%) presented with a chronic disease. Regarding the primary outcome, the concordance values were 90% or greater for skin examination (94% for rash, 100% for hemorrhagic suffusion, and 95% for signs of secondary infection), characteristics of the mucosa (98% for hydration and 97% for coloring), and heart (95% for murmur, 97% for rhythms, and 98% for sounds), lung (91% for adventitious sounds, 97% for vesicular sounds, and 90% for fever), and abdominal (92% for abdominal sounds) auscultations. Concordance values were lower for otoscopy (72% for the ear canal and 86% for the tympanic membrane), throat and oral examination (72%), and rhinoscopy (79% for mucosa and 81% for secretion). The specificity was greater than 70% (ranging from 74.5% for the ear canal to 99.7% for hemorrhagic suffusion) for all variables. The sensitivity was greater than 52% for skin examination (58.0% for rash and 54.8% for signs of secondary infection), throat and oral examination (52.7%), and otoscopy (66.1% for the ear canal and 64.4% for the tympanic membrane). Conclusions and Relevance: In this study, measurements from remote physical examination with a mobile medical device had satisfactory concordance with measurements from in-person physical examination for otoscopy, throat and oral examination, skin examination, and heart and lung auscultation, with limitations regarding heart and lung auscultation in infants and abdominal auscultation in children of all ages. Measurements from remote physical examination via a mobile medical device were comparable with those from in-person physical examination in children older than 2 years. These findings suggest that telemedicine may be an alternative to in-person examination in certain contexts and may help to optimize access to health care services and reduce social and geographic barriers. Trial Registration: Brazilian Registry of Clinical Trials Identifier: RBR-346ymn.

Development of a validated stability-indicating HPLC- DAD method for dasabuvir and the characterization of its degradation products using LC-QToF-MS/MS

Abstract A stability-indicating HPLC-DAD method was developed and validated for the simultaneous determination of dasabuvir and its degradation products in the pharmaceutical formulation. The proposed method utilized a Symmetry® C18 (4.6 x 75 mm, 3.5 µm) column, and the mobile phase consisted of an isocratic elution of formic acid (0.1%) and acetonitrile (55:45, v/v), at a flow of 1 mL min-1; analytes were detected at 244 nm. Dasabuvir was submitted to different stress degradation conditions, such as acidic, alkaline, neutral, thermal, oxidative and photolytic, and the structural elucidation of degradation products was performed using LC-QToF-MS/MS. The HPLC-DAD stability-indicating method was validated for selectivity, linearity, limit of detection and quantification, accuracy, precision and robustness, according to ICH guidelines. Dasabuvir produced two degradation products (DP1 and DP2) from the alkaline stress conditions, which were characterized in negative ion mode. Dasabuvir was linear in the range 9.78 to 136.92 µg mL-1, and DP and DP were linear in the range 2.9 to 20.2 µg mL-1 and 1.3 to 14.9 µg mL-1, respectively. The 1 2 recovery ranged between 99.16 and 100.86%, while precision ranged from 1.02 to 2.89%. As the method can effectively separate the dasabuvir from its degradation products and quantitate them, it may be employed as a stability-indicating method for the pharmaceutical formulation.

Diagnosis and prognosis of COVID-19 employing analysis of patients' plasma and serum via LC-MS and machine learning.

OBJECTIVE: To implement and evaluate machine learning (ML) algorithms for the prediction of COVID-19 diagnosis, severity, and fatality and to assess biomarkers potentially associated with these outcomes. MATERIAL AND METHODS: Serum (n = 96) and plasma (n = 96) samples from patients with COVID-19 (acute, severe and fatal illness) from two independent hospitals in China were analyzed by LC-MS. Samples from healthy volunteers and from patients with pneumonia caused by other viruses (i.e. negative RT-PCR for COVID-19) were used as controls. Seven different ML-based models were built: PLS-DA, ANNDA, XGBoostDA, SIMCA, SVM, LREG and KNN. RESULTS: The PLS-DA model presented the best performance for both datasets, with accuracy rates to predict the diagnosis, severity and fatality of COVID-19 of 93%, 94% and 97%, respectively. Low levels of the metabolites ribothymidine, 4-hydroxyphenylacetoylcarnitine and uridine were associated with COVID-19 positivity, whereas high levels of N-acetyl-glucosamine-1-phosphate, cysteinylglycine, methyl isobutyrate, l-ornithine and 5,6-dihydro-5-methyluracil were significantly related to greater severity and fatality from COVID-19. CONCLUSION: The PLS-DA model can help to predict SARS-CoV-2 diagnosis, severity and fatality in daily practice. Some biomarkers typically increased in COVID-19 patients' serum or plasma (i.e. ribothymidine, N-acetyl-glucosamine-1-phosphate, l-ornithine, 5,6-dihydro-5-methyluracil) should be further evaluated as prognostic indicators of the disease.

Bioactive profile of edible nasturtium and rose flowers during simulated gastrointestinal digestion.

Rose and nasturtium are common ornamental edible flowers rich in phytochemicals whose application as food is not widely explored. The gastrointestinal environment can modify these compounds, resulting in new combinations with different bioactivity. This study aimed to evaluate the effects of simulated gastrointestinal digestion (SGD) on rose and nasturtium flower extracts. Using UPLC-HRMS, 38 phenolic compounds were identified, and the SGD caused significant changes, mainly in the glycosylated phenolic. Furthermore, antioxidant activity was correlated with the increase in the concentrations of some polyphenols. Tested Gram-negative bacteria showed sensitivity to the flower extracts; their growth was inhibited by up to 82.7%. SGD interrupted the bacterial growth inhibition power of the rose extracts. On the other hand, an increase in inhibition ranging from 52.25 to 54.72%was found for nasturtium extracts, correlated to the behavior of some bioactive. Hence, SGD resulted in significant changes in phenolic profiles of the edible flowers, increasing antioxidant activity and changing antimicrobial effects.

A multivariate analysis of risk factors associated with death by Covid-19 in the USA, Italy, Spain, and Germany.

Aim: Our aim was to investigate the risk factors associated with death from COVID-19 in four countries: The USA, Italy, Spain, and Germany. Subject and methods: We used data from the Institute for Health Metrics and Evaluation with projection information from January-August 2020. A multivariate analysis of logistic regression was performed. The following factors were analyzed (per day): number of beds needed for the hospital services, number of intensive care units (ICU) beds required, number of ventilation devices, number of both hospital and ICU admissions due to COVID-19. Nagelkerke's R2 coefficient of determination was used to evaluate the model's predictive ability. The quality of the model's fit was assessed by the Hosmer-Lemeshow and the chi-square tests. Results: Among the evaluated countries, Italy presented greater need for ICU beds/day (≤ 98; OR = 2315.122; CI 95% [334.767-16,503.502]; p < 0.001) and daily ventilation devices (≤ 118; OR = 1784.168; CI 95% [250.217-12,721.995]; p < 0.001). It is expected that both Italy and Spain have a higher ICU admission rate due to COVID-19 (n = 14/day). Spain will need more beds/day (≤ 357; OR = 146.838; CI 95% [113.242-190.402]; p  < 0.001) and probably will have a higher number of daily hospital admissions (n = 48/day). All the above-mentioned factors have an important impact on patients' mortality due to COVID-19 in all four countries. Conclusions: Further investments in hospitals' infrastructure, as well as the development of innovative devices for patient's ventilation, are paramount to fight the pandemic in the USA, Italy, Spain, and Germany.