In-silico molecular designs to treat neurologic and ophthalmologic diseases caused by sorbitol excess: engineering the Agrobacterium vitis protein.

This work presents the design of a new protein based on the adenosine triphosphate-binding cassette (ABC) transporter solute binding protein (SBP) derived from Agrobacterium vitis, a gram-negative plant pathogen. The Protein Data Bank in Europe's dictionary of chemical components was utilized to identify sorbitol and D-allitol. Allitol bound to an ABC transporter SBP was identified in the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB). Wizard Pair Fitting and Sculpting tools in PyMOL were used to replace bound allitol with sorbitol. PackMover Python code was used to induce mutations in the ABC transporter SBP's binding pocket, and changes in free energy for each protein-sorbitol complex were identified. The results indicate that adding charged side chains forms polar bonds with sorbitol in the binding pocket, thus increasing its stabilization. In theory, the novel protein can be used as a molecular sponge to remove sorbitol from tissue and therefore treat conditions affected by sorbitol dehydrogenase deficiency.

Geospatial Distribution of Ambulatory Surgery Center Utilization for Otorhinolaryngologic Surgeries Among Medicare Patients From 2015 to 2019.

Objective: To investigate the geographic clustering of ambulatory surgical center (ASC) utilization in otolaryngology to determine hot spot areas of high utilization and cold spot areas of low utilization and socioeconomic factors that correlate with these hot spots and cold spots. Study Design: To develop a national epidemiologic study of ASC utilization in otolaryngology in the United States. Setting: United States of America. Methods: Multiple county-level national databases were reviewed including Center for Medicare Services (CMS) physician billing data, CMS Medicare demographic data, and US Census socioeconomic data. The analysis was conducted using the average of all Medicare billing information from 2015 to 2019. Whether a procedure was performed in an ASC was extracted from CMS data using the CMS definition of an ASC. The percentage ASC billing was calculated as the fraction of CMS payments that were performed in ASCs for the top ENT procedures. A Python-based script for database building and GeoDa, Moran's I clustering coefficient, and a 1-way analysis of variance was utilized to chart and analyze demographic, geographic, and socioeconomic trends. Results: Hot spots of utilization, with an average ASC billing of 80.13%, were seen in Southern California, Florida, Mid-Atlantic, and clusters throughout the Deep South. Cold spot clusters, with an average ASC billing of 2.21%, were located in large swaths of New England, Ohio, and the Deep South with clusters bisecting the Midwest. Cold spots had a higher percentage of poverty and percent eligible for Medicaid. Conclusion: ASC utilization is best used to improve cost-effectiveness and accessibility of care but what is seen is that ASC use is currently highest in cities in coastal areas which already have high levels of care access and are making the most proportional money compared to their rural counterparts.

Using a condom or glove to improve pelvic exam visualization: A guide.

Objectives: Pelvic exams are a cornerstone of gynecological care, necessary for both regular screenings and diagnostics. The collapse of lateral vaginal walls during a pelvic exam is a frequently encountered problem in clinical practice. Methods: Practitioners often utilize tools found in a typical clinical setting to counter this issue, such as a condom or glove over the speculum to prevent the lateral vaginal walls collapsing inward and obscuring cervical views. Results: These techniques have been passed down from mentor to mentee over the years, though scarcely described in literature. This article aims to provide instructions on how to use these two methods in clinical practice to improve pelvic exams for the practitioner and the patient. Conclusion: Utilizing a condom or glove to prevent lateral vaginal wall collapse has the potential to improve pelvic exams for both practitioners and patients.

Geospatial distribution of relative cesarean section rates within the USA.

OBJECTIVE: To evaluate the existence of statistically significant clusters of Cesarean section rates at the county level and assess the relationship of such clusters with previously implicated socioeconomic factors. RESULTS: County-level obstetrics data was extracted from March of Dimes, originally sourced from National Center for Health Statistics. County-level demographic data were extracted from the US Census Bureau. Access to obstetricians was extracted from National Provider Identifier records. Rural counties were identified using Rural Urban Commuting Area codes developed by the department of agriculture. The dataset was geospatially analyzed using Moran's I statistic, a metric of local spatial autocorrelation, to identify clusters of increased or decreased Cesarean section rates. The American South, especially the Deep South, is a major cluster of increased Cesarean section rates. As a general but not absolute pattern, the American West and Midwest had lower Cesarean section rates than the Northeast. Focal areas of increased Cesarean section rates included the Kansas-Nebraska border, Michigan's upper peninsula, and the New York City metropolitan area. The gross geospatial differences were not explained by rurality, obstetric access, or ethnic and racial factors alone.

Experimental Technologies in the Diagnosis and Treatment of COVID-19 in Patients with Comorbidities.

The COVID-19 pandemic has impacted the whole world and raised concerns about its effects on different human organ systems. Early detection of COVID-19 may significantly increase the rate of survival; thus, it is critical that the disease is detected early. Emerging technologies have been used to prevent, diagnose, and manage COVID-19 among the populace in the USA and globally. Numerous studies have revealed the growing implementation of novel engineered systems during the intervention at various points of the disease's pathogenesis, especially as it relates to comorbidities and complications related to cardiovascular and respiratory organ systems. In this review, we provide a succinct, but extensive, review of the pathogenesis of COVID-19, particularly as it relates to angiotensin-converting enzyme 2 (ACE2) as a viral entry point. This is followed by a comprehensive analysis of cardiovascular and respiratory comorbidities of COVID-19 and novel technologies that are used to diagnose and manage hospitalized patients. Continuous cardiorespiratory monitoring systems, novel machine learning algorithms for rapidly triaging patients, various imaging modalities, wearable immunosensors, hotspot tracking systems, and other emerging technologies are reviewed. COVID-19 effects on the immune system, associated inflammatory biomarkers, and innovative therapies are also assessed. Finally, with emphasis on the impact of wearable and non-wearable systems, this review highlights future technologies that could help diagnose, monitor, and mitigate disease progression. Technologies that account for an individual's health conditions, comorbidities, and even socioeconomic factors can drastically reduce the high mortality seen among many COVID-19 patients, primarily via disease prevention, early detection, and pertinent management.

Investigation of the Effects of Cardiovascular Therapeutic Ultrasound Applied in Female and Male Rats' Hearts of Different Ages.

This study investigates the role of age and sex on the cardiovascular effects of 3.5-MHz pulsed ultrasound (US) in a rat model. Ultrasonic bursts of 2.0-MPa peak rarefactional pressure amplitude (equivalent to an in vitro spatial-peak temporal-peak intensity of ~270 W/cm2 and a mechanical index of 1.1) were delivered in five consecutive 10-s intervals, one interval for each pulse repetition frequency (PRF) (6, 5, 4, 5, and 6 Hz; always the same order) for a total exposure duration of 50 consecutive seconds. Sixty F344 rats were split into 12 groups in a 3×2×2 factorial design (three ages, male versus female, and US application versus control). This study is the first study on US-induced cardiac effects that contains data across three age groups of rats (premenopause, fertile, and postmenopause) to mimic the fertile and nonfertile human window. US was applied transthoracically, while heart rate, stroke volume, ejection fraction, temperature, and other physiologic parameters were recorded at baseline and after exposure. Significant decreases in cardiac output compared to respective control groups were observed in multiple experimental groups, spanning both females and males. A negative chronotropic effect was observed in young male (~7%) and female (~16%) rats, in five-month-old male (~9%) and female (~15%) rats, and in old rats where the effect was not statistically significant. Younger groups and, to a lesser extent, lower weight groups generally had more significant effects. The pathophysiology of US-induced cardiovascular effects appears to be multifactorial and not strictly related to hormones, menopause, weight, sex, or age, individually.

Positive chronotropic effect caused by transthoracic ultrasound in heart of rats.

Pulsed ultrasound can produce chronotropic and inotropic effects on the heart with potential therapeutic applications. Fourteen 3-month-old female rats were exposed transthoracically to 3.5-MHz 2.0-MPa peak rarefactional pressure amplitude ultrasonic pulses of increasing 5-s duration pulse repetition frequency (PRF) sequences. An increase in the heart rate was observed following each PRF sequence: an ∼50% increase after the 4-5-6 Hz sequence, an ∼57% increase after the 5-6-7 Hz sequence, and an ∼48% increase after the 6-7-8 Hz sequence. Other cardiac parameters showed a normal or indicated a compensatory decrease at 3 and 15 min post-ultrasound compared to control.

Modeling the mechanics of fibrous-porous scaffolds for skeletal muscle regeneration.

The scaffolds for skeletal muscle regeneration are designed to mimic the structure, stiffness, and strains applied to the muscle under physiologic conditions. The external strains are also used to stimulate myogenesis of the (stem) cells seeded on the scaffold. The time- and location-dependent mechanics inside the scaffold determine the microenvironment for the seeded cells. Here, fibrous-porous cylindrical scaffolds under the action of external cyclic strains are considered. The scaffold mechanics are described as two-phase (poroelastic) where the solid phase is associated with the fibers and the fluid phase is associated with the liquid-containing pores. In response to an applied cyclic strain, pressure oscillates and fluid moves radially toward and away from the axis of the scaffold. We compute the directions and magnitudes of the radial gradients of the poroelastic characteristics (solid-phase displacement, strain, and velocity; fluid-phase pressure and velocity; relative fluid-solid-phase velocity) determined by the boundary conditions and geometry of the scaffold. Several kinds of the external cyclic strain are analyzed and the resulting poroelastic functions are found. The poroelastic characteristics are obtained in closed form which is convenient for further consideration of myogenesis of the seeded cells and ultimately for the design of the scaffolds for skeletal muscle regeneration. Graphical abstract.

IntraOmmaya compartmental radioimmunotherapy using 131I-omburtamab-pharmacokinetic modeling to optimize therapeutic index.

PURPOSE: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody 131I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya 131I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. METHODS: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of 131I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [CIAR(t)], (b) the AUC of the unbound "harmful" antibody, AUC [CIA(t)], and (c) the therapeutic index, AUC [CIAR(t)] ÷ AUC [CIA(t)]. RESULTS: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of 131I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [CIA(t)]) was predicted to increase more quickly than AUC [CIAR(t)] as a function of 131I-omburtamab dose, but the balance of therapeutic index and AUC [CIAR(t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%. CONCLUSION: The 2-compartmental pharmacokinetic model when applied to intraOmmaya 131I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT00089245.