Prioritizing drug targets by perturbing biological network response functions.

Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with conventional small molecule drugs. Accordingly, many identified gene-regulatory drivers and downstream effectors are currently undruggable. Drivers and effectors are often connected by druggable signaling and regulatory intermediates. Methods to identify druggable intermediates therefore have general value in expanding the set of targets available for hypothesis-driven validation. Here we identify and prioritize potential druggable intermediates by developing a network perturbation theory, termed NetPert, for response functions of biological networks. Dynamics are defined by a network structure in which vertices represent genes and proteins, and edges represent gene-regulatory interactions and protein-protein interactions. Perturbation theory for network dynamics prioritizes targets that interfere with signaling from driver to response genes. Applications to organoid models for metastatic breast cancer demonstrate the ability of this mathematical framework to identify and prioritize druggable intermediates. While the short-time limit of the perturbation theory resembles betweenness centrality, NetPert is superior in generating target rankings that correlate with previous wet-lab assays and are more robust to incomplete or noisy network data. NetPert also performs better than a related graph diffusion approach. Wet-lab assays demonstrate that drugs for targets identified by NetPert, including targets that are not themselves differentially expressed, are active in suppressing additional metastatic phenotypes.

Soft tissue injury events associated with neural integrity monitoring endotracheal tubes: A MAUDE database analysis.

OBJECTIVE: Neural integrity monitoring (NIM) endotracheal tubes are widely used to provide intraoperative monitoring of the recurrent laryngeal nerve during certain neck surgeries, especially thyroidectomy, in order to reduce the risk of nerve injury and subsequent vocal fold paralysis. The unique design of NIM tubes and the increased technical skill required for correct placement compared to standard endotracheal tubes may increase the risk of upper aerodigestive tract soft tissue injury. This study aims to describe adverse events related to NIM endotracheal tubes. STUDY DESIGN: Retrospective cross-sectional study. SETTING: The US Food and Drug Administration's MAUDE database (2010-2022); (Manufacturer and User Facility Device Experience). METHODS: The MAUDE database was queried for reports of adverse events that resulted in patient soft tissue injury involving the use of endotracheal tubes approved by the Food and Drug Administration. RESULTS: There were 28 reported soft tissue injuries, with all events being related to the NIM EMG family of endotracheal tubes manufactured by Medtronic Xomed, Inc. Overall, 24 were categorized as device-related adverse events, and 4 were unspecified in the event description. The most common soft tissue injuries were edema (n = 7) and perforation (n = 7), each accounting for 25 % of adverse events. The second most common injury type was laceration (n = 4), representing 14 % of all adverse events. Overall, 9 patients (32 %) in our cohort required a surgical intervention to treat their injuries, which consisted of 6 tracheotomies and 3 instances of suture repair. CONCLUSIONS: The most commonly reported types of soft tissue injury included edema and perforation, followed by laceration. Increased awareness of device-related patient injuries associated with NIM endotracheal tubes can be used to better inform surgeons and anesthesiologists during the process of intubation and surgical decision-making.

A digital media literacy intervention increases discernment between mainstream and false news in the United States and India.

Widespread belief in misinformation circulating online is a critical challenge for modern societies. While research to date has focused on psychological and political antecedents to this phenomenon, few studies have explored the role of digital media literacy shortfalls. Using data from preregistered survey experiments conducted around recent elections in the United States and India, we assess the effectiveness of an intervention modeled closely on the world's largest media literacy campaign, which provided "tips" on how to spot false news to people in 14 countries. Our results indicate that exposure to this intervention reduced the perceived accuracy of both mainstream and false news headlines, but effects on the latter were significantly larger. As a result, the intervention improved discernment between mainstream and false news headlines among both a nationally representative sample in the United States (by 26.5%) and a highly educated online sample in India (by 17.5%). This increase in discernment remained measurable several weeks later in the United States (but not in India). However, we find no effects among a representative sample of respondents in a largely rural area of northern India, where rates of social media use are far lower.

IncobotulinimtoxinA (Xeomin) for the treatment of adductor laryngeal dystonia: A prospective, open-label clinical trial.

OBJECTIVES: Demonstrate an understanding of incobotulinumtoxinA efficacy in the treatment of adductor spasmodic dysphonia (SD). Understand that incobotulinumtoxinA can successfully be used as an alternative to onabotulinumtoxinA and for secondary non-responders. METHODS: We conducted a prospective open-label trial from 2016 until 2019 regarding the use of incobotulinimtoxinA for the treatment of adductor spasmodic dysphonia. Exclusion criteria included pregnant/nursing women, botulinum toxin for other indications, known allergy, neuromuscular or systemic diseases, use of aminoglycoside antibiotics, substance abuse, litigation regarding prior therapy, or other confounding conditions. Sixty-four injection sessions with completed with sixteen patients who were enrolled in the study and underwent EMG-guided incobotulinumtoxinA injections to the thyroarytenoid (TA) muscle using a hollow monopolar Teflon-coated needle via a trans-cricothyroid membrane approach. Dosages to each TA muscle were recorded and patients completed a Voice Handicap Index-10 (VHI-10), a validated worksheet regarding their perceived percent of normal function (PNF) following treatment, and a side effect profile. Outcomes were analyzed using the paired t-test. RESULTS: For primary transitioners to incobotulinimtoxinA, VHI-10 scores and best percent normal function did not significantly change. For non-responders, VHI-10 decreased from 32.5 on Botox to 19.5 on incobotulinimtoxinA and best PNF increased from 37.6 to 90 %, which was statistically significant. Transient side effects included breathiness. CONCLUSIONS: Our study demonstrates that incobotulinimtoxinA may be used successfully for adductor SD either as first line treatment or in secondary non-responders to onabotulinumtoxinA.

Adequate short- and long-term pain control with non-opiate analgesics after microdirect laryngoscopy.

OBJECTIVE: In otolaryngology, it is important to minimize the use of opioids for post-operative analgesia given the rise in opioid abuse and mortality due to overdose in the United States. We sought to quantitatively determine the efficacy of non-opiate analgesia in postoperative pain management after microdirect laryngoscopy (MDL). METHODS: This is a single institution prospective study monitoring post-operative pain using a visual analog scale (VAS, 1-10). Patients with a history of vocal fold lesions, paralysis, and stenosis who underwent MDL were surveyed for one month following their procedure (daily for the first week and weekly thereafter). Student's t-test was used to determine whether short (1 week) and long term (1 month) pain was controlled by over-the-counter (OTC) medications. We defined adequate pain control as an average daily VAS score below 4 for the first 4 days and below 1 in the following 3 weeks and hypothesized that patients would report adequate pain control without the use of opioids. RESULTS: Post-operative pain after MDL was generally mild. The average daily VAS score was 2.16 (95% CI [0.0-5.2], P = 0.0014) in the first 4 days post-procedure and 0.28 (95% CI [0.0-1.3], P = 0.0007) in the 3 weeks post-procedure confirming our hypothesis. On average, patients used 3.14 (CI: [0.0-12.8]) pills of acetaminophen and 0.57 (CI: [0.0-4.7]) pills of an NSAID per day in the first week. Only three patients required opioid analgesia, all of whom used opioids in the first 48 h. CONCLUSIONS: OTC analgesics provide sufficient pain control after microdirect laryngoscopy for most patients. Given the potential for substance abuse from opioid medications, this study demonstrates that adequate pain control requires, at most, 48 h of opioid medications. Further study is needed to determine factors that contribute to increased pain after laryngoscopy.

High-Volume Billing and Reimbursement Trends for Endoscopic Swallowing Studies in the Medicare Population.

The aim of this study is to delineate the reimbursement trends in fiberoptic endoscopic evaluation of swallowing with sensory testing (FEESST) and without sensory testing (FEES) in relation to that of speech-language pathology's (SLP) portion of modified barium swallow studies (MBS), as well as to document the types of providers billing for these procedures. We performed descriptive analyses of the volume of FEES/FEESST and MBS, and total reimbursements data obtained from 2013-2018 Medicare Part B National Summary files. We also utilized the 2017 Medicare Provider Utilization and Payment Data to analyze the higher volume providers (> 10 procedures annually) of either FEES and/or FEESST. From 2003 to 2018, there has been an average, annual increase of approximately 318 FEES/FEESST performed within the Medicare fee-for-service population (R = 0.9505 [95% CI 0.860-0.983]; p < 0.001) covered under Part B (which is largely outpatient coverage). Similarly, there was an increase in Medicare-specific FEES/FEESST reimbursement from $302,840 in 2003 to $1.2 million in 2018 (R = 0.9721 [95% CI 0.920-0.990; p < 0.001]). Prior to 2010, FEESST was performed more frequently than FEES (maximum annual difference of 1174), though from 2010 onward, relatively more annual FEES was performed. From 2003-2018, the reimbursement per procedure increased by $16.79 and $35.36 for FEESST and FEES, respectively, and by $32.84 for the SLP portion of the MBS. Among high-volume FEES/FEESST billers, 65.4% were otolaryngologists and 32.3% were independently billing SLPs. From 2003 to 2018, there has been a significant rise in the number of performed and reimbursed FEES/FEESST. From 2014 onward, compared to SLP-involved MBS, there has been a relative increase in performance of FEES/FEESST.

Safety considerations for esophageal dilation by anesthetic type: A systematic review.

OBJECTIVES: Esophageal dilation (ED) may be performed in the office under local anesthesia or in a procedure/operating room under general anesthesia or intravenous (IV) sedation. However, indications for type of anesthesia during these procedures have not been established. The purpose of this review is to assess outcomes of esophageal dilation performed using different types of anesthesia to assess the safety of office-based techniques. METHODS: We conducted a systematic review and meta-analysis comparing the outcomes of anesthesia techniques for ED in adults. Exclusion criteria included reviews, small case series, use of stents, diagnoses with high morbidity, and rare diseases. A comprehensive literature search of the PubMed, CINAHL, and EMBASE databases was performed for articles relating to esophageal dilation. RESULTS: 876 papers were identified of which 164 full text studies were assessed and 25 were included in the analysis using the PRISMA guidelines. Data regarding demographics, dilation technique, and adverse events were extracted. The DerSimonian-Laird random-effect models with inverse-variance weighting were fit to estimate the combined effects. There were no statistically significant differences among mortality, perforation, or bleeding based on anesthetic. CONCLUSIONS: With office-based procedures gaining popularity in laryngology, there is a need to profile their safety. Office-based ED appears to have equivalent safety to general and IV sedation, although further research is necessary to define indications favoring office-based techniques.

Reversible M-M Bonding by Alkaline Earth Metals (Mg, Ca, Sr, Ba) in Graphite Intercalation Compounds.

The alkaline earth metals (M=Mg, Ca, Sr, and Ba) exhibit a +2 oxidation state in nearly all known stable compounds, but MI dimeric complexes with M-M bonding, [M2 (en)2 ]2+ , (en=ethylenediamine) of all these metals can be stabilized within the galleries of donor-type graphite intercalation compounds (GICs). These metals can also form GICs with more conventional metal (II) ion complexes, [M(en)2 ]2+ . Here, the facile interconversion between dimeric-MI and monomeric-MII intercalates upon the addition/removal of en are reported. Thermogravimetry, powder X-ray diffraction, and pair distribution function analysis of total scattering data support the presence of either [M2 (en)2 ]2+ or [M(en)2 ]2+ guests. This phase conversion requires coupling graphene and metal redox centers, with associated reversible M-M bond formation within graphene galleries. This chemistry allows the facile isolation of unusual oxidation states, reveals M0 →M2+ reaction pathways, and present new opportunities in the design of hybrid conversion/intercalation materials for applications such as charge storage.

Reversible Insertion of Mg-Cl Superhalides in Graphite as a Cathode for Aqueous Dual-Ion Batteries.

Oxidative anion insertion into graphite in an aqueous environment represents a significant challenge in the construction of aqueous dual-ion batteries. In dilute aqueous electrolytes, the oxygen evolution reaction (OER) dominates the anodic current before anions can be inserted into the graphite gallery. Herein, we report that the reversible insertion of Mg-Cl superhalides in graphite delivers a record-high reversible capacity of 150 mAh g-1 from an aqueous deep eutectic solvent comprising magnesium chloride and choline chloride. The insertion of Mg-Cl superhalides in graphite does not form staged graphite intercalation compounds; instead, the insertion of Mg-Cl superhalides makes the graphite partially turbostratic.

Graphite Intercalation by Mg Diamine Complexes.

The first structural and compositional details of a low-stage graphite interaction compound (GIC) containing Mg are reported, with the GIC obtained by combining magnesium metal and graphite powder in ethylenediamine (en) at 100 °C under an inert atmosphere. Thermal analyses indicate the bottle-green stage 1 product has a composition of [Mg(en)1.0]C13. X-ray diffraction shows a c-axis expansion of 0.55 nm, indicating the presence of intercalate monolayers with the en cointercalate oriented perpendicular to the encasing graphene layers. Redox titration indicates two electrons are transferred per Mg. A structural model is proposed with dimeric [Mg2(en)2]2+ intercalate species.

Pillared graphite anodes for reversible sodiation.

There has been a major effort recently to develop new rechargeable sodium-ion electrodes. In lithium ion batteries, LiC6 forms from graphite and desolvated Li cations during the first charge. With sodium ions, graphite only shows a significant capacity when Na+ intercalates as a solvated complex, resulting in ternary graphite intercalation compounds (GICs). Although this chemistry has been shown to be highly reversible and to support high rates in small test cells, these GICs can require >250% volume expansion and contraction during cycling. Here we demonstrate the first example of GICs that reversibly sodiate/desodiate without any significant volume change. These pillared GICs are obtained by electrochemical reduction of graphite in an ether/amine co-solvent electrolyte. The initial gallery expansion, 0.36 nm, is less than half of that in diglyme-based systems, and shows a similar capacity. Thermal analyses suggest the pillaring phenomenon arises from stronger co-intercalate interactions in the GIC galleries.

Mg-Ion Battery Electrode: An Organic Solid's Herringbone Structure Squeezed upon Mg-Ion Insertion.

We report that crystalline 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA), an organic solid, is highly amenable to host divalent metal ions, i.e., Mg2+ and Ca2+, in aqueous electrolytes, where the van der Waals structure is intrinsically superior in hosting charge-dense ions. We observe that the divalent nature of Mg2+ causes unique squeezing deformation of the electrode structure, where it contracts and expands in different crystallographic directions when hosting the inserted Mg-ions. This phenomenon is revealed experimentally by ex situ X-ray diffraction and transmission electron microscopy, and is investigated theoretically by first-principles calculations. Interestingly, hosting one Mg2+ ion requires the coordination from three PTCDA molecules in adjacent columns of stacked molecules, which rotates the columns, thus reducing the (011) spacing but increasing the (021) spacing. We demonstrate that a PTCDA Mg-ion electrode delivers a reversible capacity of 125 mA h g-1, which may include a minor contribution of hydronium storage, a good rate capability by retaining 75 mA h g-1 at 500 mA g-1 (or 3.7 C), and a stable cycle life. We also report Ca2+ storage in PTCDA, where a reversible capacity of over 80 mA h g-1 is delivered.

Abrasion and blunt tissue trauma study of a novel flexible robotic system in the porcine model.

OBJECTIVES: The objective of this study was to determine if a flexible robotic system caused increased tissue reaction when accessing the oropharynx and hypopharynx compared to intubation controls in only 2 scenarios: high speed tissue impact and multiple unit insertions and retractions. The data obtained were submitted as part of the entirety of information submitted for FDA approval. METHODS: This study consisted of 5 groups of Yorkshire pigs (2 animals per group). On Day 0, all animals were intubated. For group 1 (control), a second endotracheal tube was advanced to just above the vocal cords. In abrasion groups 2 and 3, the flexible robotic system was advanced against the oropharyngeal and hypopharyngeal tissues, respectively. In blunt trauma groups 4 and 5, the flexible robotic system was advanced at maximum speed (22mm/s) to collide with oropharyngeal and hypopharyngeal tissues, respectively. Pre- and post-procedure endoscopic assessments of tissue reaction were performed daily for 4 days. An independent reviewer graded tissue reaction using a 0-3 point scale. RESULTS: Tissue reaction scores at each observation time point for all test groups were less than or equal to control scores except for one instance of moderate scoring (2 out of 3) on Day 2 for an animal in the blunt trauma group where reaction was likely intubation-related rather than device impact related. Otherwise, all flexible robotic system-treated animal scores were less than 1 by Day 4. CONCLUSIONS: In this limited study, the flexrobotic system afforded surgical access to the oropharynx and hypopharynx without an increased level of abrasion or tissue trauma when compared to intubation alone.

Preparation of Graphite Intercalation Compounds Containing Crown Ethers.

Crown ethers are well established as cointercalates in many layered hosts, but there are no reports of crown ethers incorporated into graphite. Here, we describe the preparation of the first graphite intercalation compounds (GICs) containing crown ethers. These GICs are obtained either by reductive intercalation of an alkali metal-amine complex followed by cointercalate exchange or by the direct reaction of graphite with a crown ether, alkali metal, and an electrocatalyst. Structural and compositional characterization of these new GICs using powder X-ray diffraction, thermal analysis, and GC/MS indicates the formation of well-ordered, stage-1 bilayer galleries.

Web-based computational chemistry education with CHARMMing II: Coarse-grained protein folding.

A lesson utilizing a coarse-grained (CG) Go-like model has been implemented into the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org) to the Chemistry at HARvard Macromolecular Mechanics (CHARMM) molecular simulation package. While widely used to model various biophysical processes, such as protein folding and aggregation, CG models can also serve as an educational tool because they can provide qualitative descriptions of complex biophysical phenomena for a relatively cheap computational cost. As a proof of concept, this lesson demonstrates the construction of a CG model of a small globular protein, its simulation via Langevin dynamics, and the analysis of the resulting data. This lesson makes connections between modern molecular simulation techniques and topics commonly presented in an advanced undergraduate lecture on physical chemistry. It culminates in a straightforward analysis of a short dynamics trajectory of a small fast folding globular protein; we briefly describe the thermodynamic properties that can be calculated from this analysis. The assumptions inherent in the model and the data analysis are laid out in a clear, concise manner, and the techniques used are consistent with those employed by specialists in the field of CG modeling. One of the major tasks in building the Go-like model is determining the relative strength of the nonbonded interactions between coarse-grained sites. New functionality has been added to CHARMMing to facilitate this process. The implementation of these features into CHARMMing helps automate many of the tedious aspects of constructing a CG Go model. The CG model builder and its accompanying lesson should be a valuable tool to chemistry students, teachers, and modelers in the field.

Strong influence of periodic boundary conditions on lateral diffusion in lipid bilayer membranes.

The Saffman-Delbrück hydrodynamic model for lipid-bilayer membranes is modified to account for the periodic boundary conditions commonly imposed in molecular simulations. Predicted lateral diffusion coefficients for membrane-embedded solid bodies are sensitive to box shape and converge slowly to the limit of infinite box size, raising serious doubts for the prospects of using detailed simulations to accurately predict membrane-protein diffusivities and related transport properties. Estimates for the relative error associated with periodic boundary artifacts are 50% and higher for fully atomistic models in currently feasible simulation boxes. MARTINI simulations of LacY membrane protein diffusion and LacY dimer diffusion in DPPC membranes and lipid diffusion in pure DPPC bilayers support the underlying hydrodynamic model.

Determination of biomembrane bending moduli in fully atomistic simulations.

The bilayer bending modulus (Kc) is one of the most important physical constants characterizing lipid membranes, but precisely measuring it is a challenge, both experimentally and computationally. Experimental measurements on chemically identical bilayers often differ depending upon the techniques employed, and robust simulation results have previously been limited to coarse-grained models (at varying levels of resolution). This Communication demonstrates the extraction of Kc from fully atomistic molecular dynamics simulations for three different single-component lipid bilayers (DPPC, DOPC, and DOPE). The results agree quantitatively with experiments that measure thermal shape fluctuations in giant unilamellar vesicles. Lipid tilt, twist, and compression moduli are also reported.

Symptoms and observations: differences in time course during electroconvulsive therapy in geriatric depressed patients.

Electroconvulsive therapy is used for the management of severe and refractory depression across the age spectrum. Treatment is guided by clinical response. However, there may be differences between the time course of improvement in clinical observations and patients' self-report of improvements. We report 4 cases of depression in late life that illustrate this issue. We discuss the potential significance of such differences and the need for research.

Adverse Events Associated With Tracheostomy: A MAUDE Database Analysis.

OBJECTIVE: Tracheotomy is one of the most common procedures. Although tracheostomy complications have been extensively studied, literature related to device complications is scarce. The objective of this study is to describe complications associated with tracheostomies utilizing the Manufacturer and User Facility Device Experience (MAUDE) database. STUDY DESIGN: Retrospective cross-sectional study. SETTING: The US Food and Drug Administration's (FDA) MAUDE database (2015-2020). METHODS: The FDA's MAUDE database was queried for all reports on adverse events related to tracheostomy from January 1, 2015 to December 31, 2020. RESULTS: A total of 3086 adverse events related to open tracheostomy and 52 related to percutaneous tracheostomy were identified. For open tracheostomy, 2872 (93%), were related to device malfunction, and 214 (7%) consisted of patient-related factors. The most frequently reported device-related adverse event was cuff malfunction, with 1834 (59%) reported events, which includes cuff deflation, pilot balloon malfunction, and cuff inflation line malfunction. The most frequently reported patient-related adverse events were tracheostomy tube obstruction with 67 events (2%). For percutaneous tracheostomy, 38 (73%) events were related to device malfunction, and 14 (27%) were related to patient injury. The most frequently reported adverse events were cuff malfunction (29%), safety ridge malfunction (17%), and bleeding (10%). CONCLUSION: The MAUDE database is a useful tool that can be utilized to complement existing literature in identifying common and rare adverse events associated with tracheostomy device-related failures, which are mostly reliant on isolated, published case reports.