Tools for telehealth: A correlational analysis of app-based hearing testing.

Objective: Telehealth evaluation of hearing is rapidly evolving; however, the lack of consensus on the most accurate remote hearing test application has made hearing evaluation complicated. The objective of this study was to evaluate the correlation between the pure tone audiometry results obtained from app-based hearing testing programs and a traditional audiogram. Methods: A prospective within-subject and between-subject study design was used to correlate audiogram results between app-based hearing programs and a traditional audiogram. All participants completed a traditional audiogram, 1 commercial app-based test (ShoeBox), 2 consumer app-based tests (EarTrumpet and Hearing Test and Ear Age Test [HTEAT]), and a Hearing Handicap Inventory screening version (HHI-S). Testing was conducted in an acoustically controlled environment (traditional) and a quiet room (app-based hearing tests). Results: A total of 39 participants were enrolled in the study (21 with normal hearing and 18 with hearing loss). In patients with normal hearing, only the commercial hearing testing app (ShoeBox) had a statistically significant pure tone average correlation in both ears with traditional audiometry (Right ear-r = 0.7, p = .005, Left ear-r = 0.66, p = .001). Both consumer and commercial apps had statistically significant correlations with both ears in patients with hearing loss (ranging from r = 0.62 to r = 0.9). Regarding accuracy within 10 dB of the pure tone average of the traditional audiogram of all tested ears, the commercial app-based test was accurate in 94% for all ears (normal and hearing loss), while consumer app-based tests were between 14% and 36% for all ears. The HHI-S indicated no hearing impairment in 95% of those with normal hearing and indicated hearing impairment in 89% of those with hearing loss. Conclusion: Commercial-grade app-based pure tone audiometry demonstrates overall strong correlation and accuracy with traditional audiometry. The HHI-S assessment remains a valid and useful tool to predict normal hearing and hearing impairment. Level of Evidence: 2.

Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein 1 (FABP1) and FABP1 Binding Alters Drug Metabolism.

Liver fatty acid binding protein 1 (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data are available for human FABP1 (hFABP1). FABP1 has a large binding pocket, and up to two fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses, native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1, and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (Kd,1 = 0.2 µM) and low (Kd,2 > 10 µM) affinity binding sites. Nine drugs bound to hFABP1 with equilibrium dissociation constant (Kd) values ranging from 1 to 20 µM. None of the tested drugs completely displaced DAUDA from hFABP1, and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-hFABP1-diclofenac ternary complex was verified with native MS. Docking predicted diclofenac binding in the portal region of FABP1 with DAUDA in the binding cavity. The catalytic rate constant of diclofenac hydroxylation by CYP2C9 was decreased by ∼50% (P < 0.01) in the presence of FABP1. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 binding in the liver will alter drug metabolism and clearance. SIGNIFICANCE STATEMENT: Many commonly prescribed drugs bind fatty acid binding protein 1 (FABP1), forming ternary complexes with FABP1 and the fluorescent fatty acid 11-(dansylamino)undecanoic acid. These findings suggest that drugs will bind to apo-FABP1 and fatty acid-bound FABP1 in the human liver. The high expression of FABP1 in the liver, together with drug binding to FABP1, may alter drug disposition processes in vivo.

Clinical Practice Guideline: Age-Related Hearing Loss Executive Summary.

OBJECTIVE: Age-related hearing loss (ARHL) is a prevalent but often underdiagnosed and undertreated condition among individuals aged 50 and above. It is associated with various sociodemographic factors and health risks including dementia, depression, cardiovascular disease, and falls. While the causes of ARHL and its downstream effects are well defined, there is a lack of priority placed by clinicians as well as guidance regarding the identification, education, and management of this condition. PURPOSE: The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the identification and management of ARHL. These opportunities are communicated through clear actionable statements with an explanation of the support in the literature, the evaluation of the quality of the evidence, and recommendations on implementation. The target patients for the guideline are any individuals aged 50 years and older. The target audience is all clinicians in all care settings. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the Guideline Development Group (GDG). It is not intended to be a comprehensive, general guide regarding the management of ARHL. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS: The GDG made strong recommendations for the following key action statements (KASs): (KAS 4) If screening suggests hearing loss, clinicians should obtain or refer to a clinician who can obtain an audiogram. (KAS 8) Clinicians should offer, or refer to a clinician who can offer, appropriately fit amplification to patients with ARHL. (KAS 9) Clinicians should refer patients for an evaluation of cochlear implantation candidacy when patients have appropriately fit amplification and persistent hearing difficulty with poor speech understanding. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should screen patients aged 50 years and older for hearing loss at the time of a health care encounter. (KAS 2) If screening suggests hearing loss, clinicians should examine the ear canal and tympanic membrane with otoscopy or refer to a clinician who can examine the ears for cerumen impaction, infection, or other abnormalities. (KAS 3) If screening suggests hearing loss, clinicians should identify sociodemographic factors and patient preferences that influence access to and utilization of hearing health care. (KAS 5) Clinicians should evaluate and treat or refer to a clinician who can evaluate and treat patients with significant asymmetric hearing loss, conductive or mixed hearing loss, or poor word recognition on diagnostic testing. (KAS 6) Clinicians should educate and counsel patients with hearing loss and their family/care partner(s) about the impact of hearing loss on their communication, safety, function, cognition, and quality of life. (KAS 7) Clinicians should counsel patients with hearing loss on communication strategies and assistive listening devices. (KAS 10) For patients with hearing loss, clinicians should assess if communication goals have been met and if there has been improvement in hearing-related quality of life at a subsequent health care encounter or within 1 year. The GDG offered the following KAS as an option: (KAS 11) Clinicians should assess hearing at least every 3 years in patients with known hearing loss or with reported concern for changes in hearing.

Clinical Practice Guideline: Age-Related Hearing Loss.

OBJECTIVE: Age-related hearing loss (ARHL) is a prevalent but often underdiagnosed and undertreated condition among individuals aged 50 and above. It is associated with various sociodemographic factors and health risks including dementia, depression, cardiovascular disease, and falls. While the causes of ARHL and its downstream effects are well defined, there is a lack of priority placed by clinicians as well as guidance regarding the identification, education, and management of this condition. PURPOSE: The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the identification and management of ARHL. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. The target patients for the guideline are any individuals aged 50 years and older. The target audience is all clinicians in all care settings. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of ARHL. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. ACTION STATEMENTS: The GDG made strong recommendations for the following key action statements (KASs): (KAS 4) If screening suggests hearing loss, clinicians should obtain or refer to a clinician who can obtain an audiogram. (KAS 8) Clinicians should offer, or refer to a clinician who can offer, appropriately fit amplification to patients with ARHL. (KAS 9) Clinicians should refer patients for an evaluation of cochlear implantation candidacy when patients have appropriately fit amplification and persistent hearing difficulty with poor speech understanding. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should screen patients aged 50 years and older for hearing loss at the time of a health care encounter. (KAS 2) If screening suggests hearing loss, clinicians should examine the ear canal and tympanic membrane with otoscopy or refer to a clinician who can examine the ears for cerumen impaction, infection, or other abnormalities. (KAS 3) If screening suggests hearing loss, clinicians should identify sociodemographic factors and patient preferences that influence access to and utilization of hearing health care. (KAS 5) Clinicians should evaluate and treat or refer to a clinician who can evaluate and treat patients with significant asymmetric hearing loss, conductive or mixed hearing loss, or poor word recognition on diagnostic testing. (KAS 6) Clinicians should educate and counsel patients with hearing loss and their family/care partner(s) about the impact of hearing loss on their communication, safety, function, cognition, and quality of life (QOL). (KAS 7) Clinicians should counsel patients with hearing loss on communication strategies and assistive listening devices. (KAS 10) For patients with hearing loss, clinicians should assess if communication goals have been met and if there has been improvement in hearing-related QOL at a subsequent health care encounter or within 1 year. The GDG offered the following KAS as an option: (KAS 11) Clinicians should assess hearing at least every 3 years in patients with known hearing loss or with reported concern for changes in hearing.

Metastability of Protein Solution Structures in the Absence of a Solvent: Rugged Energy Landscape and Glass-like Behavior.

Native ion mobility/mass spectrometry is well-poised to structurally screen proteomes but characterizes protein structures in the absence of a solvent. This raises long-standing unanswered questions about the biological significance of protein structures identified through ion mobility/mass spectrometry. Using newly developed computational and experimental ion mobility/ion mobility/mass spectrometry methods, we investigate the unfolding of the protein ubiquitin in a solvent-free environment. Our data suggest that the folded, solvent-free ubiquitin observed by ion mobility/mass spectrometry exists in a largely native fold with an intact ß-grasp motif and α-helix. The ensemble of folded, solvent-free ubiquitin ions can be partitioned into kinetically stable subpopulations that appear to correspond to the structural heterogeneity of ubiquitin in solution. Time-resolved ion mobility/ion mobility/mass spectrometry measurements show that folded, solvent-free ubiquitin exhibits a strongly stretched-exponential time dependence, which simulations trace to a rugged energy landscape with kinetic traps. Unfolding rate constants are estimated to be approximately 800 to 20,000 times smaller than in the presence of water, effectively quenching the unfolding process on the time scale of typical ion mobility/mass spectrometry measurements. Our proposed unfolding pathway of solvent-free ubiquitin shares substantial characteristics with that established for the presence of solvent, including a polarized transition state with significant native content in the N-terminal ß-hairpin and α-helix. Our experimental and computational data suggest that (1) the energy landscape governing the motions of folded, solvent-free proteins is rugged in analogy to that of glassy systems; (2) large-scale protein motions may at least partially be determined by the amino acid sequence of a polypeptide chain; and (3) solvent facilitates, rather than controls, protein motions.

Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism.

Liver fatty acid binding protein (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data is available for human FABP1 (hFABP1). FABP1 has a large binding pocket and multiple fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1 and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (Kd,1=0.2 µM) and low affinity (Kd,2 >10 µM) binding sites. Nine drugs bound to hFABP1 with Kd values ranging from 1 to 20 µM. None of the tested drugs completely displaced DAUDA from hFABP1 and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-diclofenac-hFABP1 ternary complex was verified with native MS. Docking placed diclofenac in the portal region of FABP1 with DAUDA in the binding cavity. Presence of hFABP1 decreased the kcat and Km,u of diclofenac with CYP2C9 by ~50% suggesting that hFABP1 binding in the liver will alter drug metabolism and clearance. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 interacts with CYP2C9.

Effects of charge on protein ion structure: Lessons from cation-to-anion, proton-transfer reactions.

Collision cross-section values, which can be determined using ion mobility experiments, are sensitive to the structures of protein ions and useful for applications to structural biology and biophysics. Protein ions with different charge states can exhibit very different collision cross-section values, but a comprehensive understanding of this relationship remains elusive. Here, we review cation-to-anion, proton-transfer reactions (CAPTR), a method for generating a series of charge-reduced protein cations by reacting quadrupole-selected cations with even-electron monoanions. The resulting CAPTR products are analyzed using a combination of ion mobility, mass spectrometry, and collisional activation. We compare CAPTR to other charge-manipulation strategies and review the results of various CAPTR-based experiments, exploring their contribution to a deeper understanding of the relationship between protein ion structure and charge state.

Quantitatively Differentiating Antibodies Using Charge-State Manipulation, Collisional Activation, and Ion Mobility-Mass Spectrometry.

Antibody-based therapeutics continue to expand both in the number of products and in their use in patients. These heterogeneous proteins challenge traditional drug characterization strategies, but ion mobility (IM) and mass spectrometry (MS) approaches have eased the challenge of higher-order structural characterization. Energy-dependent IM-MS, e.g., collision-induced unfolding (CIU), has been demonstrated to be sensitive to subtle differences in structure. In this study, we combine a charge-reduction method, cation-to-anion proton-transfer reactions (CAPTR), with energy-dependent IM-MS and varied solution conditions to probe their combined effects on the gas-phase structures of IgG1κ and IgG4κ from human myeloma. CAPTR paired with MS-only analysis improves the confidence of charge-state assignments and the resolution of the interfering protein species. Collision cross-section distributions were determined for each of the charge-reduced products. Similarity scoring was used to quantitatively compare distributions determined from matched experiments analyzing samples of the two antibodies. Relative to workflows using energy-dependent IM-MS without charge-state manipulation, combining CAPTR and energy-dependent IM-MS enhanced the differentiation of these antibodies. Combined, these results indicate that CAPTR can benefit many aspects of antibody characterization and differentiation.

Elucidating the impact of bacterial lipases, human serum albumin, and FASII inhibition on the utilization of exogenous fatty acids by Staphylococcus aureus.

IMPORTANCE: Incorporation of host-derived exogenous fatty acids (eFAs), particularly unsaturated fatty acids (UFAs), by Staphylococcus aureus could affect the bacterial membrane fluidity and susceptibility to antimicrobials. In this work, we found that glycerol ester hydrolase (Geh) is the primary lipase hydrolyzing cholesteryl esters and, to a lesser extent, triglycerides and that human serum albumin (HSA) could serve as a buffer of eFAs, where low levels of HSA facilitate the utilization of eFAs but high levels of HSA inhibit it. The fact that the type II fatty acid synthesis (FASII) inhibitor, AFN-1252, leads to an increase in UFA content even in the absence of eFA suggests that membrane property modulation is part of its mechanism of action. Thus, Geh and/or the FASII system look to be promising targets to enhance S. aureus killing in a host environment by restricting eFA utilization or modulating membrane properties, respectively.

Factors Associated with No-Show Rates in a Pediatric Audiology Clinic.

OBJECTIVE: To evaluate factors associated with no-show rates in a pediatric audiology clinic. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PARTICIPANTS: All pediatric patients younger than 18 years whose parents/guardians scheduled an appointment at a tertiary Audiology Clinic between June 1, 2015, and July 1, 2017. MAIN OUTCOME MEASURES: Data included whether the patient came to their appointment, patient age, sex, race, insurance type, appointment type, location, season of appointment, and day of the week of the appointment. RESULTS: Of the 7,784 pediatric appointments scheduled with audiology, the overall no-show rate was 24.3% (n = 1893). Lower age was significantly associated with no-shows ( p = 0.0003). Black/African American children were more likely to no-show compared with White/Caucasians ( p = 0.0001). Compared with self-pay/military/other insurance, those with Medicaid were more likely to no-show ( p = 0.0001). The highest rate of no-shows occurred during summer (27%). On multivariate analysis, younger age, Black/African American race, and Medicaid insurance were associated with increased no-show rates. CONCLUSION: A variety of factors influence no-show rates in a pediatric audiology setting. No-shows can affect treatment quality and affect overall hearing outcomes. Further investigation is necessary to assess barriers to appointment adherence and to develop interventions to improve adherence and care.

Sample pH Can Drift during Native Mass Spectrometry Experiments: Results from Ratiometric Fluorescence Imaging.

The ability of nanoelectrospray ionization (nanoESI) to generate a continuous flow of charged droplets relies on the electrolytic nature of the process. This electrochemistry can lead to the accumulation of redox products in the sample solution. This consequence can have significant implications for native mass spectrometry (MS), which aims to probe the structures and interactions of biomolecules in solution. Here, ratiometric fluorescence imaging and a pH-sensitive, fluorescent probe are used to quantify changes in solution pH during nanoESI under conditions relevant to native MS. Results show that the extent and rate of change in sample pH depends on several experimental parameters. There is a strong correlation between the extent and rate of change in solution pH and the magnitude of both the nanoESI current and electrolyte concentration. Smaller changes in solution pH are observed during experiments when a negative potential is applied than for those when a positive potential is applied. Finally, we make specific recommendations for designing native MS experiments that control for these effects.

Elucidating the Impact of Bacterial Lipases, Human Serum Albumin, and FASII Inhibition on the Utilization of Exogenous Fatty Acids by Staphylococcus aureus.

Staphylococcus aureus only synthesizes straight-chain or branched-chain saturated fatty acids (SCFAs or BCFAs) via the type II fatty acid synthesis (FASII) pathway, but as a highly adaptive pathogen, S. aureus can also utilize host-derived exogenous fatty acids (eFAs), including SCFAs and unsaturated fatty acids (UFAs). S. aureus secretes three lipases, Geh, sal1, and SAUSA300_0641, which could perform the function of releasing fatty acids from host lipids. Once released, the FAs are phosphorylated by the fatty acid kinase, FakA, and incorporated into the bacterial lipids. In this study, we determined the substrate specificity of S. aureus secreted lipases, the effect of human serum albumin (HSA) on eFA incorporation, and the effect of FASII inhibitor, AFN-1252, on eFA incorporation using comprehensive lipidomics. When grown with major donors of fatty acids, cholesteryl esters (CEs) and triglycerides (TGs), Geh was found to be the primary lipase responsible for hydrolyzing CEs, but other lipases could compensate for the function of Geh in hydrolyzing TGs. Lipidomics showed that eFAs were incorporated into all major S. aureus lipid classes and that fatty acid-containing HSA can serve as a source of eFAs. Furthermore, S. aureus grown with UFAs displayed decreased membrane fluidity and increased production of reactive oxygen species (ROS). Exposure to AFN-1252 enhanced UFAs in the bacterial membrane, even without a source of eFAs, indicating a FASII pathway modification. Thus, the incorporation of eFAs alters the S. aureus lipidome, membrane fluidity, and ROS formation, which could affect host-pathogen interactions and susceptibility to membrane-targeting antimicrobials.

Perioperative factors influencing hospitalization duration for pediatric neck abscesses.

PURPOSE: Pediatric neck abscesses are a common pathology seen in an ambulatory setting. Although some pediatric neck abscesses are managed medically with antibiotics, surgical intervention is often required. Given the often non-emergent presentation of many abscesses, a variety of logistical and perioperative factors may delay time to care and subsequently prolong hospital stay. The objective of this study was to examine factors that influence the overall time to surgery (TTS) and hospital length of stay (LOS) in a pediatric population with neck abscesses who ultimately require surgical drainage. MATERIALS AND METHODS: 161 pediatric patients who underwent incision and drainage of a neck abscess over a ten-year period at a tertiary referral children's center were reviewed. Demographic information, radiographic studies, and surgical information were extracted from patient charts. Descriptive statistics, Mann-Whitney U tests, and multivariate analyses were performed. RESULTS: The most common subcategory location was deep neck abscesses (33.1 %). Computed tomography (CT) was the most common pre-operative imaging modality (54.1 %) followed by ultrasound (US) (49.1 %) and magnetic resonance imaging (2.6 %). US and a combination of multiple preoperative imaging modalities were associated with increased LOS and TTS. Repeat surgery was associated with increased LOS. Pre-admission antibiotic use was associated with increased LOS and TTS. Younger patients were more likely to have a longer LOS. CONCLUSIONS: A variety of factors can influence TTS, LOS, and time from surgery to discharge including patient age, abscess location, a non-optimized utilization of imaging modalities, the utilization of pre-admission antibiotics, and the need for repeat operations.

Are the Gas-Phase Structures of Molecular Elephants Enduring or Ephemeral? Results from Time-Dependent, Tandem Ion Mobility.

The structural stability of biomolecules in the gas phase remains an important topic in mass spectrometry applications for structural biology. Here, we evaluate the kinetic stability of native-like protein ions using time-dependent, tandem ion mobility (IM). In these tandem IM experiments, ions of interest are mobility-selected after a first dimension of IM and trapped for up to ∼14 s. Time-dependent, collision cross section distributions are then determined from separations in a second dimension of IM. In these experiments, monomeric protein ions exhibited structural changes specific to both protein and charge state, whereas large protein complexes did not undergo resolvable structural changes on the timescales of these experiments. We also performed energy-dependent experiments, i.e., collision-induced unfolding, as a comparison for time-dependent experiments to understand the extent of unfolding. Collision cross section values observed in energy-dependent experiments using high collision energies were significantly larger than those observed in time-dependent experiments, indicating that the structures observed in time-dependent experiments remain kinetically trapped and retain some memory of their solution-phase structure. Although structural evolution should be considered for highly charged, monomeric protein ions, these experiments demonstrate that higher-mass protein ions can have remarkable kinetic stability in the gas phase.

Risk factors for developing subglottic and tracheal stenosis from the medical intensive care unit.

Objective: Endotracheal intubation is a common procedure in the medical intensive care unit (MICU), but it carries risk of complications including, but not limited to, subglottic stenosis (SGS) and tracheal stenosis (TS). Current literature suggests identifiable risk factors for the development of airway complications. This study is a comprehensive evaluation of potential risk factors in patients who developed SGS and TS following endotracheal intubation in our MICU. Methods: Patients intubated in our MICU were identified from 2013 to 2019. Diagnoses of SGS or TS within 1 year of MICU admission were identified. Data extracted included age, sex, body measurements, comorbidities, bronchoscopies, endotracheal tube size, tracheostomy, social history, and medications. Patients with prior diagnosis of airway complication, tracheostomy, or head and neck cancer were excluded. Univariate and multivariate logistic regressions were performed. Results: A total of 136 patients with TS or SGS were identified out of a sample of 6603 patients intubated in the MICU. Cases were matched to controls who did not develop airway stenosis based on identical Charlson Comorbidity Index scores. Eighty six controls were identified with a complete record of endotracheal/tracheostomy tube size, airway procedures, sociodemographic data, and medical diagnosis. Regression analysis showed that SGS or TS were associated with tracheostomy, bronchoscopy, chronic obstructive pulmonary disease, current tobacco use, gastroesophageal reflux disease, systemic lupus erythematosus, pneumonia, bronchitis, and numerous medication classes. Conclusion: Various conditions, procedures, and medications are associated with an increased risk of developing SGS or TS. Level of evidence: 4.

A Flexible, Modular Platform for Multidimensional Ion Mobility of Native-like Ions.

Native ion mobility (IM) mass spectrometry (MS) is used to probe the size, shape, and assembly of biomolecular complexes. IM-IM-MS can increase the amount of information available in structural studies by isolating subpopulations of structures for further analysis. Previously, IM-IM-MS has been implemented using the Structures for Lossless Ion Manipulations (SLIM) architecture to probe the structural stability of gas-phase protein ions. Here, a new multidimensional IM instrument constructed from SLIM devices is characterized using multiple operational modes. In this new design, modular devices are used to perform all ion manipulations, including initial accumulation, injection, separation, selection, and trapping. Using single-dimension IM, collision cross section (Ω) values are determined for a set of native-like ions. These Ω values are within 3% of those reported previously based on measurements using RF-confining drift cells. Tandem IM experiments are performed on a sample of ubiquitin ions that contains both compact and partially unfolded structures, demonstrating that this platform can isolate subpopulations of structures. Finally, additional modes of analysis, including multiplexed IM and inverse IM, are demonstrated using this platform. The ability of this platform to quickly switch between different modes of IM analysis makes it a highly flexible tool for studying protein structures and dynamics.

Global Effects of the Developmental Regulator BldB in Streptomyces venezuelae.

In Streptomyces, the Bld (Bald) regulators control formation of the reproductive aerial hyphae. The functions of some of these regulators have been well characterized, but BldB has remained enigmatic. In addition to the bldB gene itself, Streptomyces venezuelae has 10 paralogs of bldB that sit next to paralogs of whiJ and abaA. Transcriptome sequencing (RNA-seq) revealed that loss of BldB function causes the dramatic transcriptional upregulation of the abaA paralogs and a novel inhibitor of sporulation, iosA, and that cooverexpression of just two of these genes, iosA and abaA6, was sufficient to recapitulate the bldB mutant phenotype. Further RNA-seq analysis showed that the transcription factor WhiJ9 is required for the activation of iosA seen in the bldB mutant, and biochemical studies showed that WhiJ9 mediates the activation of iosA expression by binding to direct repeats in the iosA-whiJ9 intergenic region. BldB and BldB9 hetero-oligomerize, providing a potential link between BldB and the iosA-whiJ9-bldB9 locus. This work greatly expands our overall understanding of the global effects of the BldB developmental regulator. IMPORTANCE To reproduce and disperse, the filamentous bacterium Streptomyces develops specialized reproductive structures called aerial hyphae. The formation of these structures is controlled by the bld (bald) genes, many of which encode transcription factors whose functions have been characterized. An exception is BldB, a protein whose biochemical function is unknown. In this study, we gain insight into the global effects of BldB function by examining the genome-wide transcriptional effects of deleting bldB. We identify a small set of genes that are dramatically upregulated in the absence of BldB. We show that their overexpression causes the bldB phenotype and characterize a transcription factor that mediates the upregulation of one of these target genes. Our results provide new insight into how BldB influences Streptomyces development.

The Role of Telemedicine for Evaluation and Management of Dizzy Patients: A Systematic Review.

OBJECTIVES: To conduct a scoping systematic review of the literature on the use of telemedicine to evaluate, diagnose, and manage patients with dizziness. DATA SOURCES: Web of Science, SCOPUS, and MEDLINE PubMed databases. STUDY SELECTION: The inclusion criteria included the following: pertaining to telemedicine and the evaluation, diagnosis, treatment, or management of dizziness. Exclusion criteria included the following: single-case studies, meta-analyses, and literature and systematic reviews. DATA EXTRACTION: Outcomes recorded for each article included the following: study type, patient population, telemedicine format, dizziness characteristics, level of evidence, and quality assessment. DATA SYNTHESIS: The search returned 15,408 articles, and a team of four screened the articles for inclusion criteria status. A total of 9 articles met the inclusion criteria and were included for review. Of the nine articles, four were randomized clinical trials, three were prospective cohort studies, and two were qualitative studies. The telemedicine format was synchronous in three studies and asynchronous in six studies. Two of the studies involved acute dizziness only, four involved chronic dizziness only, one involved both acute and chronic dizziness, and two did not specify dizziness type. Six of the studies included the diagnosis of dizziness, two involved the evaluation of dizziness, and three involved treatment/management. Some of the reported benefits of telemedicine for dizziness patients included cost savings, convenience, high patient satisfaction, and improvement in dizziness symptoms. Limitations included access to telemedicine technology, Internet connectivity, and dizziness symptoms interfering with the telemedicine application. CONCLUSIONS: Few studies investigate the evaluation, diagnosis, or management of dizziness using telemedicine. The lack of protocols and standards of care for telemedicine evaluation of dizzy patients creates some challenges in care delivery; however, these reviewed studies provide examples of the breadth of care that has been provided remotely.

Enhancing the Depth of Analyses with Next-Generation Ion Mobility Experiments.

Recent developments in ion mobility (IM) technology have expanded the capability to separate and characterize gas-phase ions of biomolecules, especially when paired with mass spectrometry. This next generation of IM technology has been ushered in by creative innovation focused on both instrument architectures and how electric fields are applied. In this review, we focus on the application of high-resolution and multidimensional IM to biomolecular analyses, encompassing the fields of glycomics, lipidomics, peptidomics, and proteomics. We highlight selected research that demonstrates the application of the new IM toolkit to challenging biomolecular systems. Through our review of recently published literature, we outline the current strengths of respective technologies and perspectives for future applications.