Electrical Stimulation of Vocal Fold Adduction Triggered by Laryngeal Electromyography Using a Custom Implant.

PURPOSE: Medialization procedures for unilateral vocal fold (VF) paralysis generally improve voice but do not fully replace dynamic VF adduction. Paralyzed VFs typically experience synkinetic reinnervation, which makes it feasible to elicit movement through electrical stimulation. We tested a novel laryngeal pacing implant capable of providing closed-loop (automatic) stimulation of a VF triggered by electromyography (EMG) potentials from the contralateral VF. METHOD: A custom, battery-powered, microprocessor-based stimulator was tested in eight dogs with bipolar electrodes implanted for recording EMG from the left VF and stimulating adduction of the right VF. A cuff electrode on the left recurrent laryngeal nerve (RLN) stimulated unilateral VF adduction, modeling voluntary control in anesthetized animals. Closed-loop stimulation was tested in both acute and chronic experiments. Synkinetic reinnervation was created in two animals by right RLN transection and suture repair to model unilateral VF paralysis. RESULTS: In all animals, left VF activation through RLN stimulation generated a robust EMG response that rapidly triggered stimulation of contralateral thyroarytenoid and lateral cricoarytenoid muscles, causing nearly simultaneous bilateral adduction. Optimal triggering of VF stimulation from elicited EMG was achieved using independent onset and offset thresholds. Real-time artifact blanking allowed closed-loop stimulation without self-perpetuating feedback, despite the proximity of recording and stimulation electrodes. CONCLUSIONS: Using a custom implant system, we demonstrated real-time closed-loop stimulation of one VF triggered by the activation of the contralateral VF. This approach could potentially restore dynamic glottic closure for reflexive behaviors or phonation in cases of unilateral VF paralysis with synkinetic reinnervation. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24492133.

Minimizing Thermal Damage During Thulium Laser-Assisted Partial Arytenoidectomy: Pulsed Versus Continuous Cutting in an Ex-Vivo Calf Model.

OBJECTIVES: The 2 µm-wavelength thulium laser is an effective cutter during partial arytenoidectomy, but thermal trauma can damage adjacent laryngeal tissue. Pulsing laser energy may reduce trauma when compared to continuous-wave cutting. This study measured temperature changes, thermal trauma, and time to complete partial arytenoidectomy, with and without pulsing, in an ex-vivo calf model. METHODS: Tissue temperature and time to complete a trans-cartilaginous cut were measured during partial arytenoidectomy on ex-vivo calf vocal folds (N = 24) using a thulium laser in continuous-wave (CW, N = 12) and pulsed-wave (PW, N = 12) modes. Energy was 5 W for CW and PW cuts; pulse-widths were 250, 500, and 750 ms. Thermal damage was analyzed histologically by measuring the depth of lactate dehydrogenase (LDH) inactivation perpendicular to the laser-cut edge at the vocal process. Paired t-tests compared CW and PW modes. RESULTS: Change in temperature was lower using CW (6.5°C) compared to PW modes (250 ms = 18°; 500 ms = 16°; 750 = 19°; P < .05). Trans-cartilaginous cuts were completed faster using CW (37 seconds) compared to PW (250 ms = 136 seconds; 500 ms = 61 seconds; 750 = 44 seconds; P < .05), and both modes delivered the same total Joules. The average depth of LDH depletion (thermal damage) was similar for all cuts. CONCLUSIONS: 1. Thulium laser cuts in continuous-mode unexpectedly produced less tissue heating yet created similar thermal damage than pulsed-mode cuts during simulated partial arytenoidectomy. 2. Trans-cartilaginous cuts were completed significantly faster in continuous-mode as compared to pulsed-mode cutting. 3. Pulsing the thulium laser does not minimize thermal damage compared to continuous wave cutting during thulium laser-assisted partial arytenoidectomy.

Surgeon Positioning During Awake Laryngeal Surgery: An Ergonomic Analysis.

OBJECTIVES: While it is acknowledged that otolaryngologists performing microlaryngeal surgery can develop musculoskeletal symptoms due to suboptimal body positioning relative to the patient, flexible laryngoscopy and awake laryngeal surgeries (ALSs) can also pose ergonomic risk. This prospective study measured the effects of posture during ergonomically good and bad positions during laryngoscopy using ergonomic analysis, skin-surface electromyography (EMG), and self-reported pain ratings. STUDY DESIGN: Prospective cohort study. METHODS: Eight participants trained in laryngoscopy assumed four ergonomically distinct standing positions (side/near, side/far, front/near, front/far) at three different heights (neutral-top of patient's head in line with examiner's shoulder, high-6 inches above neutral, and low-6 inches below neutral) in relation to a simulated patient. Participants' postures were analyzed using the validated Rapid Upper Limb Assessment (RULA, 1 [best] to 7 [worst]) tool for the 12 positions. Participants then simulated ALS for 10 minutes in a bad position (low-side-far) and a good position (neutral-front-near) with 12 EMG sensors positioned on the limbs and torso. RESULTS: The position with the worst RULA score was the side/near/high (7.0), and the best was the front/near/neutral (4.5). EMG measurements revealed significant differences between simulated surgery in the bad and good positions, with bad position eliciting an average of 206% greater EMG root-mean-squared magnitude across all sampled muscles compared to the good posture (paired t-test, df = 7, P < .01), consistent with self-reported fatigue/pain when positioned poorly. CONCLUSION: Quantitative and qualitative measurements demonstrate the impact of surgeon posture during simulated laryngoscopy and suggest ergonomically beneficial posture that should facilitate ALSs. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2752-2758, 2021.

Mass drug administration for the acceleration of malaria elimination in a region of Myanmar with artemisinin-resistant falciparum malaria: a cluster-randomised trial.

BACKGROUND: To contain multidrug-resistant Plasmodium falciparum, malaria elimination in the Greater Mekong subregion needs to be accelerated while current antimalarials remain effective. We evaluated the safety, effectiveness, and potential resistance selection of dihydroartemisinin-piperaquine mass drug administration (MDA) in a region with artemisinin resistance in Myanmar. METHODS: We did a cluster-randomised controlled trial in rural community clusters in Kayin (Karen) state in southeast Myanmar. Malaria prevalence was assessed using ultrasensitive quantitative PCR (uPCR) in villages that were operationally suitable for MDA (villages with community willingness, no other malaria control campaigns, and a population of 50-1200). Villages were eligible to participate if the prevalence of malaria (all species) in adults was greater than 30% or P falciparum prevalence was greater than 10% (or both). Contiguous villages were combined into clusters. Eligible clusters were paired based on P falciparum prevalence (estimates within 10%) and proximity. Community health workers provided routine malaria case management and distributed long-lasting insecticidal bed-nets (LLINs) in all clusters. Randomisation of clusters (1:1) to the MDA intervention group or control group was by public coin-flip. Group allocations were not concealed. Three MDA rounds (3 days of supervised dihydroartemisinin-piperaquine [target total dose 7 mg/kg dihydroartemisinin and 55 mg/kg piperaquine] and single low-dose primaquine [target dose 0·25 mg base per kg]) were delivered to intervention clusters. Parasitaemia prevalence was assessed at 3, 5, 10, 15, 21, 27, and 33 months. The primary outcomes were P falciparum prevalence at months 3 and 10. All clusters were included in the primary analysis. Adverse events were monitored from the first MDA dose until 1 month after the final dose, or until resolution of any adverse event occurring during follow-up. This trial is registered with ClinicalTrials.gov, NCT01872702. FINDINGS: Baseline uPCR malaria surveys were done in January, 2015, in 43 villages that were operationally suitable for MDA (2671 individuals). 18 villages met the eligibility criteria. Three villages in close proximity were combined into one cluster because a border between them could not be defined. This gave a total of 16 clusters in eight pairs. In the intervention clusters, MDA was delivered from March 4 to March 17, from March 30 to April 10, and from April 27 to May 10, 2015. The weighted mean absolute difference in P falciparum prevalence in the MDA group relative to the control group was -10·6% (95% CI -15·1 to -6·1; p=0·0008) at month 3 and -4·5% (-10·9 to 1·9; p=0·14) at month 10. At month 3, the weighted P falciparum prevalence was 1·4% (0·6 to 3·6; 12 of 747) in the MDA group and 10·6% (7·0 to 15·6; 56 of 485) in the control group. Corresponding prevalences at month 10 were 3·2% (1·5 to 6·8; 34 of 1013) and 5·8% (2·5 to 12·9; 33 of 515). Adverse events were reported for 151 (3·6%) of 4173 treated individuals. The most common adverse events were dizziness (n=109) and rash or itching (n=20). No treatment-related deaths occurred. INTERPRETATION: In this low-transmission setting, the substantial reduction in P falciparum prevalence resulting from support of community case management was accelerated by MDA. In addition to supporting community health worker case management and LLIN distribution, malaria elimination programmes should consider using MDA to reduce P falciparum prevalence rapidly in foci of higher transmission. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria.

Surface Electromyography-Based Recognition, Synthesis, and Perception of Prosodic Subvocal Speech.

Purpose This study aimed to evaluate a novel communication system designed to translate surface electromyographic (sEMG) signals from articulatory muscles into speech using a personalized, digital voice. The system was evaluated for word recognition, prosodic classification, and listener perception of synthesized speech. Method sEMG signals were recorded from the face and neck as speakers with (n = 4) and without (n = 4) laryngectomy subvocally recited (silently mouthed) a speech corpus comprising 750 phrases (150 phrases with variable phrase-level stress). Corpus tokens were then translated into speech via personalized voice synthesis (n = 8 synthetic voices) and compared against phrases produced by each speaker when using their typical mode of communication (n = 4 natural voices, n = 4 electrolaryngeal [EL] voices). Naïve listeners (n = 12) evaluated synthetic, natural, and EL speech for acceptability and intelligibility in a visual sort-and-rate task, as well as phrasal stress discriminability via a classification mechanism. Results Recorded sEMG signals were processed to translate sEMG muscle activity into lexical content and categorize variations in phrase-level stress, achieving a mean accuracy of 96.3% (SD = 3.10%) and 91.2% (SD = 4.46%), respectively. Synthetic speech was significantly higher in acceptability and intelligibility than EL speech, also leading to greater phrasal stress classification accuracy, whereas natural speech was rated as the most acceptable and intelligible, with the greatest phrasal stress classification accuracy. Conclusion This proof-of-concept study establishes the feasibility of using subvocal sEMG-based alternative communication not only for lexical recognition but also for prosodic communication in healthy individuals, as well as those living with vocal impairments and residual articulatory function. Supplemental Material https://doi.org/10.23641/asha.14558481.

Structure Driven Prediction of Chromatographic Retention Times: Applications to Pharmaceutical Analysis.

Pharmaceutical drug development relies heavily on the use of Reversed-Phase Liquid Chromatography methods. These methods are used to characterize active pharmaceutical ingredients and drug products by separating the main component from related substances such as process related impurities or main component degradation products. The results presented here indicate that retention models based on Quantitative Structure Retention Relationships can be used for de-risking methods used in pharmaceutical analysis and for the identification of optimal conditions for separation of known sample constituents from postulated/hypothetical components. The prediction of retention times for hypothetical components in established methods is highly valuable as these compounds are not usually readily available for analysis. Here we discuss the development and optimization of retention models, selection of the most relevant structural molecular descriptors, regression model building and validation. We also present a practical example applied to chromatographic method development and discuss the accuracy of these models on selection of optimal separation parameters.

Investigating the Impact of Crohn's Disease on the Bioaccessibility of a Lipid-Based Formulation with an In Vitro Dynamic Gastrointestinal Model.

The aim of the study was to investigate the impact of Crohn's disease (CD) on the performance of a lipid-based formulation of ciprofloxacin in a complex gastrointestinal simulator (TIM-1, TNO) and to compare the luminal environment in terms of bile salt and lipid composition in CD and healthy conditions. CD conditions were simulated in the TIM-1 system with a reduced concentration of porcine pancreatin and porcine bile. The bioaccessibility of ciprofloxacin was similar in simulated CD and healthy conditions considering its extent as well as its time course in the jejunum and ileum filtrate. Differences were observed in terms of the luminal concentration of triglycerides, monoglycerides, and fatty acids in the different TIM-1 compartments, indicating a reduction and delay in the lipolysis of formulation excipients in CD. The quantitative analysis of bile salts revealed higher concentrations for healthy conditions (standard TIM-1 fasted-state protocol) in the duodenum and jejunum TIM-1 compartments compared to published data in human intestinal fluids of healthy subjects. The reduced concentrations of bile salts in simulated CD conditions correspond to the levels observed in human intestinal fluids of healthy subjects in the fasted state.A lipidomics approach with ultra performance liquid chromatography (UPLC)/mass spectrometry (MS) has proven to be a time-efficient method to semiquantitatively analyze differences in fatty acid and bile salt levels between healthy and CD conditions. The dynamic luminal environment in CD and healthy conditions after administration of a lipid-based formulation can be simulated using the TIM-1 system. For ciprofloxacin, an altered luminal lipid composition had no impact on its performance indicating a low risk of altered performance in CD patients.

Subcutaneous Ports for Chronic Nerve Cuff and Intramuscular Electrode Stimulation in Animal Models.

OBJECTIVE: Tracking recovery after nerve injury may require many intermittent assessments over long periods, preferably with non- or minimally invasive methods. We developed subcutaneous electrical connection ports (ECPs) for repeated connection to nerve cuff or intramuscular electrodes via transdermal needles and evaluated them during studies of laryngeal reinnervation. STUDY DESIGN: Animal experiment. SETTING: Laboratory. METHODS: ECPs were designed and 3-dimensionally printed for connection to bipolar electrodes with biocompatible polymers. Dual compartments filled with conductive silicone capped with nonconductive silicone were used to make the connections between electrode leads and transdermally inserted needles. Ten dogs (19-29 kg) were implanted with 22 ECPs. In 7 dogs, 11 electrodes were placed on recurrent laryngeal nerves proximal to transection and suture repair to track laryngeal reinnervation. In 6 dogs, 8 spinal accessory nerve cuff electrodes were used to stimulate neck muscle contraction. In 2 dogs, 3 electrodes were implanted in the thyroarytenoid muscle. Stimulation thresholds, electromyography, and videolaryngoscopic imaging were obtained in 156 tests over survival periods up to 32 months. Stimulation data provided information about ECP performance. RESULTS: ECPs added negligible resistance to electrodes (mean ± SD, 2.14 ± 0.9 Ω). Despite some electrode leads breaking distally, ECPs were reliable and well tolerated at implant sites and enabled periodic assessment of nerve and muscle function over the time course of laryngeal reinnervation. Histology showed ECP encapsulation as thin layers of connective tissue and minimal acute inflammation. CONCLUSION: Custom ECPs are easily fabricated and cause little tissue reaction over months to years of subcutaneous implantation, facilitating long-term physiologic studies.

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.

BACKGROUND: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. METHODS: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. FINDINGS: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50). INTERPRETATION: Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. FUNDING: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Aerodynamically driven phonation of individual vocal folds under general anesthesia in canines.

OBJECTIVES/HYPOTHESIS: We previously developed an instrument called the Aerodynamic Vocal Fold Driver (AVFD) for intraoperative magnified assessment of vocal fold (VF) vibration during microlaryngoscopy under general anesthesia. Excised larynx testing showed that the AVFD could provide useful information about the vibratory characteristics of each VF independently. The present investigation expands those findings by testing new iterations of the AVFD during microlaryngoscopy in the canine model. STUDY DESIGN: Animal model. METHODS: The AVFD is a handheld instrument that is positioned to contact the phonatory mucosa of either VF during microlaryngoscopy. Airflow delivered through the AVFD shaft to the subglottis drives the VF into phonation-like vibration, which enables magnified observation of mucosal-wave function with stroboscopy or high-speed video. AVFD-driven phonation was tested intraoperatively (n = 26 VFs) using either the original instrument design or smaller and larger versions three-dimensionally printed from a medical grade polymer. A high-fidelity pressure sensor embedded within the AVFD measured VF contact pressure. Characteristics of individual VF phonation were compared with typical two-fold phonation and compared for VFs scarred by electrocautery (n = 4) versus controls (n = 22). RESULTS: Phonation was successful in all 26 VFs, even when scar prevented conventional bilateral phonation. The 15-mm-wide AVFD fits best within the anteroposterior dimension of the musculo-membranous VF, and VF contact pressure correlated with acoustic output, driving pressures, and visible modes of vibration. CONCLUSIONS: The AVFD can reveal magnified vibratory characteristics of individual VFs during microlaryngoscopy (e.g., without needing patient participation), potentially providing information that is not apparent or available during conventional awake phonation, which might facilitate phonosurgical decision making. LEVEL OF EVIDENCE: NA Laryngoscope, 130: 1980-1988, 2020.

Retrospective Review of Need for Delayed Naloxone or Oxygen in Emergency Department Patients Receiving Naloxone for Heroin Reversal.

BACKGROUND: Emergency departments (EDs) are experiencing an increasing number of heroin overdose visits. Currently, there is no generally agreed upon ED observation period for heroin overdose patients who receive naloxone. OBJECTIVES: We aimed to determine the safety of a 2-h observation period for heroin overdose patients who receive naloxone. METHODS: We performed a chart review of all patients who presented with any opioid-related complaint between 2009 and 2014 to our urban academic trauma center. Subset analysis of patients with isolated heroin overdose who received naloxone was performed, with the intent of excluding patients intoxicated with long-acting/enteral opioids. The primary outcome was the number of patients who required delayed intervention-specifically, additional naloxone or supplemental oxygen. RESULTS: Between 2009 and 2014, we recorded 806 visits to our ED for heroin use after receiving naloxone. Twenty-nine patients (3.6%) received a repeat dose of naloxone, and 17 patients (2%) received oxygen ≥2 h after initial naloxone administration. Our 2-h intervention rate was 4.6% (N = 37). This decreased to 1.9% (N = 15) after 3 h and 0.9% (N = 7) after 4 h. Patients with polysubstance use were more likely to receive repeat naloxone (p < 0.01), but not oxygen (p = 0.10). Preexisting cardiopulmonary conditions did not correlate with a need for supplemental oxygen (p = 0.24) or repeat naloxone (p = 0.30). CONCLUSIONS: A 2-h ED observation period for heroin overdose patients reversed with naloxone resulted in a delayed intervention rate of 5%. Clinicians may consider a 3-h observation period, with extra scrutiny in polysubstance abuse.

Vocal Fold Injection of Absorbable Materials: A Histologic Analysis With Clinical Ramifications.

OBJECTIVES:: Gels composed of carboxymethylcellulose (CMC) and cross-linked hyaluronic acid are commonly used as temporary or resorbable injectable materials for vocal fold medialization. However, there is limited information about tissue injection patterns, soft tissue reaction, degradation, and residence time, particularly for the newer CMC gels. STUDY DESIGN:: Prospective, laboratory. METHODS:: Ten canines underwent paraglottic (deep to the vocal ligament) microlaryngoscopic injection with about 100 µL (0.1 mL) of cross-linked hyaluronic acid (Restylane) in the right vocal fold and about 100 µl (0.1 mL) of CMC gel in the left vocal fold. Two commercial CMC gels of similar formulation (Prolaryn Gel and Renú Gel) were used in 5 animals each. Two subjects were sacrificed for histologic analysis at 3, 13, 29, 42, and 55 days. RESULTS:: Histology showed that injected Restylane formed cohesive ovoid-shaped aggregated implants with minimal dispersion, inflammation, or cellular invasion in all subjects. Approximately 86% of Restylane injected remained at 8 weeks, as estimated from postmortem, high-resolution magnetic resonance imaging scans. In contrast, histology showed that both CMC gels dispersed widely through fascial planes during and after injection within and outside the thyroarytenoid muscle fascicles. There was a robust macrophage and histiocyte phagocytic response, with moderate to severe inflammation noted around residual CMC gel at early time points, and at 6 to 8 weeks, very little free gel was observed. CONCLUSIONS:: None of the studied materials induced a clinical inflammatory reaction on laryngoscopy such that they would be considered problematic or dangerous. Restylane demonstrated superior injection localization, tissue compatibility, and residence time. Both CMC gels did not localize well in the paraglottic region, and there was a robust inflammatory response, with clearance by macrophages and short residence time. These results suggest that CMC gels may have a more limited application than previously thought for vocal fold medialization in patients in whom the injection is being used to achieve voice enhancement while awaiting reinnervation. Level of Evidence: NA.

Glottic Stenosis: An Anatomic Analysis and New Treatment With a Self-Retaining Interarytenoid Spring.

INTRODUCTION:: Endotracheal (ET) intubation is a common cause of acquired glottic stenosis. Severe cases often require an irreversible arytenoidectomy/cordectomy, which typically results in poor voice quality. Adult human cadaver larynges were studied to gain insights about ET tube-induced posterior glottic injuries, hoping to create a less invasive remedy. STUDY DESIGN:: Human cadaver investigation and case reports. METHODS:: Microlaryngeal assessments were done on 10 human cadaver larynges (5 men, 5 women) with and without ET tubes. After supracricoid soft tissue resection, measurements were obtained, including the distance between the outer diameter of the ET tube and the medial aspect of the cricoarytenoid joint facet. Additionally, measurements of the circumferential arc of differently sized ET tubes were made alongside both cricoarytenoid joint capsules. This information was used to design a silastic stent that would function as a self-retaining interarytenoid spring to treat posterior glottic stenosis in 5 patients. Four of 5 patients included in the clinical study were tracheotomy dependent, primarily because of glottic stenosis. The human surgical technique is described in detail. RESULTS:: The shortest distance between the outer diameter of the ET tube to the medial cricoid facet averaged 5.02 mm in men and 3.62 mm in women. On the basis of the diameter of the intralaryngeal component of the initially round stent, and the position of the cricoarytenoid joint facets, the interarytenoid spring would have a subtended arc between 110° and 175°. These data helped fashion parameters for modifying a conventional T-tube to form a new self-retaining silastic interarytenoid spring. The first 5 human cases have been successful, allowing effective tracheotomy tube decannulation and excellent voice quality. CONCLUSIONS:: The anatomic investigation herein provided key insights into ET tube-induced glottic stenosis and facilitated a new straightforward procedure to surgically improve the airway yet preserve excellent vocal function in patients with acquired glottic stenosis. Level of Evidence: NA.

Development of a Closed-Loop Stimulator for Laryngeal Reanimation, Part 1: Devices.

OBJECTIVE:: The goal of this work was to create implantable stimulator systems that could be used in animal experiments on laryngeal paralysis, including "closed-loop" stimulation of impaired muscles triggered by electromyographic (EMG) potentials from healthy muscles. STUDY DESIGN:: Iterative device design and testing. METHODS:: A series of microcontroller-based implantable devices were built that incorporated increasingly sophisticated features for stimulation, EMG recording, and communication across the skin. Specific engineering challenges included minimizing power consumption, achieving charge-balanced and relatively high stimulation capacity, implementing noninvasive communication across the skin, providing real-time processing of EMG signals, and mitigating effects of shock artifacts. Bench testing was used to verify performance. RESULTS:: Two prototypes are described in detail. Each system is based on an "implant" and an external "communication adapter" that interfaces both with the implant and with external computers for adjustments and monitoring. The first version described is inductively powered and referred to as the "inductive laryngeal stimulator." It uses inductive coupling for both power and communication and performs EMG processing in the communication adapter module. The second version, a "battery-powered laryngeal stimulator," consists of an autonomous battery-powered implant with onboard EMG processing and artifact control; it communicates by infrared light with the external communication adapter for setup and monitoring. CONCLUSIONS:: The devices met design and performance specifications and have proved useful in the animal experiments that are described in Part 2 of this series. Detailed descriptions of the circuits and their firmware are made available in the Appendix. Level of Evidence: NA.

Development of a Closed-Loop Stimulator for Laryngeal Reanimation: Part 2. Device Testing in the Canine Model of Laryngeal Paralysis.

OBJECTIVE:: Laryngeal paralysis of central or peripheral origin can potentially be treated using functional electrical stimulation (FES) of laryngeal muscles. Experiments in canines (dogs) were performed using implant prototypes capable of closed-loop FES to refine engineering designs and specifications, test surgical approaches for implantation, and better understand the in vivo effects of laryngeal muscle stimulation on short- and long-term glottic function. STUDY DESIGN:: Prospective, laboratory. METHODS:: We designed and tested a series of microprocessor-based implantable devices that can stimulate glottic opening or closing based on input from physiological control signals (real-time processing of electromyographic [EMG] signals). After acute device testing experiments, 2 dogs were implanted for 8 and 24 months, with periodic testing of closed-loop laryngeal muscle stimulation triggered from EMG signals. In total, 5 dogs were tested for the effects of laryngeal muscle stimulation on vocal fold (VF) posturing in larynges with nerve supplies that were intact (7 VFs), synkinetically reinnervated (2 VFs), or chronically denervated (1 VF). In 3 cases, the stimulation was combined with airflow-driven phonation to study the consequent modulation of phonatory parameters. RESULTS:: Initial device prototypes used inductive coupling for power and communication, while later iterations used battery power and infrared light communication (detailed descriptions are provided in the Part 1 companion paper). Two animals were successfully implanted with the inductively powered units, which operated until removed at 8 months in 1 animal or for more than 16 months in the second animal. Surgically, the encapsulated implants were well tolerated, and procedures for placing, attaching, and connecting the devices were developed. To simulate EMG control signals in anesthetized animals, we created 2 types of nerve/muscle signal sources. In one approach, a neck muscle had a cuff electrode placed on its motor nerve that was connected to transdermal electrical connection ports for periodic testing. In the second approach, the recurrent laryngeal nerve on one side of the larynx was stimulated to generate a VF EMG signal, which was then used to trigger FES of the paralyzed contralateral side (eg, restoring VF movement symmetry). Implant testing identified effective stimulation parameters and closed-loop stimulation artifact rejection techniques for FES of both healthy and paralyzed VFs. Stimulation levels effective for VF adduction did not cause signs of discomfort during awake testing. CONCLUSION:: Our inductive and battery-powered prototypes performed effectively during in vivo testing, and the 2 units that were implanted for long-term evaluation held up well. As a proof of concept, we demonstrated that elicited neck strap muscle or laryngeal EMG potentials could be used as a control signal for closed-loop stimulation of laryngeal adduction and vocal pitch modulation, depending on electrode positioning, and that VFs were stimulable in the presence of synkinetic reinnervation or chronic denervation.

Retention characteristics of some antibiotic and anti-retroviral compounds in hydrophilic interaction chromatography using isocratic elution, and gradient elution with repeatable partial equilibration.

The separation of some zwitterionic, basic and neutral antibiotic and antiretroviral compounds was studied using hydrophilic interaction chromatography (HILIC) on bare silica, bonded amide and urea superficially porous phases. The differences in the selectivity and retentivity of these stationary phases were evaluated for compounds with widely different physicochemical properties (logD -3.43 to 2.41 at wwpH 3.0). The mobile phase was acetonitrile-ammonium formate buffered at low wwpH. Compounds containing quinolone and serine groups showed poor peak shapes on all columns, attributed to metal-oxide interactions with system metals. Peak shapes were improved by addition of citrate buffers. Gradient elution, particularly with regard to column equilibration, was also studied due to the large differences in retention factors observed under isocratic conditions. Full equilibration in HILIC was slow for both ionogenic and neutral solutes, requiring as much as ∼40 column volumes. However, highly repeatable partial equilibration, suitable for gradient elution, was achieved in only a few minutes. Pronounced selectivity differences in the separations were shown dependent on the partial equilibration time.

Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an open-label, randomised, controlled trial.

BACKGROUND: In southeast Asia, antibiotic prescription in febrile patients attending primary care is common, and a probable contributor to the high burden of antimicrobial resistance. The objective of this trial was to explore whether C-reactive protein (CRP) testing at point of care could rationalise antibiotic prescription in primary care, comparing two proposed thresholds to classify CRP concentrations as low or high to guide antibiotic treatment. METHODS: We did a multicentre, open-label, randomised, controlled trial in participants aged at least 1 year with a documented fever or a chief complaint of fever (regardless of previous antibiotic intake and comorbidities other than malignancies) recruited from six public primary care units in Thailand and three primary care clinics and one outpatient department in Myanmar. Individuals were randomly assigned using a computer-based randomisation system at a ratio of 1:1:1 to either the control group or one of two CRP testing groups, which used thresholds of 20 mg/L (group A) or 40 mg/L CRP (group B) to guide antibiotic prescription. Health-care providers were masked to allocation between the two intervention groups but not to the control group. The primary outcome was the prescription of any antibiotic from day 0 to day 5 and the proportion of patients who were prescribed an antibiotic when CRP concentrations were above and below the 20 mg/L or 40 mg/L thresholds. The primary outcome was analysed in the intention-to-treat and per-protocol populations. The trial is registered with ClinicalTrials.gov, number NCT02758821, and is now completed. FINDINGS: Between June 8, 2016, and Aug 25, 2017, we recruited 2410 patients, of whom 803 patients were randomly assigned to CRP group A, 800 to CRP group B, and 807 to the control group. 598 patients in CRP group A, 593 in CRP group B, and 767 in the control group had follow-up data for both day 5 and day 14 and had been prescribed antibiotics (or not) in accordance with test results (per-protocol population). During the trial, 318 (39%) of 807 patients in the control group were prescribed an antibiotic by day 5, compared with 290 (36%) of 803 patients in CRP group A and 275 (34%) of 800 in CRP group B. The adjusted odds ratio (aOR) of 0·80 (95% CI 0·65-0·98) and risk difference of -5·0 percentage points (95% CI -9·7 to -0·3) between group B and the control group were significant, although lower than anticipated, whereas the reduction in prescribing in group A compared with the control group was not significant (aOR 0·86 [0·70-1·06]; risk difference -3·3 percentage points [-8·0 to 1·4]). Patients with high CRP concentrations in both intervention groups were more likely to be prescribed an antibiotic than in the control group (CRP ≥20 mg/L: group A vs control group, p<0·0001; CRP ≥40 mg/L: group B vs control group, p<0·0001), and those with low CRP concentrations were more likely to have an antibiotic withheld (CRP <20 mg/L: group A vs control group, p<0·0001; CRP <40 mg/L: group B vs control group, p<0·0001). 24 serious adverse events were recorded, consisting of 23 hospital admissions and one death, which occurred in CRP group A. Only one serious adverse event was thought to be possibly related to the study (a hospital admission in CRP group A). INTERPRETATION: In febrile patients attending primary care, testing for CRP at point of care with a threshold of 40 mg/L resulted in a modest but significant reduction in antibiotic prescribing, with patients with high CRP being more likely to be prescribed an antibiotic, and no evidence of a difference in clinical outcomes. This study extends the evidence base from lower-income settings supporting the use of CRP tests to rationalise antibiotic use in primary care patients with an acute febrile illness. A key limitation of this study is the individual rather than cluster randomised study design which might have resulted in contamination between the study groups, reducing the effect size of the intervention. FUNDING: Wellcome Trust Institutional Strategic Support Fund grant (105605/Z/14/Z) and Foundation for Innovative New Diagnostics (FIND) funding from the Australian Government.

Development of sEMG sensors and algorithms for silent speech recognition.

OBJECTIVE: Speech is among the most natural forms of human communication, thereby offering an attractive modality for human-machine interaction through automatic speech recognition (ASR). However, the limitations of ASR-including degradation in the presence of ambient noise, limited privacy and poor accessibility for those with significant speech disorders-have motivated the need for alternative non-acoustic modalities of subvocal or silent speech recognition (SSR). APPROACH: We have developed a new system of face- and neck-worn sensors and signal processing algorithms that are capable of recognizing silently mouthed words and phrases entirely from the surface electromyographic (sEMG) signals recorded from muscles of the face and neck that are involved in the production of speech. The algorithms were strategically developed by evolving speech recognition models: first for recognizing isolated words by extracting speech-related features from sEMG signals, then for recognizing sequences of words from patterns of sEMG signals using grammar models, and finally for recognizing a vocabulary of previously untrained words using phoneme-based models. The final recognition algorithms were integrated with specially designed multi-point, miniaturized sensors that can be arranged in flexible geometries to record high-fidelity sEMG signal measurements from small articulator muscles of the face and neck. MAIN RESULTS: We tested the system of sensors and algorithms during a series of subvocal speech experiments involving more than 1200 phrases generated from a 2200-word vocabulary and achieved an 8.9%-word error rate (91.1% recognition rate), far surpassing previous attempts in the field. SIGNIFICANCE: These results demonstrate the viability of our system as an alternative modality of communication for a multitude of applications including: persons with speech impairments following a laryngectomy; military personnel requiring hands-free covert communication; or the consumer in need of privacy while speaking on a mobile phone in public.

Factors Affecting Voice Therapy Completion in Singers.

OBJECTIVE: The purpose of this study was to determine (a) which factors may affect singers' completing voice therapy, and (b) develop predictive profiles to capture those singers at risk for dropping out of voice therapy. STUDY DESIGN: A case-control study was conducted comparing singers who completed voice therapy to singers who dropped out of voice therapy. METHODS: Six factors, including age, gender, diagnosis, length of time between laryngology referral and commencement of therapy, type of singer, and referral source were investigated in relation to voice therapy completion using the medical records of 409 singers in the Massachusetts General Hospital Voice Center database. RESULTS: Referral source and type of singer were demonstrated to be the most robust predictor of singers' completion of therapy. CONCLUSIONS: Forty-seven percent of singers who were referred to voice therapy completed their course of treatment. Sixty percent of singers who dropped out of voice therapy were reliably identified based on what types of music they sing (type of singer) and who referred them for laryngology evaluation (referral source), aiding in early identification of those singers who may need additional support to reach their therapy goals. Identifying specific characteristics of singers completing or dropping out of voice therapy may allow medical professionals to better serve the specialized needs of singers who use their voices professionally and recreationally.

Integrated Analytical and Statistical Two-Dimensional Spectroscopy Strategy for Metabolite Identification: Application to Dietary Biomarkers.

A major purpose of exploratory metabolic profiling is for the identification of molecular species that are statistically associated with specific biological or medical outcomes; unfortunately, the structure elucidation process of unknowns is often a major bottleneck in this process. We present here new holistic strategies that combine different statistical spectroscopic and analytical techniques to improve and simplify the process of metabolite identification. We exemplify these strategies using study data collected as part of a dietary intervention to improve health and which elicits a relatively subtle suite of changes from complex molecular profiles. We identify three new dietary biomarkers related to the consumption of peas (N-methyl nicotinic acid), apples (rhamnitol), and onions (N-acetyl-S-(1Z)-propenyl-cysteine-sulfoxide) that can be used to enhance dietary assessment and assess adherence to diet. As part of the strategy, we introduce a new probabilistic statistical spectroscopy tool, RED-STORM (Resolution EnhanceD SubseT Optimization by Reference Matching), that uses 2D J-resolved 1H NMR spectra for enhanced information recovery using the Bayesian paradigm to extract a subset of spectra with similar spectral signatures to a reference. RED-STORM provided new information for subsequent experiments (e.g., 2D-NMR spectroscopy, solid-phase extraction, liquid chromatography prefaced mass spectrometry) used to ultimately identify an unknown compound. In summary, we illustrate the benefit of acquiring J-resolved experiments alongside conventional 1D 1H NMR as part of routine metabolic profiling in large data sets and show that application of complementary statistical and analytical techniques for the identification of unknown metabolites can be used to save valuable time and resources.