Delivering transcutaneous auricular neurostimulation (tAN) to improve symptoms associated with opioid withdrawal: results from a prospective clinical trial.

BACKGROUND: As pharmacological treatments are the primary option for opioid use disorder, neuromodulation has recently demonstrated efficacy in managing opioid withdrawal syndrome (OWS). This study investigated the safety and effectiveness of transcutaneous auricular neurostimulation (tAN) for managing OWS. METHODS: This prospective inpatient trial included a 30-minute randomized, sham-controlled, double-blind period followed by a 5-day open-label period. Adults with physical dependence on opioids were randomized to receive active or sham tAN following abrupt opioid discontinuation. The Clinical Opiate Withdrawal Scale (COWS) was used to determine withdrawal level, and participants were required to have a baseline COWS score ≥ 13 before enrollment. The double-blind period of the study occurred during the first 30-minutes to assess the acute effects of tAN therapy compared to a sham control. Group 1 received active tAN during both the 30-minute double-blind period and the 5-day open-label period. Group 2 received passive sham tAN (no stimulation) during the double-blind period, followed by active tAN during the 5-day open-label period. The primary outcome was change in COWS from baseline to 60-minutes of active tAN (pooled across groups, accounting for 30-minute delay). Secondary outcomes included difference in change in COWS scores between groups after 30-minutes of active or sham tAN, change in COWS scores after 120-minutes of active tAN, and change in COWS scores on Days 2-5. Non-opioid comfort medications were administered during the trial. RESULTS: Across all thirty-one participants, the mean (SD) COWS scores relative to baseline were reduced by 7.0 (4.7) points after 60-minutes of active tAN across both groups (p < 0.0001; Cohen's d = 2.0), demonstrating a significant and clinically meaningful reduction of 45.9%. After 30-minutes of active tAN (Group 1) or sham tAN (Group 2), the active tAN group demonstrated a significantly greater COWS score reduction than the sham tAN group (41.7% vs. 24.1%; p = 0.036). Participants across both groups achieved an average COWS reduction up to 74.7% on Days 2-5. CONCLUSION: Results demonstrate tAN is a safe and effective non-opioid approach for reducing symptoms of OWS. This study supported an FDA clearance. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04075214 , Identifier: NCT04075214, Release Date: August 28, 2019.

Enhancing Parathyroid Gland Visualization Using a Near Infrared Fluorescence-Based Overlay Imaging System.

BACKGROUND: Misidentifying parathyroid glands (PGs) during thyroidectomies or parathyroidectomies could significantly increase postoperative morbidity. Imaging systems based on near infrared autofluorescence (NIRAF) detection can localize PGs with high accuracy. These devices, however, depict NIRAF images on remote display monitors, where images lack spatial context and comparability with actual surgical field of view. In this study, we designed an overlay tissue imaging system (OTIS) that detects tissue NIRAF and back-projects the collected signal as a visible image directly onto the surgical field of view instead of a display monitor, and tested its ability for enhancing parathyroid visualization. STUDY DESIGN: The OTIS was first calibrated with a fluorescent ink grid and initially tested with parathyroid, thyroid, and lymph node tissues ex vivo. For in vivo measurements, the surgeon's opinion on tissue of interest was first ascertained. After the surgeon looked away, the OTIS back-projected visible green light directly onto the tissue of interest, only if the device detected relatively high NIRAF as observed in PGs. System accuracy was determined by correlating NIRAF projection with surgeon's visual confirmation for in situ PGs or histopathology report for excised PGs. RESULTS: The OTIS yielded 100% accuracy when tested ex vivo with parathyroid, thyroid, and lymph node specimens. Subsequently, the device was evaluated in 30 patients who underwent thyroidectomy and/or parathyroidectomy. Ninety-seven percent of exposed tissue of interest was visualized correctly as PGs by the OTIS, without requiring display monitors or contrast agents. CONCLUSIONS: Although OTIS holds novel potential for enhancing label-free parathyroid visualization directly within the surgical field of view, additional device optimization is required for eventual clinical use.

Innovative surgical guidance for label-free real-time parathyroid identification.

BACKGROUND: Difficulty in identifying the parathyroid gland during neck operations can lead to accidental parathyroid gland excisions and postsurgical hypocalcemia. A clinical prototype called as PTeye was developed to guide parathyroid gland identification using a fiber-optic probe that detects near-infrared autofluorescence from parathyroid glands as operating room lights remain on. An Overlay Tissue Imaging System was designed concurrently to detect near-infrared autofluorescence and project visible light precisely onto parathyroid gland location. METHODS: The PTeye and the Overlay Tissue Imaging System were tested in 20 and 15 patients, respectively, and a modified near-infrared imaging system was investigated in 6 patients. All 41 patients underwent thyroidectomy or parathyroidectomy. System accuracy was ascertained with surgeon's visual confirmation for in situ parathyroid glands and histology for excised parathyroid glands. RESULTS: There was no observable difference between near-infrared autofluorescence of healthy and diseased parathyroid glands. The PTeye identified 98% of the parathyroid gland, whereas the near-infrared imaging system and the Overlay Tissue Imaging System identified 100% and 97% of the parathyroid glands, respectively. CONCLUSION: The PTeye can guide in real-time parathyroid gland identification even with ambient operating room lights. The near-infrared imaging system performs parathyroid gland imaging with high sensitivity, whereas the Overlay Tissue Imaging System enhances parathyroid gland visualization directly within the surgical field without requiring display monitors. These label-free technologies can be valuable adjuncts for identifying parathyroid glands intraoperatively.

Developing a Clinical Prototype to Guide Surgeons for Intraoperative Label-Free Identification of Parathyroid Glands in Real Time.

BACKGROUND: Patients undergoing thyroidectomy may have inadvertent damage or removal of the parathyroid gland(s) due to difficulty in real-time parathyroid identification. Near-infrared autofluorescence (NIRAF) has been demonstrated as a label-free modality for intraoperative parathyroid identification with high accuracy. This study presents the translation of that approach into a user-friendly clinical prototype for rapid intraoperative guidance in parathyroid identification. METHODS: A laboratory (lab)-built spectroscopy system that measures NIRAF in tissue was evaluated for identifying parathyroid glands in vivo across 162 patients undergoing thyroidectomy and/or parathyroidectomy. Based on these results, a clinical prototype called PTeye was designed with a user-friendly interface and subsequently investigated in 35 patients. The performance of the lab-built system and the clinical prototype were concurrently compared side by side by a single user with 20 patients in each group. The influence of (i) intrapatient and interpatient variability of NIRAF in thyroid and parathyroid glands and (ii) thyroid and parathyroid pathology on intraoperative parathyroid identification were investigated. The effect of blood on NIRAF intensity of parathyroid and thyroid was tested ex vivo with the PTeye system to assess if a hemorrhagic surgical field would affect parathyroid identification. Accuracy of both systems were determined by correlating the acquired data with either visual confirmation by a surgeon for unexcised parathyroid glands or histology reports for excised parathyroid glands. RESULTS: The overall accuracy of the lab-built system in guiding parathyroid identification was 92.5%, while the PTeye system achieved an accuracy of 96.1%. Unlike the lab-built system, the PTeye could guide parathyroid identification even as the operating room lights remained on and required only 25% of the laser power used by the lab-built setup. Parathyroid glands had elevated NIRAF intensity compared to thyroid and other neck tissues, regardless of thyroid or parathyroid pathology. Blood did not seem to affect tissue NIRAF measurements obtained with both systems. CONCLUSION: In this study, the clinical prototype PTeye demonstrated high accuracy for label-free intraoperative parathyroid identification. The intuitive interface of the PTeye that can guide in identifying parathyroid tissue in the presence of ambient room lights suggests that it is a reliable and easy-to-use tool for surgical personnel.

Development of a modular fluorescence overlay tissue imaging system for wide-field intraoperative surgical guidance.

Fluorescence imaging is a well-established optical modality that has been used to localize and track fluorophores in vivo and has demonstrated great potential for surgical guidance. Despite the variety of fluorophores currently being researched, many existing intraoperative fluorescence imaging systems are specifically designed for a limited number of applications. We present a modular wide-field fluorescence overlay tissue imaging system for intraoperative surgical guidance that is comprised of commercially available standardized components. Its modular layout allows for the accommodation of a broad range of fluorophores, fields of view (FOV), and spatial resolutions while maintaining an integrated portable design for intraoperative use. Measurements are automatic and feature a real-time projection overlay technique that intuitively displays fluorescence maps directly onto a [Formula: see text] FOV from a working distance of 35 cm. At a 20-ms exposure time, [Formula: see text] samples of indocyanine green could be measured with high signal-to-noise ratio and was later tested in an in vivo mouse model before finally being demonstrated for intraoperative autofluorescence imaging of human soft tissue sarcoma margins. The system's modular design and ability to enable naked-eye visualization of wide-field fluorescence allow for the flexibility to adapt to numerous clinical applications and can potentially extend the adoption of fluorescence imaging for intraoperative use.

Epidemiology and mapping of serious and fatal road traffic injuries in Guyana: results from a cross-sectional study.

OBJECTIVE: To describe the epidemiology of Guyana's road traffic injuries and perform the first geocoding of road traffic injuries in this setting. METHODS: This was a registry-based retrospective cross-sectional study investigating collisions resulting in serious and fatal injuries. Police reports from two police divisions were used to identify victim, second party (ie, non-victim) and collision characteristics of all serious and fatal collisions between January 2012 and June 2015. Collisions with available location data were geocoded using Geographic Information Systems. Distributions of characteristics were compared for urban and rural areas. Multivariable logistic regression was used to assess variables associated with fatal collisions. RESULTS: The study included 751 collisions, resulting in 1002 seriously or fatally injured victims. Fatally injured victims tended to be older, male and either pedestrians or cyclists. Fatal collisions tended to take place in rural areas, occur on weekends and involve speeding. Fifty-three per cent of fatalities occurred due to non-motorised road users being struck by motorised road users, and the most common fatal collision type was between pedestrians and motor vehicles (35%). The distribution of collisions was similar for urban (43.8%) and rural (56.2%) areas. Fatal collisions were more likely to occur in rural settings. CONCLUSIONS: Road traffic injuries pose a considerable public health burden in Guyana. These results suggest a pattern of high mortality in rural collisions and a disproportionate burden of injuries on vulnerable road users. The spatial distribution of collisions should be considered in order to target interventions and improve road traffic safety.

Establishing the clinical utility of autofluorescence spectroscopy for parathyroid detection.

BACKGROUND: The inability of surgeons to identify parathyroid glands accurately during cervical endocrine surgery hinders patients from achieving postoperative normocalcemia. An intrinsic, near-infrared fluorescence method was developed for real-time parathyroid identification with high accuracy. This study assesses the clinical utility of this approach. METHODS: Autofluorescence measurements were obtained from 137 patients (264 parathyroid glands) undergoing parathyroidectomy and/or thyroidectomy. Measurements were correlated to disease state, calcium levels, parathyroid hormone, vitamin D levels, age, sex, ethnicity, and body mass index. Statistical analysis identified which factors affect parathyroid detection. RESULTS: High parathyroid fluorescence was detected consistently and showed wide variability across patients. Near-infrared fluorescence was used to identify 256 of 264 (97%) of glands correctly. The technique showed high accuracy over a wide variety of disease states, although patients with secondary hyperparathyroidism demonstrated confounding results. Analysis revealed body mass index (P < .01), disease state (P < .01), vitamin D (P < .05), and calcium levels (P < .05) account greatly for variability in signal intensity. Age, sex, parathyroid hormone, and ethnicity had no effect. CONCLUSION: This intrinsic fluorescence-based intraoperative technique can detect nearly all parathyroid glands accurately in real time. Its discrimination capacity is largely unlimited by patient variables, but several factors affect signal intensity. These results demonstrate potential clinical utility of optical guidance for parathyroid detection.

Label-free intraoperative parathyroid localization with near-infrared autofluorescence imaging.

CONTEXT: The inability to accurately localize the parathyroid glands during parathyroidectomy and thyroidectomy procedures can prevent patients from achieving postoperative normocalcemia. There is a critical need for an improved intraoperative method for real-time parathyroid identification. OBJECTIVE: The objective of the study was to test the accuracy of a real-time, label-free technique that uses near-infrared (NIR) autofluorescence imaging to localize the parathyroid. SETTING: The study was conducted at the Vanderbilt University endocrine surgery center. SUBJECTS AND METHODS: Patients undergoing parathyroidectomy and/or thyroidectomy were included in this study. To validate the intrinsic fluorescence signal in parathyroid, point measurements from 110 patients were collected using NIR fluorescence spectroscopy. Fluorescence imaging was performed on 6 patients. Imaging contrast is based on a previously unreported intrinsic NIR fluorophore in the parathyroid gland. The accuracy of fluorescence imaging was analyzed in comparison with visual assessment and histological findings. MAIN OUTCOME MEASURE: The detection rate of parathyroid glands was measured. RESULTS: The parathyroid glands in 100% of patients measured with fluorescence imaging were successfully detected in real time. Fluorescence images consistently showed 2.4 to 8.5 times higher emission intensity from the parathyroid than surrounding tissue. Histological validation confirmed that the high intrinsic fluorescence signal in the parathyroid gland can be used to localize the parathyroid gland regardless of disease state. CONCLUSION: NIR fluorescence imaging represents a highly sensitive, real-time, label-free tool for parathyroid localization during surgery. The elegance and effectiveness of NIR autofluorescence imaging of the parathyroid gland makes it highly attractive for clinical application in endocrine surgery.

Chronic electrical stimulation with a suprachoroidal retinal prosthesis: a preclinical safety and efficacy study.

PURPOSE: To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. METHODS: Seven normally-sighted feline subjects were implanted for 96-143 days with a suprachoroidal electrode array and six were chronically stimulated for 70-105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. RESULTS: All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11-15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. CONCLUSIONS: Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents.

A novel optical approach to intraoperative detection of parathyroid glands.

BACKGROUND: Inadvertent removal of parathyroid glands is a challenge in endocrine operations. There is a critical need for a diagnostic tool that provides sensitive, real-time parathyroid detection during procedures. We have developed an intraoperative technique using near-infrared (NIR) fluorescence for in vivo, real-time detection of the parathyroid regardless of its pathologic state. METHODS: NIR fluorescence was measured intraoperatively from 45 patients undergoing parathyroidectomy and thyroidectomy. Spectra were measured from the parathyroid and surrounding neck tissues during the operation with the use of a portable, probe-based fluorescence system at 785-nm excitation. Accuracy was evaluated by comparison with histology or visual recognition by the surgeon. RESULTS: NIR fluorescence detected the parathyroid in 100% of patients. Parathyroid fluorescence was stronger (1.2-18 times) than that of the thyroid with peak fluorescence at 822 nm. Surrounding tissues showed no auto-fluorescence. Disease state did not affect the ability to discriminate parathyroid glands but may account for signal variability. CONCLUSION: NIR fluorescence spectroscopy can detect intraoperatively the parathyroid regardless of tissue pathology. The signal may be caused by calcium-sensing receptors present in the parathyroid. The signal strength and consistency indicates the simplicity and effectiveness of this method. Its implementation may limit operative time, decrease costs, and improve operative success rates.