Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin.

Systemic diseases of liver origin (SDLO) are complex diseases in multiple organ systems, such as cardiovascular, musculoskeletal, endocrine, renal, respiratory, and sensory organ systems, caused by irregular liver metabolism and production of functional factors. Examples of such diseases discussed in this article include primary hyperoxaluria, familial hypercholesterolemia, acute hepatic porphyria, hereditary transthyretin amyloidosis, hemophilia, atherosclerotic cardiovascular diseases, α-1 antitrypsin deficiency-associated liver disease, and complement-mediated diseases. Nucleic acid therapeutics use nucleic acids and related compounds as therapeutic agents to alter gene expression for therapeutic purposes. The two most promising, fastest-growing classes of nucleic acid therapeutics are antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). For each listed SDLO disease, this article discusses epidemiology, symptoms, genetic causes, current treatment options, and advantages and disadvantages of nucleic acid therapeutics by either ASO or siRNA drugs approved or under development. Furthermore, challenges and future perspectives on adverse drug reactions and toxicity of ASO and siRNA drugs for the treatment of SDLO diseases are also discussed. In summary, this review article will highlight the clinical advantages of nucleic acid therapeutics in targeting the liver for the treatment of SDLO diseases. SIGNIFICANCE STATEMENT: Systemic diseases of liver origin (SDLO) contain rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO. This article aims to provide the most updated information on targeting the liver with antisense oligonucleotides and small interfering RNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of SDLO, which currently have no or limited options for treatment.

Network-based multi-task learning models for biomarker selection and cancer outcome prediction.

MOTIVATION: Detecting cancer gene expression and transcriptome changes with mRNA-sequencing or array-based data are important for understanding the molecular mechanisms underlying carcinogenesis and cellular events during cancer progression. In previous studies, the differentially expressed genes were detected across patients in one cancer type. These studies ignored the role of mRNA expression changes in driving tumorigenic mechanisms that are either universal or specific in different tumor types. To address the problem, we introduce two network-based multi-task learning frameworks, NetML and NetSML, to discover common differentially expressed genes shared across different cancer types as well as differentially expressed genes specific to each cancer type. The proposed frameworks consider the common latent gene co-expression modules and gene-sample biclusters underlying the multiple cancer datasets to learn the knowledge crossing different tumor types. RESULTS: Large-scale experiments on simulations and real cancer high-throughput datasets validate that the proposed network-based multi-task learning frameworks perform better sample classification compared with the models without the knowledge sharing across different cancer types. The common and cancer-specific molecular signatures detected by multi-task learning frameworks on The Cancer Genome Atlas ovarian, breast and prostate cancer datasets are correlated with the known marker genes and enriched in cancer-relevant Kyoto Encyclopedia of Genes and Genome pathways and gene ontology terms. AVAILABILITY AND IMPLEMENTATION: Source code is available at: https://github.com/compbiolabucf/NetML. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

First-to-second antibiotic delay and hospital mortality among emergency department patients with suspected sepsis.

OBJECTIVE: To evaluate whether delay between the first and second antibiotic administered for suspected sepsis is associated with hospital mortality. DESIGN: Retrospective cohort. SETTING: Twelve hospitals in Southeastern United States from 2014 to 2017. PATIENTS: 25,717 adults with suspected sepsis presenting to 12 Emergency Departments who received at least two antibiotics within 12 h. MEASUREMENTS AND MAIN RESULTS: The primary exposure was first-to-second antibiotic delay >1 h. We used generalized linear mixed models to model the association between first-to-second antibiotic delay and hospital death in the overall cohort, and in subgroups of patients with and without septic shock. Overall, 13,852 (54%) patients had first-to-second antibiotic delay >1 h and 1666 (7%) died. Adjusting for other risk factors, first-to-second antibiotic delay was associated with increased risk of hospital death in the subgroup of patients with septic shock (OR 1.34; 95% CI: 1.05-1.70), but not among patients without shock (OR 0.99; 95% CI: 0.88-1.12) or in the overall cohort (OR 1.08; 95% CI: 0.97-1.20). CONCLUSIONS: First-to-second antibiotic delay of greater than one hour was associated with an increased risk of hospital death among patients meeting criteria for septic shock but not all patients with suspected sepsis. Tracking and improving first-to-second antibiotic delays may be considered in septic shock.

Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial.

PURPOSE: Injection of pharmacotherapy into the suprachoroidal space, between the sclera and choroid, is an alternative delivery technique developed with the rationale of providing higher drug concentrations to posterior ocular structures compared with other intraocular and periocular injection procedures. This study was conducted to evaluate the safety and efficacy of suprachoroidally injected triamcinolone acetonide formulation (CLS-TA), a suspension of triamcinolone acetonide, in improving vision among patients with noninfectious uveitis complicated by macular edema (ME). DESIGN: Phase 3 masked, randomized trial. PARTICIPANTS: One hundred sixty patients with ME secondary to noninfectious uveitis. Patients were required to have a best-corrected visual acuity (BCVA) of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/800) and 70 or fewer ETDRS letters read (Snellen equivalent, 20/40) in the study eye. METHODS: Patients were randomized 3:2 to suprachoroidally injected CLS-TA or sham treatment, with administrations at day 0 and week 12. MAIN OUTCOME MEASURES: The primary end point was improvement from baseline of 15 or more ETDRS letters in BCVA at week 24. The secondary end point was reduction from baseline in central subfield thickness (CST) at week 24. RESULTS: In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA versus 16% in the control arm (P < 0.001), meeting the primary end point. Mean reductions in CST from baseline were 153 µm versus 18 µm (P < 0.001). No serious adverse events (AEs) related to treatment were reported. Corticosteroid-associated AEs of elevated intraocular pressure occurred in 11.5% and 15.6% of the CLS-TA and control groups, respectively. Cataract AE rates were comparable (7.3% and 6.3%, respectively). CONCLUSIONS: Patients in the CLS-TA study arm experienced clinically significant improvement in vision relative to the sham procedure, demonstrating the efficacy of suprachoroidal injection of CLS-TA for the treatment of ME in a vision-threatening disorder.

Trends in utilization and perioperative outcomes in live donor nephrectomies: a multi-surgical discipline analysis.

OBJECTIVE: We aim to analyze the trends in donor nephrectomy (DN) across three surgical disciplines-urology, general surgery, and transplant surgery, specifically to analyze the surgical techniques and perioperative outcomes. MATERIALS AND METHODS: We reviewed all live DN reported in the Statewide Planning and Research Cooperative System database of New York State (NYS) from 1995 to 2015. Surgeons were grouped in their respective disciplines using their state license number and the American Medical Association masterfile. We analyzed the volume of DN performed by each group along with how the surgical approach is, such as open, laparoscopic or robotic. Perioperative outcomes assessed were length of stay (LOS), 30-day and 90-day readmission rates, and complication rates RESULTS: A total of 6803 DN were performed with urologists, transplant surgeons and general surgeons accounting for 42%, 29%, and 29% of them, respectively. Urologists performed a higher case volume with a mean surgical volume of 17.4 ± 6.5 per year (p < 0.0001). During the study period, case volumes for urologists and transplant surgeons trended upward, while those for general surgeons trended downward. Urologists also utilized a minimally invasive surgery (MIS) such as laparoscopy or robotic approach in a higher percentage of their cases (p < 0.0001). Regarding perioperative outcomes, general surgeons had a higher mean LOS (p < 0.0001), while transplant surgeons had higher rates of 30-day and 90-day readmission rates (p < 0.0001). There were no statistically significant differences in complication rates following DN among the groups. CONCLUSION: Urologists remain vital members of the renal transplantation team as they perform a majority of DN in NYS and are increasingly achieving them via an MIS approach when compared to their general and transplant surgery counterparts. Perioperative outcomes are similar amongst all disciplines; however, general surgeons have higher mean LOS, while transplant surgeons have higher readmission rates.

Safety and Efficacy of CLS-TA by Anatomic Location of Inflammation: Results from the Phase 3 PEACHTREE Clinical Trial.

PURPOSE: To explore the efficacy of CLS-TA, a proprietary suprachoroidal injectable suspension of triamcinolone acetonide, in noninfectious uveitis (NIU) with macular edema (ME), categorized by anatomic subtype. METHODS: Patients diagnosed with ME associated with NIU of any etiology and anatomic subtype were eligible for the phase 3 PEACHTREE trial of CLS-TA. Post-hoc analyses were performed, stratified by discrete anatomic subtype of uveitis (anterior, intermediate, posterior, and panuveitis.). RESULTS: Across all anatomic subtypes at 24 weeks, patients receiving CLS-TA at baseline and week 12 demonstrated mean increases in BCVA ranging from +12.1 to +15.9 letters, mean central subfield thickness (CST) improvement ranging from -120.1 µm to -189.0 µm, and IOP changes ranging from +0.5 to +3.1 mmHg. Overall, reports of adverse events were similar among subtypes. CONCLUSIONS: Irrespective of the uveitic anatomic subtype among patients treated for ME associated with NIU, a clinical benefit in participants treated with CLS-TA was demonstrated, with a comparable safety profile.

Pad count is a poor measure of the severity of urinary incontinence.

PURPOSE: We analyzed the correlation between pad use, as determined by objective pad count, and the severity of urinary incontinence, as measured by pad weight. MATERIALS AND METHODS: We performed a retrospective study of consecutive incontinent patients who wore pads on a daily basis and were instructed to complete a 24-hour pad test. They were told to use the usual pads, change them as usual and place each in a separate plastic bag the day before the scheduled appointment. All pads were weighed and total urine loss was calculated by subtracting dry pad weight from wet pad weight, assuming that a 1 gm weight increase was equivalent to 1 ml of urine loss. The number of pads was correlated to pad weight using the Spearman rank correlation coefficient due to the nonparametric nature of the data. RESULTS: The 116 patients included 51 men 39 to 89 years old (mean age 66) and 65 women 27 to 95 years old (mean age 72). When comparing the number of pads used to the gm of urine lost, the Spearman ρ was 0.26 (p=0.005) in the total cohort, and 0.40 and 0.26 (each p<0.05) in males and females, respectively. CONCLUSIONS: There was little correlation between the number of pads used and the severity of urinary incontinence (r=0.26). These data suggest that pad count should not be used as an objective measure of incontinence severity. Instead, pad weight on a 24-hour pad test should be used.

The rhizodynamics robot: Automated imaging system for studying long-term dynamic root growth.

The study of plant root growth in real time has been difficult to achieve in an automated, high-throughput, and systematic fashion. Dynamic imaging of plant roots is important in order to discover novel root growth behaviors and to deepen our understanding of how roots interact with their environments. We designed and implemented the Generating Rhizodynamic Observations Over Time (GROOT) robot, an automated, high-throughput imaging system that enables time-lapse imaging of 90 containers of plants and their roots growing in a clear gel medium over the duration of weeks to months. The system uses low-cost, widely available materials. As a proof of concept, we employed GROOT to collect images of root growth of Oryza sativa, Hudsonia montana, and multiple species of orchids including Platanthera integrilabia over six months. Beyond imaging plant roots, our system is highly customizable and can be used to collect time- lapse image data of different container sizes and configurations regardless of what is being imaged, making it applicable to many fields that require longitudinal time-lapse recording.

The Assessment of Social Determinants of Health in Postsepsis Mortality and Readmission: A Scoping Review.

To summarize knowledge and identify gaps in evidence about the relationship between social determinants of health (SDH) and postsepsis outcomes. DATA SOURCES: We conducted a comprehensive search of PubMed/Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, and the Cochrane Library. STUDY SELECTION: We identified articles that evaluated SDH as risk factors for mortality or readmission after sepsis hospitalization. Two authors independently screened and selected articles for inclusion. DATA EXTRACTION: We dual-extracted study characteristics with specific focus on measurement, reporting, and interpretation of SDH variables. DATA SYNTHESIS: Of 2,077 articles screened, 103 articles assessed risk factors for postsepsis mortality or readmission. Of these, 28 (27%) included at least one SDH variable. Inclusion of SDH in studies assessing postsepsis adverse outcomes increased over time. The most common SDH evaluated was race/ethnicity (n = 21, 75%), followed by payer type (n = 10, 36%), and income/wealth (n = 9, 32%). Of the studies including race/ethnicity, nine (32%) evaluated no other SDH. Only one study including race/ethnicity discussed the use of this variable as a surrogate for social disadvantage, and none specifically discussed structural racism. None of the studies specifically addressed methods to validate the accuracy of SDH or handling of missing data. Eight (29%) studies included a general statement that missing data were infrequent. Several studies reported independent associations between SDH and outcomes after sepsis discharge; however, these findings were mixed across studies. CONCLUSIONS: Our review suggests that SDH data are underutilized and of uncertain quality in studies evaluating postsepsis adverse events. Transparent and explicit ontogenesis and data models for SDH data are urgently needed to support research and clinical applications with specific attention to advancing our understanding of the role racism and racial health inequities in postsepsis outcomes.

NETISCE: a network-based tool for cell fate reprogramming.

The search for effective therapeutic targets in fields like regenerative medicine and cancer research has generated interest in cell fate reprogramming. This cellular reprogramming paradigm can drive cells to a desired target state from any initial state. However, methods for identifying reprogramming targets remain limited for biological systems that lack large sets of experimental data or a dynamical characterization. We present NETISCE, a novel computational tool for identifying cell fate reprogramming targets in static networks. In combination with machine learning algorithms, NETISCE estimates the attractor landscape and predicts reprogramming targets using signal flow analysis and feedback vertex set control, respectively. Through validations in studies of cell fate reprogramming from developmental, stem cell, and cancer biology, we show that NETISCE can predict previously identified cell fate reprogramming targets and identify potentially novel combinations of targets. NETISCE extends cell fate reprogramming studies to larger-scale biological networks without the need for full model parameterization and can be implemented by experimental and computational biologists to identify parts of a biological system relevant to the desired reprogramming task.

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies.

Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

Pulse Rate Guided Oxygen Saturation Monitoring Using a Wearable Armband Sensor.

Continuous clinical grade measurement of SpO2 in out-of-hospital settings remains a challenge despite the widespread use of photoplethysmography (PPG) based wearable devices for health and wellness applications. This article presents two SpO2 algorithms: PRR (pulse rate derived ratio-of-ratios) and GPDR (green-assisted peak detection ratio-of-ratios), that utilize unique pulse rate frequency estimations to isolate the pulsatile (AC) component of red and infrared PPG signals and derive SpO2 measurements. The performance of the proposed SpO2 algorithms are evaluated using an upper-arm wearable device derived green, red, and infrared PPG signals, recorded in both controlled laboratory settings involving healthy subjects (n=36) and an uncontrolled clinic application involving COVID-19 patients (n=52). GPDR exhibits the lowest root mean square error (RMSE) of 1.6±0.6% for a respiratory exercise test, 3.6 ±1.0% for a standard hypoxia test, and 2.2±1.3% for an uncontrolled clinic use-case. In contrast, PRR provides relatively higher error but with greater coverage overall. Mean error across all combined datasets were 0.2±2.8% and 0.3±2.4% for PRR and GPDR respectively. Both SpO2 algorithms achieve great performance of low error with high coverage on both uncontrolled clinic and controlled laboratory conditions.

Extension study of the safety and efficacy of CLS-TA for treatment of macular oedema associated with non-infectious uveitis (MAGNOLIA).

PURPOSE: To assess the extended efficacy and safety of suprachoroidal triamcinolone acetonide injectable suspension (CLS-TA) among patients with macular oedema (ME) secondary to non-infectious uveitis (NIU). METHODS: Patients with uveitic ME were treated with suprachoroidal CLS-TA at baseline and week 12 of the Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial (PEACHTREE) study. Time to rescue was evaluated over 24 additional weeks for MAGNOLIA. Safety data, visual acuity and retinal central subfield thickness (CST) reduction were also evaluated. Of the 53 eligible patients (46 CLS-TA and 7 control), 33 patients were enrolled (28 CLS-TA and 5 control). RESULTS: Over the entire 48-week period for PEACHTREE and MAGNOLIA, the median time to rescue therapy was 257 days versus 55.5 days for the CLS-TA and sham-control arms, respectively. Of 28 CLS-TA treated patients who participated in MAGNOLIA, 14 (50%) did not require rescue therapy through approximately 9 months after the second treatment. Among CLS-TA patients not requiring rescue, there was a mean gain of 12.1 letters and mean CST reduction of 174.5 µm at week 48. No serious adverse events related to study treatment were observed. CONCLUSION: Approximately 50% of patients did not require additional treatment for up to 9 months following the last CLS-TA administration.

Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA).

PURPOSE: To evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU). DESIGN: Open-label, prospective multicentre safety study. PARTICIPANTS: Thirty-eight subjects with NIU, with and without macular oedema (MO). METHODS: Treatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations. MAIN OUTCOME MEASURES: The main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST). RESULTS: Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period. CONCLUSIONS: Suprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.

Novel Continuous Respiratory Rate Monitoring Using an Armband Wearable Sensor.

Photoplethysmography (PPG) and accelerometer (ACC) are commonly integrated into wearable devices for continuous unobtrusive pulse rate and activity monitoring of individuals during daily life. However, obtaining continuous and clinically accurate respiratory rate measurements using such wearable sensors remains a challenge. This article presents a novel algorithm for estimation of respiration rate (RR) using an upper-arm worn wearable device by deriving multiple respiratory surrogate signals from PPG and ACC sensing. This RR algorithm is retrospectively evaluated on a controlled respiratory clinical testing dataset from 38 subjects with simultaneously recorded wearable sensor data and a standard capnography monitor as an RR reference. The proposed RR method shows great performance and robustness in determining RR measurements over a wide range of 4-59 brpm with an overall bias of -1.3 brpm, mean absolute error (MAE) of 2.7±1.6 brpm, and a meager outage of 0.3±1.2%, while a standard PPG Smart Fusion method produces a bias of -3.6 brpm, an MAE of 5.5±3.1 brpm, and an outage of 0.7±2.5% for direct comparison. In addition, the proposed algorithm showed no significant differences (p=0.63) in accurately determining RR values in subjects with darker skin tones, while the RR performance of the PPG Smart Fusion method is significantly (P<0.001) affected by the darker skin pigmentation. This study demonstrates a highly accurate RR algorithm for unobtrusive continuous RR monitoring using an armband wearable device.

The Impact of Patient, Procedural, and Staffing Factors Upon Ureteroscopy Cost.

Introduction: The purpose of this study was to evaluate factors during ureteroscopy that can potentially impact procedure cost. Materials and Methods: A retrospective review of 129 consecutive elective ureteroscopy cases was performed to determine direct procedure cost. Direct cost was defined as cost incurred because of operating room expenses, including operating room time, staffing expenses, equipment, and supply costs. Data regarding patient, procedural, and operating room staffing characteristics were compared between the most and least expensive cases. Univariate and logistic regression analysis were performed to identify factors predictive of higher costs. Results: The average direct ureteroscopy cost was $3298/case. On univariate analysis, ureteroscopies in the highest 50th cost percentile had larger stone burden (170.1 vs 146 mm2; p = 0.03) and longer operative times (95.3 vs 49.9 minutes; p < 0.01), were more likely performed for non-stone indications (21.4% vs 7.2%; p = 0.03), more likely to include a resident (65.5% vs 43.6%; p = 0.02), and less likely to have a dedicated urology scrub technician (38.2% vs 61.8%; p = 0.01) compared to cases in the lowest 50th percentile. The presence of a resident, larger stone burden, absence of a dedicated scrub technician, and longer operative time were associated with an average cost increase of $516, $700, $1122, and $1401, respectively. Logistic regression analysis showed that operating room time was the only factor predicting higher cost (OR [odds ratio] 12.8, 95% confidence interval [CI] 2.0-84.0). A post-hoc logistic regression analysis demonstrated that the presence of a resident during ureteroscopy (OR 2.9, 95% CI 1.1-8.0) and larger stone burden (OR 1.01, 95% CI 1.0-1.013) were significantly associated with longer operative times. Conclusion: Operating room time is the primary determinant of ureteroscopy case cost. All efforts should be made to decrease operative time, although balancing patient safety and maintaining a quality training environment.

What Guidewire Is the Best for Bypassing an Impacted Ureteral Stone?

Introduction and Objectives: To determine the optimal guidewire for bypassing an impacted ureteral stone. Materials and Methods: Three different benchtop models of varying impaction (300, 362, and 444 mm Hg pressure) were used to compare the ability of 13 different guidewires to bypass an impacted ureteral stone. In the first and second models, we recorded the maximum force required to bypass the stone. In the first model (300 mm Hg) 10 new wires for each of the 13 types were advanced past a ureteral stone using a series 5 digital force gauge. In the second model (362 mm Hg), the top 5 performing guidewires were similarly tested. In the third model (444 mm Hg), 5 attending urologists and 5 urology residents (blinded to wire type) compared the 13 guidewires and rated the wire performance using a Likert scale. Statistical analysis was performed with analysis of variance and the chi-square test. Results: In the first model, there was a significant difference between wires (p < 0.001) with the lowest mean force to bypass a stone seen in the Glidewire (0.117 ± 0.02 lbs) and HiWire (0.130 ± 0.01 lbs). Of the five wires tested in the second model, the Glidewire (0.24 ± 0.09 lbs) and UltraTrack (0.40 ± 0.35 lbs) both required less force than the other three wires (p = 0.018). In the third model, only two wires (Roadrunner and Glidewire) bypassed the impacted stone in 100% of trials. When comparing standard, hybrid, and hydrophilic wires, the hydrophilic had the highest success rate (standard = 0%, hybrid = 36.67%, and hydrophilic = 70.67%; p = 0.000) and Likert score (standard = 1.03, hybrid = 2.38, and hydrophilic = 3.24; p = 0.000). Hydrophilic wires required the least time to bypass the stone (hybrid = 82.81 seconds vs hydrophilic = 45.37 seconds, p = 0.000). Conclusions: In this benchtop study, standard wires performed poorly and hybrid wires were not as effective as hydrophilic wires. The Glidewire required the least force, the shortest insertion time, and had the highest surgeon satisfaction rating.

Clinical Characterization of Suprachoroidal Injection Procedure Utilizing a Microinjector across Three Retinal Disorders.

Purpose: This study assessed physician-investigator experience with suprachoroidal (SC) injections, an investigational therapeutic administration technique using a 900 or 1100 µm microneedle to inject drugs into the SC space. Methods: Datasets from six clinical trials across three diseases (noninfectious uveitis; diabetic macula edema, and retinal vein occlusion) were assessed. In addition to a user survey, retrospective correlations were performed between procedural variables (needle length), and demographics, and ocular characteristics. Results: In the user survey, 84% (31/37) of physician-investigators did not perceive the SC injections to be meaningfully more challenging than other ocular injections. For the correlation analysis, the 900 µm needle was used for 71% (412/581) of baseline injections, and switching to the longer needle occured in the remaining 29% of baseline injections. No statistical correlations were found between needle lengths and age, race, disorder, refraction, visual acuity, intraocular pressure, retinal central subfield thickness, or lens status. Patient gender and needle length were statistically associated, with 76% (210/275) versus 66% (202/306) of injections administered with 900 µm needles for female and male gender, respectively. Injection quadrant correlated to needle length with 78% (214/275) of superotemporal quadrant injections administered with 900 µm needles, compared with 65% (73/113) of inferotemporal quadrant injections. Conclusions: Both the user survey and the correlation analysis demonstrated that SC injection is well accepted by physician-investigators, and the two needle lengths accommodate a wide range of anatomic and demographic variables. Translational Relevance: These results, along with the presented ex-vivo endoscopic imaging, suggest that SC injection could be readily adopted in clinical practice for targeted compartmentalized delivery of ocular therapeutics.

The Effect of Operative Field Instrument Clutter During Intraoperative Fluoroscopy on Radiation Exposure.

Introduction and Objectives: Fluoroscopy units are routinely operated in the automatic brightness control (ABC) mode to optimize image quality. During ureteroscopy, objects may be placed within the fluoroscopy beam and the effect upon radiation exposure is unknown. The purpose of this study is to investigate the effects of equipment within the fluoroscopy beam during simulated ureteroscopy. Methods: ABC fluoroscopy of a cadaver was performed in eight clinical scenarios, including a control (no equipment), and seven groups with different equipment within the fluoroscopy beam. Equipment tested included electrocardiogram (EKG) leads, a Kelly clamp, camera and light cords (straight and coiled configurations), flexible ureteroscope, rigid cystoscope, and the lateral table support beam. Ten 145-second fluoroscopy trials were performed for each arm. The primary outcome was radiation dose (mGy) compared using the Mann-Whitney test with p < 0.05 considered significant. Results: Compared with control (18.5 mGy), radiation exposure was significantly increased with the presence of a straight camera and light cords (19.3 mGy), Kelly clamp (19.4 mGy), coiled camera and light cords (20.2 mGy), a flexible ureteroscope (21.0 mGy), a rigid cystoscope (21.2 mGy), and when the lateral table support beam was in the path of the X-ray (25.0 mGy; a 35% increase; p < 0.007 for all). The EKG leads did not affect the radiation dose. Conclusions: Avoiding equipment within the fluoroscopy beam using ABC mode can reduce radiation exposure. Adjusting the table and patient position to exclude the lateral table support beam will reduce radiation exposure by 35%.

Loss of myelinated retinal nerve fibers from chronic papilledema.

An intracranial pilocytic astrocytoma was diagnosed in a 13-year-old boy after he presented with headaches and visual disturbances. The initial ophthalmoscopic examination revealed papilledema bilaterally and myelinated retinal nerve fibers (MRNFs) in the left eye. Serial ophthalmoscopic examinations demonstrated gradual fading of the MRNFs beginning 2 months after tumor resection and their complete disappearance by 2 years after surgery. The disappearance of MRNFs has been described in the presence of ischemia, compression, glaucoma, and demyelinating disease of the optic nerve. This patient demonstrates that loss of myelinated nerves fibers may also occur with the optic atrophy that may follow chronic papilledema.