What Is the Optimal Stenting Duration After Ureteroscopy and Stone Intervention? Impact of Dwell Time on Postoperative Emergency Department Visits.

PURPOSE: AUA stone management guidelines recommend stenting duration following ureteroscopy be minimized to reduce morbidity; stents with extraction strings may be used for this purpose. However, an animal study demonstrated that short dwell time results in suboptimal ureteral dilation, and a pilot clinical study showed this increases postprocedure events. Using real-world practice data we examined stent dwell time after ureteroscopy and its association with postoperative emergency department visits. MATERIALS AND METHODS: We used the Michigan Urological Surgery Improvement Collaborative registry to identify ureteroscopy and stenting procedures (2016-2019). Pre-stented cases were excluded. Stenting cohorts with and without strings were analyzed. Using multivariable logistic regression we evaluated the risk of an emergency department visit occurring on the day of, or day after, stent removal based on dwell time and string status. RESULTS: We identified 4,437 procedures; 1,690 (38%) had a string. Median dwell time was lower in patients with a string (5 vs 9 days). Ureteroscopy in younger patients, smaller stones, or renal stone location had a higher frequency of string use. The predicted probability of an emergency department visit was significantly greater in procedures with string, compared to without string, when dwell times were less than 5 days (P < .01) but were not statistically significant after. CONCLUSIONS: Patients who had ureteroscopy and stenting with a string have short dwell times. Patients are at increased risk of a postoperative emergency department visit around the time of stent removal if dwell time is ≤4 days. We recommended stenting duration of at least 5 days in nonpre-stented patients.

Closing the Gap: Evaluation of Gender Disparities in Urology Resident Operative Autonomy and Performance.

OBJECTIVE: Gender disparities have demonstrated influence on several areas of medical trainee academic performance and surgeon professional attainment. The impact of gender on perceived operative autonomy and performance of urology residents is not well understood. This single-institution pilot study explores this relationship by evaluating urology faculty and resident assessment of resident operative autonomy and performance using the Society for Improving Medical Professional Learning app. DESIGN: Using Society for Improving Medical Professional Learning, trainees in a single urology residency program were assessed in operative cases on three scales (autonomy, performance, and case complexity). Intraoperative assessments were completed by both faculty and residents (self-evaluation). Respective evaluations were compared to explore differences in ratings by gender. SETTING: University of Michigan Health, Ann Arbor, MI. PARTICIPANTS: University of Michigan Urology Residents and Faculty. RESULTS: A total of 516 evaluations were submitted from 18 urology residents and 20 urology faculty. Self-reported ratings among female and male residents did not differ significantly for autonomy (p = 0.20) or performance (p = 0.82). Female and male residents received overall similar autonomy ratings that were not significantly different from female faculty (p = 0.66) and male faculty (p = 0.81). For female residents, there was no significant difference in performance ratings by faculty gender (p = 0.20). This finding was consistent when the resident was male (p = 0.70). CONCLUSIONS: At our institution, there is no overall gender-based difference in self-rated or faculty-rated operative autonomy or performance among urology trainees. Understanding relevant facets of institutional culture as well as educational strategies between faculty and residents may identify factors contributing to this outcome.

Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson's disease.

The blood-brain barrier (BBB) prevents most drugs from gaining access to the brain parenchyma, which is a recognized impediment to the treatment of neurodegenerative disorders like Parkinson's disease (PD). Focused ultrasound (FUS), in conjunction with systemically administered microbubbles, opens the BBB locally, reversibly and non-invasively. Herein, we show that neither FUS applied over both the striatum and the ventral midbrain, without neurotrophic factors, nor intravenous administration of neurotrophic factors (either through protein or gene delivery) without FUS, ameliorates the damage to the nigrostriatal dopaminergic pathway in the sub-acute MPTP mouse model of early-stage PD. Conversely, the combination of FUS and intravenous neurotrophic (protein or gene) delivery attenuates the damage to the nigrostriatal dopaminergic pathway, by allowing the entry of these agents into the brain parenchyma. Our findings provide evidence that the application of FUS at the early stages of PD facilitates critical neurotrophic delivery that can curb the rapid progression of neurodegeneration while improving the neuronal function, seemingly opening new therapeutic avenues for the early treatment of diseases of the central nervous system.

Describing the sternalis muscle: a new variant and an amended classification.

PURPOSE: With emphasis on the clinical setting, knowledge of anatomical variation decreases misdiagnoses and surgical complications. We report a previously undocumented variant of sternalis muscle and recommend an augmented classification scheme. METHODS: Dissection of the anterior thoracic wall on an 83-year-old female cadaver revealed bilateral sternalis muscles. The Snosek et al. classification system was referenced to describe the variant types. RESULTS: The right sternalis muscle has a single belly and can be classified using the Snosek et al. classification system as a simple type, right single. The left sternalis muscle presented with three muscle bellies, each having a unique pattern of superior attachments (heads). This variation is previously undocumented and requires a more detailed classification. CONCLUSIONS: We propose the addition of a new subtype of sternalis classification, as well as a modification to the Snosek et al. (Clin Anat 27:866-884, 2014) classification scheme, to include classification of different muscle bellies when multiple are present.

Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery.

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet's sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using » dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.

Longitudinal Motor and Behavioral Assessment of Blood-Brain Barrier Opening with Transcranial Focused Ultrasound.

Focused ultrasound (FUS), in combination with microbubbles, has been found to open the blood-brain barrier (BBB) non-invasively. When this technique is used for drug delivery, repeated drug administration and BBB opening are likely required. Therefore, it is worth investigating the long-term effects of FUS-induced BBB opening. In this study, we focused on the assessment of potential behavior changes in mice that could be attributed to repeated BBB opening for up to 6 months. The striatum of animals was unilaterally sonicated either monthly or biweekly throughout the monitoring period. Behavioral assessments were conducted using open-field and rotarod performance tests. Upon completion of each sonication, mice underwent magnetic resonance imaging (MRI) to confirm and assess the volume of the BBB opening. No differences in locomotor activity between BBB-opened and control groups in both biweekly and monthly treated mice were evident up to 6 months. Similarly, there was no affinity for a particular turn angle in the sonicated mice compared with the control animals. However, the positive control group exhibited a significant decrease in locomotor activity, as well as rotation ipsilateral to the sonicated hemisphere. Our results based on the assessment using open-field and rotarod tests indicated that repeated opening of the BBB in the striatum using FUS in conjunction with microbubbles over a period of 6 mo and under the parameters used here did not cause motor impairment, behavioral changes or morphologic alterations. This reinforces the tolerability of repeated and long-term drug delivery using FUS-induced BBB opening.

Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain.

Lipid-shelled microbubbles have been used in ultrasound-mediated drug delivery. The physicochemical properties of the microbubble shell could affect the delivery efficiency since they determine the microbubble mechanical properties, circulation persistence, and dissolution behavior during cavitation. Therefore, the aim of this study was to investigate the shell effects on drug delivery efficiency in the brain via blood-brain barrier (BBB) opening in vivo using monodisperse microbubbles with different phospholipid shell components. The physicochemical properties of the monolayer were varied by using phospholipids with different hydrophobic chain lengths (C16, C18, and C24). The dependence on the molecular size and acoustic energy (both pressure and pulse length) were investigated. Our results showed that a relatively small increase in the microbubble shell rigidity resulted in a significant increase in the delivery of 40-kDa dextran, especially at higher pressures. Smaller (3kDa) dextran did not show significant difference in the delivery amount, suggesting that the observed shell effect was molecular size-dependent. In studying the impact of acoustic energy on the shell effects, it was found that they occurred most significantly at pressures causing microbubble destruction (450kPa and 600kPa); by increasing the pulse length to deliver the 40-kDa dextran, the difference between C16 and C18 disappeared while C24 still achieved the highest delivery efficiency. These indicated that the acoustic energy could be used to modulate the shell effects. The acoustic cavitation emission revealed the physical mechanisms associated with different shells. Overall, lipid-shelled microbubbles with long hydrophobic chain length could achieve high delivery efficiency for larger molecules especially with high acoustic energy. Our study, for the first time, offered evidence directly linking the microbubble monolayer shell with their efficacy for drug delivery in vivo.

Partial dopaminergic denervation-induced impairment in stimulus discrimination acquisition in parkinsonian rats: a model for early Parkinson's disease.

Parkinson's disease (PD) produces progressive nigrostriatal dopamine (DA) denervation resulting in cognitive and motor impairment. However, it is unknown whether cognitive impairments, such as instrumental learning deficits, are associated with the early stage PD-induced mild DA denervation. The current study sought to model early PD-induced instrumental learning impairments by assessing the effects of low dose (5.5µg), bilateral 6OHDA-induced striatal DA denervation on acquisition of instrumental stimulus discrimination in rats. 6OHDA (n=20) or sham (n=10) lesioned rats were tested for stimulus discrimination acquisition either 1 or 2 weeks post surgical lesion. Stimulus discrimination acquisition across 10 daily sessions was used to assess discriminative accuracy, or a probability measure of the shift toward reinforced responding under one stimulus condition (Sd) away from extinction, when reinforcement was withheld, under another (S(d) phase). Striatal DA denervation was assayed by tyrosine hydroxylase (TH) staining intensity. Results indicated that 6OHDA lesions produced significant loss of dorsal striatal TH staining intensity and marked impairment in discrimination acquisition, without inducing akinetic motor deficits. Rather 6OHDA-induced impairment was associated with perseveration during extinction (S(Δ) phase). These findings suggest that partial, bilateral striatal DA denervation produces instrumental learning deficits, prior to the onset of gross motor impairment, and suggest that the current model is useful for investigating mild nigrostriatal DA denervation associated with early stage clinical PD.

Microbubble type and distribution dependence of focused ultrasound-induced blood-brain barrier opening.

Focused ultrasound, in the presence of microbubbles, has been used non-invasively to induce reversible blood-brain barrier (BBB) opening in both rodents and non-human primates. This study was aimed at identifying the dependence of BBB opening properties on polydisperse microbubble (all clinically approved microbubbles are polydisperse) type and distribution by using a clinically approved ultrasound contrast agent (Definity microbubbles) and in-house prepared polydisperse (IHP) microbubbles in mice. A total of 18 C57 BL/6 mice (n = 3) were used in this study, and each mouse was injected with either Definity or IHP microbubbles via the tail vein. The concentration and size distribution of activated Definity and IHP microbubbles were measured, and the microbubbles were diluted to 6 × 10(8)/mL before injection. Immediately after microbubble administration, mice were subjected to focused ultrasound with the following parameters: frequency = 1.5 MHz, pulse repetition frequency = 10 Hz, 1000 cycles, in situ peak rarefactional acoustic pressures = 0.3, 0.45 and 0.6 MPa for a sonication duration of 60 s. Contrast-enhanced magnetic resonance imaging was used to confirm BBB opening and allowed for image-based analysis. Permeability of the treated region and volume of BBB opening did not significantly differ between the two types of microbubbles (p > 0.05) at peak rarefractional acoustic pressures of 0.45 and 0.6 MPa, whereas IHP microbubbles had significantly higher permeability and opening volume (p < 0.05) at the relatively lower pressure of 0.3 MPa. The results from this study indicate that microbubble type and distribution could have significant effects on focused ultrasound-induced BBB opening at lower pressures, but less important effects at higher pressures, possibly because of the stable cavitation that governs the former. This difference may have become less significant at higher pressures, where inertial cavitation typically occurs.

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature.

Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles.

The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.