Single-sided magnetic resonance-based sensor for point-of-care evaluation of muscle.

Magnetic resonance imaging is a widespread clinical tool for the detection of soft tissue morphology and pathology. However, the clinical deployment of magnetic resonance imaging scanners is ultimately limited by size, cost, and space constraints. Here, we discuss the design and performance of a low-field single-sided magnetic resonance sensor intended for point-of-care evaluation of skeletal muscle in vivo. The 11 kg sensor has a penetration depth of >8 mm, which allows for an accurate analysis of muscle tissue and can avoid signal from more proximal layers, including subcutaneous adipose tissue. Low operational power and shielding requirements are achieved through the design of a permanent magnet array and surface transceiver coil. The sensor can acquire high signal-to-noise measurements in minutes, making it practical as a point-of-care tool for many quantitative diagnostic measurements, including T2 relaxometry. In this work, we present the in vitro and human in vivo performance of the device for muscle tissue evaluation.

Single-sided magnetic resonance-based sensor for point-of-care evaluation of muscle.

Magnetic resonance (MR) imaging is a powerful clinical tool for the detection of soft tissue morphology and pathology, which often provides actionable diagnostic information to clinicians. Its clinical use is largely limited due to size, cost, time, and space constraints. Here, we discuss the design and performance of a low-field single-sided MR sensor intended for point-of-care (POC) evaluation of skeletal muscle in vivo. The 11kg sensor has a penetration depth of > 8 mm, which allows for an accurate analysis of muscle tissue and can avoid signal from more proximal layers, including subcutaneous adipose tissue. Low operational power and minimal shielding requirements are achieved through the design of a permanent magnet array and surface transceiver coil. We present the in vitro and human in vivo performance of the device for muscle tissue evaluation. The sensor can acquire high signal-to-noise (SNR > 150) measurements in minutes, making it practical as a POC tool for many quantitative diagnostic measurements, including T2 relaxometry.

Actuated tissue engineered muscle grafts restore functional mobility after volumetric muscle loss.

Damage that affects large volumes of skeletal muscle tissue can severely impact health, mobility, and quality-of-life. Efforts to restore muscle function by implanting tissue engineered muscle grafts at the site of damage have demonstrated limited restoration of force production. Various forms of mechanical and biochemical stimulation have been shown to have a potentially beneficial impact on graft maturation, vascularization, and innervation. However, these approaches yield unpredictable and incomplete recovery of functional mobility. Here we show that targeted actuation of implanted grafts, via non-invasive transcutaneous light stimulation of optogenetic engineered muscle, restores motor function to levels similar to healthy mice 2 weeks post-injury. Furthermore, we conduct phosphoproteomic analysis of actuated engineered muscle in vivo and in vitro to show that repeated muscle contraction alters signaling pathways that play key roles in skeletal muscle contractility, adaptation to injury, neurite growth, neuromuscular synapse formation, angiogenesis, and cytoskeletal remodeling. Our study uncovers changes in phosphorylation of several proteins previously unreported in the context of muscle contraction, revealing promising mechanisms for leveraging actuated muscle grafts to restore mobility after volumetric muscle loss.

Scalable, flexible carbon fiber electrode thread arrays for three-dimensional probing of neurochemical activity in deep brain structures of rodents.

We developed a flexible "electrode-thread" array for recording dopamine neurochemicals from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼10 µm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single-entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial "linear" arrays provide single-entry insertion but only allow measurements along the axis of insertion. Horizontally configured arrays inflict separate penetrations for each individual channel. We tested functional performance of our CFET arrays in vivo for recording dopamine and for providing lateral spread to multiple distributed sites in the rat striatum. Spatial spread was further characterized in agar brain phantoms as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson's disease and major mood disorders.

Scalable, flexible carbon fiber electrode thread arrays for three-dimensional spatial profiling of neurochemical activity in deep brain structures of rodents.

We developed a flexible "electrode-thread" array for recording dopamine neurochemical activity from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼ 10 µm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial "linear" arrays provide single entry insertion but only allow measurements along the axis of insertion. Horizontally configured neurochemical recording arrays inflict separate penetrations for each individual channel (i.e., electrode). We tested functional performance of our CFET arrays in vivo for recording dopamine neurochemical dynamics and for providing lateral spread to multiple distributed sites in the striatum of rats. Spatial spread was further characterized using agar brain phantoms to measure electrode deflection as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology techniques. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Neurochemical recording operations tested here can be integrated with already widely established capabilities of CF-based electrodes to record single neuron activity and local field potentials, to enable multi-modal recording functions. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson's disease and major mood disorders.

Epidemiologic and Clinical Features of Mpox-Associated Deaths - United States, May 10, 2022-March 7, 2023.

As of March 7, 2023, a total of 30,235 confirmed and probable monkeypox (mpox) cases were reported in the United States,† predominantly among cisgender men§ who reported recent sexual contact with another man (1). Although most mpox cases during the current outbreak have been self-limited, cases of severe illness and death have been reported (2-4). During May 10, 2022-March 7, 2023, 38 deaths among persons with probable or confirmed mpox¶ (1.3 per 1,000 mpox cases) were reported to CDC and classified as mpox-associated (i.e., mpox was listed as a contributing or causal factor). Among the 38 mpox-associated deaths, 94.7% occurred in cisgender men (median age = 34 years); 86.8% occurred in non-Hispanic Black or African American (Black) persons. The median interval from symptom onset to death was 68 days (IQR = 50-86 days). Among 33 decedents with available information, 93.9% were immunocompromised because of HIV. Public health actions to prevent mpox deaths include integrated testing, diagnosis, and early treatment for mpox and HIV, and ensuring equitable access to both mpox and HIV prevention and treatment, such as antiretroviral therapy (ART) (5).

COVID-19 Incidence and Mortality Among Unvaccinated and Vaccinated Persons Aged ≥12 Years by Receipt of Bivalent Booster Doses and Time Since Vaccination - 24 U.S. Jurisdictions, October 3, 2021-December 24, 2022.

On September 1, 2022, CDC recommended an updated (bivalent) COVID-19 vaccine booster to help restore waning protection conferred by previous vaccination and broaden protection against emerging variants for persons aged ≥12 years (subsequently extended to persons aged ≥6 months).* To assess the impact of original (monovalent) COVID-19 vaccines and bivalent boosters, case and mortality rate ratios (RRs) were estimated comparing unvaccinated and vaccinated persons aged ≥12 years by overall receipt of and by time since booster vaccination (monovalent or bivalent) during Delta variant and Omicron sublineage (BA.1, BA.2, early BA.4/BA.5, and late BA.4/BA.5) predominance.† During the late BA.4/BA.5 period, unvaccinated persons had higher COVID-19 mortality and infection rates than persons receiving bivalent doses (mortality RR = 14.1 and infection RR = 2.8) and to a lesser extent persons vaccinated with only monovalent doses (mortality RR = 5.4 and infection RR = 2.5). Among older adults, mortality rates among unvaccinated persons were significantly higher than among those who had received a bivalent booster (65-79 years; RR = 23.7 and ≥80 years; 10.3) or a monovalent booster (65-79 years; 8.3 and ≥80 years; 4.2). In a second analysis stratified by time since booster vaccination, there was a progressive decline from the Delta period (RR = 50.7) to the early BA.4/BA.5 period (7.4) in relative COVID-19 mortality rates among unvaccinated persons compared with persons receiving who had received a monovalent booster within 2 weeks-2 months. During the early BA.4/BA.5 period, declines in relative mortality rates were observed at 6-8 (RR = 4.6), 9-11 (4.5), and ≥12 (2.5) months after receiving a monovalent booster. In contrast, bivalent boosters received during the preceding 2 weeks-2 months improved protection against death (RR = 15.2) during the late BA.4/BA.5 period. In both analyses, when compared with unvaccinated persons, persons who had received bivalent boosters were provided additional protection against death over monovalent doses or monovalent boosters. Restored protection was highest in older adults. All persons should stay up to date with COVID-19 vaccination, including receipt of a bivalent booster by eligible persons, to reduce the risk for severe COVID-19.

Recent Incarceration Among Individuals Infected With Hepatitis A Virus During Person-to-Person Community Outbreaks, United States, 2016-2020.

OBJECTIVES: Although many people who are incarcerated have risk factors for hepatitis A virus (HAV) infection, the proportion of hepatitis A cases among people with a recent incarceration is unknown. We examined the relationship between recent incarceration and HAV infection during community-based, person-to-person outbreaks to inform public health recommendations. METHODS: The Centers for Disease Control and Prevention surveyed health departments in 33 jurisdictions reporting person-to-person HAV outbreaks during 2016-2020 on the number of outbreak-associated cases, HAV-infected people recently incarcerated, and HAV-associated hospitalizations and deaths. RESULTS: Twenty-five health departments reported 18 327 outbreak-associated hepatitis A cases during January 11, 2016-January 24, 2020. In total, 2093 (11.4%) HAV-infected people had been recently incarcerated. Of those with complete data, 1402 of 1462 (95.9%) had been held in a local jail, and 1513 of 1896 (79.8.%) disclosed hepatitis A risk factors. Eighteen jurisdictions reported incarceration timing relative to the exposure period. Of 9707 cases in these jurisdictions, 991 (10.2%) were among recently incarcerated people; 451 of 688 (65.6%) people with complete data had been incarcerated during all (n = 55) or part (n = 396) of their exposure period. CONCLUSIONS: Correctional facilities are important settings for reaching people with risk factors for HAV infection and can also be venues where transmission occurs. Providing HAV vaccination to incarcerated people, particularly people housed in jails, can be an effective component of community-wide outbreak response.

Investigative needle core biopsies for multi-omics in Glioblastoma.

Glioblastoma (GBM) is a primary brain cancer with an abysmal prognosis and few effective therapies. The ability to investigate the tumor microenvironment before and during treatment would greatly enhance both understanding of disease response and progression, as well as the delivery and impact of therapeutics. Stereotactic biopsies are a routine surgical procedure performed primarily for diagnostic histopathologic purposes. The role of investigative biopsies - tissue sampling for the purpose of understanding tumor microenvironmental responses to treatment using integrated multi-modal molecular analyses ('Multi-omics") has yet to be defined. Secondly, it is unknown whether comparatively small tissue samples from brain biopsies can yield sufficient information with such methods. Here we adapt stereotactic needle core biopsy tissue in two separate patients. In the first patient with recurrent GBM we performed highly resolved multi-omics analysis methods including single cell RNA sequencing, spatial-transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics from biopsy tissue that was obtained from a single procedure. In a second patient we analyzed multi-regional core biopsies to decipher spatial and genomic variance. We also investigated the utility of stereotactic biopsies as a method for generating patient derived xenograft models in a separate patient cohort. Dataset integration across modalities showed good correspondence between spatial modalities, highlighted immune cell associated metabolic pathways and revealed poor correlation between RNA expression and the tumor MHC Class I immunopeptidome. In conclusion, stereotactic needle biopsy cores are of sufficient quality to generate multi-omics data, provide data rich insight into a patient's disease process and tumor immune microenvironment and can be of value in evaluating treatment responses. One sentence summary: Integrative multi-omics analysis of stereotactic needle core biopsies in glioblastoma.

COVID-19 vaccine uptake among Arkansas public K-12 school teachers and staff.

In December 2020, the first coronavirus disease 2019 (COVID-19) vaccines received emergency use authorization from the Food and Drug Administration (FDA). To strategically allocate the limited availability of COVID-19 vaccines, the Advisory Committee on Immunization Practices (ACIP) developed a phased approach for eligibility that prioritized certain population groups that were more vulnerable to infection and severe outcomes. Public K-12 teachers and staff were included in Phase 1b. The Arkansas Department of Health (ADH) sought to evaluate the uptake of COVID-19 vaccines within this priority group. In partnership with the Arkansas Department of Education (ADE), ADH received a list of 66,076 certified staff, classified staff, and teachers within the public K-12 school system. This list was matched to the state immunization registry via deterministic methods across three identifiers: first name, last name and date of birth. Uptake was assessed and the population was characterized using descriptive analyses. After 13 weeks of availability, 34,783 (51.2 %) of public K-12 teachers and staff had received at least one dose and 29,870 (44.0 %) had completed the series. School districts with the least robust uptake of COVID-19 vaccines tended to be in more rural areas, with some districts having less than 10 % of teachers and staff with at least one dose. The proportion of public K-12 teachers and staff with at least one dose of any COVID-19 vaccine grew quickly between January 18th and February 14th (4 % to 43 %) but has plateaued in the most recent seven weeks (45 % to 51 %). Although not directly measured, it is possible that vaccine hesitancy could be a factor in the attenuated uptake of COVID-19 vaccines within certain factions of the Arkansas public K-12 teacher and staff population. Overcoming vaccine hesitancy during the COVID-19 vaccine rollout will be critical in bringing an end to the pandemic.

Machine-learning aided in situ drug sensitivity screening predicts treatment outcomes in ovarian PDX tumors.

Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91.

Covid-19 Rates by Time since Vaccination during Delta Variant Predominance.

BACKGROUND: With the emergence of the delta variant, the United States experienced a rapid increase in Covid-19 cases in 2021. We estimated the risk of breakthrough infection and death by month of vaccination as a proxy for waning immunity during a period of delta variant predominance. METHODS: Covid-19 case and death data from 15 U.S. jurisdictions during January 3 to September 4, 2021 were used to estimate weekly hazard rates among fully vaccinated persons, stratified by age group and vaccine product. Case and death rates during August 1 to September 4, 2021 were presented across four cohorts defined by month of vaccination. Poisson models were used to estimate adjusted rate ratios comparing the earlier cohorts to July rates. RESULTS: During August 1 to September 4, 2021, case rates per 100,000 person-weeks among all vaccine recipients for the January to February, March to April, May to June, and July cohorts were 168.8 (95% confidence interval [CI], 167.5 to 170.1), 123.5 (95% CI, 122.8 to 124.1), 83.6 (95% CI, 82.9 to 84.3), and 63.1 (95% CI, 61.6 to 64.6), respectively. Similar trends were observed by age group for BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccine recipients. Rates for the Ad26.COV2.S (Janssen-Johnson & Johnson) vaccine were higher; however, trends were inconsistent. BNT162b2 vaccine recipients 65 years of age or older had higher death rates among those vaccinated earlier in the year. Protection against death was sustained for the mRNA-1273 vaccine recipients. Across age groups and vaccine types, people who were vaccinated 6 months ago or longer (January-February) were 3.44 (3.36 to 3.53) times more likely to be infected and 1.70 (1.29 to 2.23) times more likely to die from COVID-19 than people vaccinated recently in July 2021. CONCLUSIONS: Our study suggests that protection from SARS-CoV-2 infection among all ages or death among older adults waned with increasing time since vaccination during a period of delta predominance. These results add to the evidence base that supports U.S. booster recommendations, especially for older adults vaccinated with BNT162b2 and recipients of the Ad26.COV2.S vaccine. (Funded by the Centers for Disease Control and Prevention.).

Association of the COVID-19 pandemic and dying at home due to ischemic heart disease.

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a declining volume of patients seen in the emergency department. Despite the need for seeking urgent care for conditions such as myocardial infarction, many people may not seek treatment. This study seeks to measure associations between the COVID-19 pandemic and location of death among individuals who died from ischemic heart disease (IHD). Data obtained from death certificates from the Arkansas Department of Health was used to conduct a difference-in-difference analysis to assess whether decedents of IHD were more likely to die at home during the pandemic (March 2020 through September 2020). The analysis compared location of death for decedents of IHD pre and during the pandemic to location of death for decedents from non-natural causes. Before the pandemic, 50.0% of decedents of IHD died at home compared to 57.9% dying at home during (through September 2020) the pandemic study period (p < .001). There was no difference in the proportion of decedents who died at home from non-natural causes before and during the pandemic study period (55.8% vs. 53.5%; p = .21). After controlling for confounders, there was a 48% increase in the odds of dying at home from IHD during the pandemic study period (p < .001) relative to the change in dying at home due to non-natural causes. During the study period, there was an increase in the proportion of decedents who died at home due to IHD. Despite the ongoing pandemic, practitioners should emphasize the need to seek urgent care during an emergency.

Participation in Fraternity and Sorority Activities and the Spread of COVID-19 Among Residential University Communities - Arkansas, August 21-September 5, 2020.

Preventing transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), in colleges and universities requires mitigation strategies that address on- and off-campus congregate living settings as well as extracurricular activities and other social gatherings (1-4). At the start of the academic year, sorority and fraternity organizations host a series of recruitment activities known as rush week; rush week culminates with bid day, when selections are announced. At university A in Arkansas, sorority rush week (for women) was held during August 17-22, 2020, and consisted of on- and off-campus social gatherings, including an outdoor bid day event on August 22. Fraternity rush week (for men) occurred during August 27-31, with bid day scheduled for September 5. During August 22-September 5, university A-associated COVID-19 cases were reported to the Arkansas Department of Health (ADH). A total of 965 confirmed and probable COVID-19 cases associated with university A were identified, with symptom onset occurring during August 20-September 5, 2020; 31% of the patients with these cases reported involvement in any fraternity or sorority activity. Network analysis identified 54 gatherings among all linkages of cases to places of residence and cases to events, 49 (91%) were linked by participation in fraternity and sorority activities accounting for 42 (72%) links among gatherings. On September 4, university A banned gatherings of ≥10 persons, and fraternity bid day was held virtually. The rapid increase in COVID-19 cases was likely facilitated by on- and off-campus congregate living settings and activities, and health departments should work together with student organizations and university leadership to ensure compliance with mitigation measures.

A portable single-sided magnetic-resonance sensor for the grading of liver steatosis and fibrosis.

Low-cost non-invasive diagnostic tools for staging the progression of non-alcoholic chronic liver failure from fatty liver disease to steatohepatitis are unavailable. Here, we describe the development and performance of a portable single-sided magnetic-resonance sensor for grading liver steatosis and fibrosis using diffusion-weighted multicomponent T2 relaxometry. In a diet-induced mouse model of non-alcoholic fatty liver disease, the sensor achieved overall accuracies of 92% (Cohen's kappa, κ = 0.89) and 86% (κ = 0.78) in the ex vivo grading of steatosis and fibrosis, respectively. Localization of the measurements in living mice through frequency-dependent spatial encoding led to an overall accuracy of 87% (κ = 0.81) for the grading of steatosis. In human liver samples, the sensor graded steatosis with an overall accuracy of 93% (κ = 0.88). The use of T2 relaxometry as a sensitive measure in fully automated low-cost magnetic-resonance devices at the point of care would alleviate the accessibility and cost limits of magnetic-resonance imaging for diagnosing liver disease and assessing liver health before liver transplantation.

Platform for micro-invasive membrane-free biochemical sampling of brain interstitial fluid.

Neurochemical dysregulation underlies many pathologies and can be monitored by measuring the composition of brain interstitial fluid (ISF). Existing in vivo tools for sampling ISF do not enable measuring large rare molecules, such as proteins and neuropeptides, and thus cannot generate a complete picture of the neurochemical connectome. Our micro-invasive platform, composed of a nanofluidic pump coupled to a membrane-free probe, enables sampling multiple neural biomarkers in parallel. This platform outperforms the state of the art in low-flow pumps by offering low volume control (single stroke volumes, <3 nl) and bidirectional fluid flow (<100 nl/min) with negligible dead volume (<30 nl) and has been validated in vitro, ex vivo, and in vivo in rodents. ISF samples (<1.5 µL) can be processed via liquid chromatography-tandem mass spectrometry. These label-free liquid biopsies of the brain could yield a deeper understanding of the onset, mechanism, and progression of diverse neural pathologies.

Simultaneous recording and marking of brain microstructures.

The vast majority of techniques to study the physiology of the nervous system involve inserting probes into the brain for stimulation, recording, or sampling. Research is increasingly uncovering the fine microstructure of the brain, each of its regions with dedicated functions. Accurate knowledge of the placement of probes interrogating these regions is critical. We have developed a customizable concentric marking electrode (CME) consisting of an iron core within a 125 µm-stainless steel (SS) sheath for co-localization of targeted regions in the brain. We used a dielectric layer stack of SiO2, Al2O3, SiO2 to electrically encapsulate the iron core and minimize exposure area to avoid significant increases in inflammatory response triggered by the probes. The CME can record multi-neuronal extracellular firing patterns. Appropriate electrical polarity of the iron and SS components controls the deposition of iron microdeposits on brain tissue. We show that in vivo labels by this method can be as small as 100 µm, visible via noninvasive magnetic resonance imaging (MRI) as well as post-mortem histology, and illustrate how deposit size can be tuned by varying stimulus parameters. We targeted the CA3 area of the hippocampus in adult rats and demonstrate that iron microdeposits are remarkably stable and persist up to 10 months post-deposition. Using a single probe for recording and marking avoids inaccuracies with re-insertion of separate probes and utilizes iron microdeposits as valuable fiducial markers in vivo and ex vivo.

Computationally Guided Intracerebral Drug Delivery via Chronically Implanted Microdevices.

Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage. Custom-fabricated chronic neural implants leverage rational fluidic design to achieve multi-bolus delivery in rodents through a single infusion of radioactive tracer (Cu-64). The resulting spatial distributions replicate computed spatial coverage with 5% error in vivo, as detected by positron emission tomography. COMMAND potentially enables accurate, efficacious targeting of discrete brain regions.

Identification and local delivery of vasodilators for the reduction of ureteral contractions.

Kidney stones and ureteral stents can cause ureteral colic and pain. By decreasing contractions in the ureter, clinically prescribed oral vasodilators may improve spontaneous stone passage rates and reduce the pain caused by ureteral stenting. We hypothesized that ureteral relaxation can be improved via the local administration of vasodilators and other smooth muscle relaxants. Here, by examining 18 candidate small molecules in an automated screening assay to determine the extent of ureteral relaxation, we show that the calcium channel blocker nifedipine and the Rho-kinase inhibitor ROCKi significantly relax human ureteral smooth muscle cells. We also show, by using ex vivo porcine ureter segments and sedated pigs that, with respect to the administration of a placebo, the local delivery of a clinically deployable formulation of the two drugs reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively. Finally, we show that standard oral vasodilator therapy reduced contraction amplitude by only 50% and had a minimal effect on contraction frequency. Locally delivered ureteral relaxants therefore may improve ureter-related conditions.