Structural modeling of ion channels using AlphaFold2, RoseTTAFold2, and ESMFold.

Ion channels play key roles in human physiology and are important targets in drug discovery. The atomic-scale structures of ion channels provide invaluable insights into a fundamental understanding of the molecular mechanisms of channel gating and modulation. Recent breakthroughs in deep learning-based computational methods, such as AlphaFold, RoseTTAFold, and ESMFold have transformed research in protein structure prediction and design. We review the application of AlphaFold, RoseTTAFold, and ESMFold to structural modeling of ion channels using representative voltage-gated ion channels, including human voltage-gated sodium (NaV) channel - NaV1.8, human voltage-gated calcium (CaV) channel - CaV1.1, and human voltage-gated potassium (KV) channel - KV1.3. We compared AlphaFold, RoseTTAFold, and ESMFold structural models of NaV1.8, CaV1.1, and KV1.3 with corresponding cryo-EM structures to assess details of their similarities and differences. Our findings shed light on the strengths and limitations of the current state-of-the-art deep learning-based computational methods for modeling ion channel structures, offering valuable insights to guide their future applications for ion channel research.

Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans.

BACKGROUND AND AIMS: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.

Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease.

BACKGROUND & AIMS: In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion. METHODS: In a double-blind randomized setting, hepatic 64Cu activity was examined after orally administered 64Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered one hour after the final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four patients with WD, the distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS: In healthy volunteers, TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In patients with WD, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time-points and significantly reduced cerebral 64Cu activity two hours after the intravenous 64Cu dose. CONCLUSIONS: While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting the exposure of organs like the liver and brain to 64Cu. IMPACT AND IMPLICATIONS: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study builds on our understanding of human copper metabolism and the mechanism of action of TTM.

Microcomputed Tomography Mineral Density Profile as Reference Standard for Early Carious Lesion Activity Assessment.

Early caries diagnosis is crucial to treatment decisions in dentistry and requires identification of lesion activity: whether a carious lesion is active (progressively demineralizing) or arrested (progressively remineralizing). This study aimed to identify microtomographic (micro-CT) differences between active and arrested smooth surface enamel lesions, to quantify those micro-CT differences by creating thresholds for ex vivo caries activity assessment to serve as a future reference standard, and to validate those thresholds against the remaining sample. Extracted human permanent teeth (n = 59) were selected for sound surfaces and non-cavitated smooth surface carious lesions. Each surface was then examined for caries activity by calibrated individuals via visual-tactile examination using the International Caries Classification and Management System (ICCMS) activity criteria. Each tooth was scanned via micro-CT and the mineral density was plotted against lesion depth. The area under the curve (AUC) was calculated and represented the loss of density for the outermost 96 µm of enamel. AUC thresholds obtained from micro-CT were established to classify sound, remineralized, and demineralized surfaces against the gold standard examiner's lesion assessment of sound, inactive, and active lesions, respectively. The established AUC thresholds demonstrated moderate agreement with the assessment in identifying demineralized lesions (k = 0.45), with high sensitivity (0.73) and specificity (0.77). This study demonstrated quantifiable differences among demineralized lesions, remineralized lesions, and sound surfaces, which contributes to the establishment of micro-CT as a reference standard for caries activity that may be used to improve clinical and laboratorial dental caries evaluations.

Missing the first post-operative visit is an independent risk factor for 90-day complication and re-admission following hip fracture surgery.

Introduction: Knowing the risk factors for poor outcomes following hip fracture surgery is necessary for appropriate patient care. The objective of this study was to determine if the first post-operative visit (POV) following hip fracture surgery is a risk factor for increased mortality, complications, and re-admissions. Methods: This was a retrospective review of 285 patients who underwent operative fixation of a hip fracture at an academic acute care hospital. Outcome measurements were 90-day and one year mortality, 90-day complications, and 90-day re-admission rates in patients who missed or attended their first post-operative visit following hip fracture surgery. Results: 279 patients met inclusion criteria and had sufficient data for analysis, of which 213 (76.3%) made their first post-operative visit. 90-day and one-year mortality were significantly higher in the patients who missed their first POV (31.8% vs. 4.2%; 51.5% vs. 12.7%). Independent risk factors for 90-day complications were missing the first POV, coronary artery disease, and lower pre-injury status (ORs = 10.65, 2.80, 7.89, respectively). Independent risk factors for 90-day re-admission were missing the first POV, chronic obstructive pulmonary disease on home oxygen, and lower re-injury status (ORs = 8.04, 5.44, 5.47, respectively). Conclusion: Missing the first POV was the strongest independent risk factor for 90-day complications and 90-day readmission. Patients who miss their first POV have significantly higher 90-day and one year mortality rates.

Anesthesia and pain management of pediatric cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy has shown to improve survival in patients with extensive or refractory abdominal tumors of many different histologies. Postoperative pain control can be challenging as the surgical procedure is performed through a midline laparotomy incision from xiphoid to symphysis pubis, and patients are usually nothing by mouth for the first 8-10 postoperative days. AIMS: We present the anesthetic management and postoperative pain control strategies for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy using a multimodal, opioid-sparing, and total intravenous anesthetic technique with a tunneled thoracic epidural. METHODS: A single institution retrospective review of anesthetic management, intraoperative fluid and blood administration, and postoperative pain control for pediatric patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy between July 2018 and December 2020 was conducted. We employed a novel anesthetic and analgesia protocol consisting of premedication with gabapentin followed by intraoperative infusions of propofol, dexmedetomidine, ketamine, and cisatracurium. A tunneled thoracic epidural catheter was placed for management of pain. RESULTS: We reviewed and analyzed the first 25 patient records. The most common diagnosis was desmoplastic small round cell tumor (n = 12). Median age of patients was 14 years (range 21 months-22 years). All patients were extubated in the operating room and no patients required reintubation. There were no incidences of acute kidney injury. Epidural infusions were used for a median of 8 days (range 2-14 days). Median postoperative intravenous opioid use (morphine equivalent) through postoperative day 10 was 0.02 mg/kg/day (range 0-0.86 mg/kg/day) administered for a median of 2 days (range 0-17 days). Nine patients (36%) did not require any intravenous opioids in the postoperative period. CONCLUSIONS: Utilizing a multimodal, opioid-sparing, total intravenous anesthetic technique in conjunction with a tunneled thoracic epidural catheter, we were able to avoid the need for postoperative mechanical ventilation and minimize both intraoperative and postoperative opioid requirements.

A Step Forward for Smart Clothes─Fabric-Based Microfluidic Sensors for Wearable Health Monitoring.

We report the first demonstration of fabric-based microfluidics for wearable sensing. A new technology to develop microfluidics on fabrics, as a part of an undergarment, is described here. Compared to conventional microfluidics from polydimethylsiloxane, fabric-based microfluidics are simple to make, robust, and suitable for efficient sweat delivery. Specifically, acrylonitrile butadiene styrene (ABS) films with precut microfluidic patterns were infused through fabrics to form hydrophobic areas in a specially controlled sandwich structure. Experimental tests and simulations confirmed the sweat delivery efficiency of the microfluidics. Electrodes were screen-printed onto the fabric-based microfluidic. A novel wearable potentiometer based on Arduino was also developed as the transducer and signal readouts, which was low-cost, standardized, open-source, and capable of wireless data transfer. We applied the sensor system as a standalone or as a module of a T-shirt to quantify [Ca2+] in a wearer's sweat, with physiological and accurate results generated. Overall, this work represents a critical step in turning regular undergarments into biochemically smart platforms for health monitoring, which will broadly benefit human healthcare.

Manufacturing-dependent change in biological activity of the TLR4 agonist GSK1795091 and implications for lipid A analog development.

A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty-four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid-study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose-dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP-10, IL10, IL1-RA). Most patients (51/54; 94%) experienced ≥1 treatment-emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti-tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds.

Palliative Care: A Survey of Program Benchmarking for Productivity and Compensation.

Background: Palliative Care (PC) encompasses an integrated health care philosophy of care for individuals with serious illnesses and their families. Referrals to palliative care often come from other healthcare clinicians who lack the time and skill required to address the needs of the patient and their caregivers. At its heart, palliative care is individualized to the values, beliefs, and goals of the patient. The process of eliciting values, beliefs, and goals takes time and expertise, and correspondingly, palliative care is labor intensive. To date, there has been no concentrated focus on how to accurately capture the productivity or work of palliative care clinicians. As a result, there is not a universally accepted method of measuring the effort which includes impact, activity, composition, and productivity of a palliative care program. Objective: This paper reviews results obtained during a telephone survey of similar hospital-based palliative care programs on how they measure productivity. Currently, based on the survey, there are two focused methods for benchmarking: work relative value units (wRVU) and consult volume. This paper highlights the variability of wRVUs and the challenge of using them to compare different PC programs. Design: The design was an open-ended question telephone survey. Using the characteristics of our hospital program, the team created a composite of descriptions to consider for comparison. Then, various hospital-based palliative care teams were selected based on publicly reported data through Vizient, a national benchmarking organization. Based on a literature review, an open-ended question survey was created. These questions explored program composition, clinician productivity and performance benchmarks. Data was collected manually and stored in a confidential file. Result: Ninety-four programs were queried that met the following composite: (1) participated in Vizient program and (2) self-reported a hospital-based, inpatient palliative program. Forty-one programs responded to the request to participate. Of these, 32 programs consisted of facilities who had hospitalists who provided palliative care, but there was not a dedicated palliative care team. Nine programs had a dedicated palliative care team with clinicians who only practiced palliative medicine. Inquiry to these programs revealed that within these nine programs-two methods of capturing clinician productivity were used-five sites used a wRVU metric and four sites used a consult volume metric. Conclusion: Preliminary findings support the complexity of benchmarking PC programs against peer institutions with a standard productivity model based on the variability in program composition.

Clinically applicable deep learning-based decision aids for treatment of neovascular AMD.

PURPOSE: Anti-vascular endothelial growth factor (Anti-VEGF) therapy is currently seen as the standard for treatment of neovascular AMD (nAMD). However, while treatments are highly effective, decisions for initial treatment and retreatment are often challenging for non-retina specialists. The purpose of this study is to develop convolutional neural networks (CNN) that can differentiate treatment indicated presentations of nAMD for referral to treatment centre based solely on SD-OCT. This provides the basis for developing an applicable medical decision support system subsequently. METHODS: SD-OCT volumes of a consecutive real-life cohort of 1503 nAMD patients were analysed and two experiments were carried out. To differentiate between no treatment class vs. initial treatment nAMD class and stabilised nAMD vs. active nAMD, two novel CNNs, based on SD-OCT volume scans, were developed and tested for robustness and performance. In a step towards explainable artificial intelligence (AI), saliency maps of the SD-OCT volume scans of 24 initial indication decisions with a predicted probability of > 97.5% were analysed (score 0-2 in respect to staining intensity). An AI benchmark against retina specialists was performed. RESULTS: At the first experiment, the area under curve (AUC) of the receiver-operating characteristic (ROC) for the differentiation of patients for the initial analysis was 0.927 (standard deviation (SD): 0.018), for the second experiment (retreatment analysis) 0.865 (SD: 0.027). The results were robust to downsampling (» of the original resolution) and cross-validation (tenfold). In addition, there was a high correlation between the AI analysis and expert opinion in a sample of 102 cases for differentiation of patients needing treatment (κ = 0.824). On saliency maps, the relevant structures for individual initial indication decisions were the retina/vitreous interface, subretinal space, intraretinal cysts, subretinal pigment epithelium space, and the choroid. CONCLUSION: The developed AI algorithms can define and differentiate presentations of AMD, which should be referred for treatment or retreatment with anti-VEGF therapy. This may support non-retina specialists to interpret SD-OCT on expert opinion level. The individual decision of the algorithm can be supervised by saliency maps.

A quantitative sensing system based on a 3D-printed ion-selective electrode for rapid and sensitive detection of bacteria in biological fluid.

Bacterial infections, such as urinary tract infections, are crucial health problems. Here, we report a new potentiometric sensor to detect bacteria sensitively, accurately, and quickly. First, a customizable, 3D printed Ag+ selective electrode was fabricated as the probe. Our 3D printed electrode showed sensitive, linear, and selective responses to Ag+. Compared to commercial Ag+ selective electrodes, ours required less sample volume, shorter responding time, and lower costs. Next, a novel potentiometer was developed with Arduino to couple the electrode for data transducing and transferring, which was programmed to transfer results to cell phones wirelessly. Moreover, a filter was designed to quickly remove interfering species in a biofluid sample (e.g., Cl-). By detecting the lost Ag+ taken by bacteria, the bacterial number could be elucidated. With this sensor system, bacteria numbers could be detected as low as 80 CFU/mL (LOD) within 15 min, which is sufficient for many diagnoses (e.g., urinary tract infection >1000 CFU/mL). An amplification method was presented for single-digit bacteria detection. Overall, we are presenting a bacteria detector with three innovative components: the electrode (signal transduction and detection), the potentiometer (transducer and data processing), and the 3D printed filter (sample preparation), which showed robust and improved (than previously reported ones) analytical merits. The low-cost and customizable (the electrode and the open-source coding) nature enhances the transnationality of the system, especially in underdeveloped areas.

Knowledge and the brain: Why the knowledge-centric theory of mind program needs neuroscience.

The knowledge-centric theory of mind research program suggested by Phillips et al. stands to gain significant value by embracing a neurocognitive approach that takes full advantage of techniques such as fMRI and EEG. This neurocognitive approach has already begun providing important insights into the mechanisms of knowledge attribution, insights which support the claim that it is more basic than belief attribution.

How does Covid-19 affect urban slums? Evidence from settlement leaders in India.

Slum settlements have received significant attention for their vulnerabilities to the spread of Covid-19. To mitigate risks of transmission, and alleviate economic distress associated with containment measures, public health experts and international agencies are calling for community-driven solutions that harness local participation. In slum settlements, such approaches will encounter the informal slum leaders present across cities of the Global South. How are slum leaders positioned to address the health and livelihood threats of the pandemic within their neighborhoods? What problem-solving activities, if any, have they performed for residents during the pandemic? What factors shape success in those efforts? To answer these questions, we conducted a phone survey of 321 slum leaders across 79 slum settlements in two north Indian cities. The survey was conducted in April and May 2020, at the height of India's stringent national lockdown in response to the virus. Our survey reveals striking continuities with pre-pandemic politics. First, slum leaders persist in their problem-solving roles, even as they shift their efforts towards requesting urgently needed government relief (particularly food rations). Second, slum leaders vary in their reported ability to gather information about relief schemes, make claims, and command government responsiveness. The factors that inform the effectiveness of slum leaders during 'normal times', notably their education and degree of embeddedness in party networks, continue to do so during the lockdown. Slum leader reliance on partisan networks raises concerns regarding the inclusiveness of their efforts. Finally, slums are not uniformly challenged in maintaining social distancing. Pre-pandemic disparities in infrastructural development fragment the degree to which residents must depart from social distancing guidelines to secure essential services.

Making quantitative biomicrofluidics from microbore tubing and 3D-printed adapters.

Microfluidic technology has tremendously facilitated the development of in vitro cell cultures and studies. Conventionally, microfluidic devices are fabricated with extensive facilities by well-trained researchers, which hinder the widespread adoption of the technology for broader applications. Enlightened by the fact that low-cost microbore tubing is a natural microfluidic channel, we developed a series of adaptors in a toolkit that can twine, connect, organize, and configure the tubing to produce functional microfluidic units. Three subsets of the toolkit were thoroughly developed: the tubing and scoring tools, the flow adaptors, and the 3D cell culture suite. To demonstrate the usefulness and versatility of the toolkit, we assembled a microfluidic device and successfully applied it for 3D macrophage cultures, flow-based stimulation, and automated near real-time quantitation with new knowledge generated. Overall, we present a new technology that allows simple, fast, and robust assembly of customizable and scalable microfluidic devices with minimal facilities, which is broadly applicable to research that needs or could be enhanced by microfluidics.

Performance of the Wells score in predicting deep vein thrombosis in medical and surgical hospitalized patients with or without thromboprophylaxis: The R-WITT study.

The Wells score had shown weak performance to determine pre-test probability of deep vein thrombosis (DVT) for inpatients. So, we evaluated the impact of thromboprophylaxis on the utility of the Wells score for risk stratification of inpatients with suspected DVT. This bicentric cross-sectional study from February 1, 2018 to January 31, 2019 included consecutive medical and surgical inpatients who underwent lower limb ultrasound study for suspected DVT. Wells score clinical predictors were assessed by both ordering and vascular physicians within 24 h after clinical suspicion of DVT. Primary outcome was the Wells score's accuracy for pre-test risk stratification of suspected DVT, accounting for anticoagulation (AC) treatment (thromboprophylaxis for ⩾ 72 hours or long-term anticoagulation). We compared prevalence of proximal DVT among the low, moderate and high pre-test probability groups. The discrimination accuracy was defined as area under the receiver operating characteristics (ROC) curve. Of the 415 included patients, 30 (7.2%) had proximal DVT. Prevalence of proximal DVT was lower than expected in all pre-test probability groups. The prevalence in low, moderate and high pre-test probability groups was 0.0%, 3.1% and 8.2% (p = 0.22) and 1.7%, 4.2% and 25.8% (p < 0.001) for inpatients with or without AC, respectively. Area under ROC curves for discriminatory accuracy of the Wells score, for risk of proximal DVT with or without AC, was 0.72 and 0.88, respectively. The Wells score performed poorly for discrimination of risk for proximal DVT in hospitalized patients with AC but performed reasonably well among patients without AC; and showed low inter-rater reliability between physicians. ClinicalTrials.gov Identifier: NCT03784937.

Novel bilateral bifurcation of the coronary vasculature.

Multiple variants and anomalies in the coronary vasculature have been reported. Some variants, particularly those with duplication, can be advantageous, many are insignificant and some are ultimately lethal. Many of these variants and anomalies are not identified until imaged or post-mortem. A novel bilateral bifid variation of the coronary arteries was observed in 49-year-old male cadaver. The respective origins were associated with the left and right aortic cusps from single ostia. Immediate bifurcation followed on either side. A right sided accessory branch supplied the pulmonary trunk and right ventricle. A more standard branch continued to form the posterior interventricular artery. The left sided variation demonstrated a solitary circumflex artery (towards the posterior interventricular septum) and, left marginal and anterior interventricular branches shortly after bifurcation. This case may be beneficial in surviving adverse cardiac events, particularly those associated with lifestyle. They also present a 'double' challenge for clinicians.

Novel bilateral bifurcation of the coronary vasculature / 대한해부학회지

Multiple variants and anomalies in the coronary vasculature have been reported. Some variants, particularly those with duplication, can be advantageous, many are insignificant and some are ultimately lethal. Many of these variants and anomalies are not identified until imaged or post-mortem. A novel bilateral bifid variation of the coronary arteries was observed in 49-year-old male cadaver. The respective origins were associated with the left and right aortic cusps from single ostia. Immediate bifurcation followed on either side. A right sided accessory branch supplied the pulmonary trunk and right ventricle. A more standard branch continued to form the posterior interventricular artery. The left sided variation demonstrated a solitary circumflex artery (towards the posterior interventricular septum) and, left marginal and anterior interventricular branches shortly after bifurcation. This case may be beneficial in surviving adverse cardiac events, particularly those associated with lifestyle. They also present a ‘double’ challenge for clinicians.

Novel bilateral bifurcation of the coronary vasculature / 대한해부학회지

Multiple variants and anomalies in the coronary vasculature have been reported. Some variants, particularly those with duplication, can be advantageous, many are insignificant and some are ultimately lethal. Many of these variants and anomalies are not identified until imaged or post-mortem. A novel bilateral bifid variation of the coronary arteries was observed in 49-year-old male cadaver. The respective origins were associated with the left and right aortic cusps from single ostia. Immediate bifurcation followed on either side. A right sided accessory branch supplied the pulmonary trunk and right ventricle. A more standard branch continued to form the posterior interventricular artery. The left sided variation demonstrated a solitary circumflex artery (towards the posterior interventricular septum) and, left marginal and anterior interventricular branches shortly after bifurcation. This case may be beneficial in surviving adverse cardiac events, particularly those associated with lifestyle. They also present a ‘double’ challenge for clinicians.

Transrectal Ureteroscopic Stone Management in a Patient with Ureterosigmoidostomy.

Background: Published case reports on the management of ureteral stones in patients with prior ureterosigmoidostomy have described the challenges of direct retrograde access to the ureter using standard endourologic instruments. In light of these challenges, reported effective techniques have involved either (1) direct retrograde access utilizing sigmoid endoscopy with air insufflation or (2) percutaneous antegrade access. We report the first experience of effective retrograde ureteroscopy utilizing traditional endourologic instruments in a patient without percutaneous access. Case Presentation: The patient is a 70-year-old man born with bladder exstrophy who underwent end colostomy and ureterosigmoidostomy as a child. He presented with a symptomatic 6 mm stone at the right ureterosigmoid junction. A trial of spontaneous passage failed because of persistent pain. Treatment options were limited by the patient's recent history of coronary stent placement, requiring uninterrupted antiplatelet therapy with clopidogrel. As such, we attempted retrograde ureteroscopy through a transrectal approach. Anticipating some difficulty in the identification of the ureteral orifices, we administered methylene blue at the time of induction. After placing the patient in lithotomy position, we advanced a flexible cystoscope to the rectosigmoid junction where we identified a ureteral orifice. Guidewire access was obtained and we confirmed right-sided laterality with fluoroscopic imaging. A semirigid ureteroscope was passed to the ureterosigmoid junction where the stone was encountered and retrieved intact using a basket. A 6 × 26 Double-J stent was placed with a string to facilitate removal 5 days later. The postoperative course was unremarkable. Conclusion: Despite the previously reported challenges of the approach, retrograde ureteroscopy without percutaneous access represents a viable treatment option for ureteral stones in patients with ureterosigmoidostomy.