Bisphosphonium Benzene Diimides.

The incorporation of cationic groups onto electron-poor compounds is a viable strategy for achieving potent electron acceptors, as evidenced by reports of air-stable radical forms of large aromatic diimides such as naphthalene and perylene diimides. These ions have also been observed to exhibit anion-π interaction tendencies of interest in molecular recognition applications. The benefits of phosphonium incorporation, however, have not yet been extended to the smallest benzene diimides. Here, we report that dibrominated pyromellitic diimide and mellophanic diimide both readily undergo substitution reactions with phosphine sources to yield bisphosphonium compounds. In the single crystalline form, these dications display anion-π interactions and, in the case of mellophanic diimide, the stabilization of a bromide-water H-bonding ring pattern. The reaction of these dications with chemical reductants readily provides the singly and doubly reduced redox states, which were characterized by UV-vis spectroscopy and found to exhibit intense absorptions extending into the near-IR region. Taken together, this work demonstrates that phosphonium incorporation onto congested aromatic diimide scaffolds is synthetically viable and produces unusual electron-poor compounds.

Coherent magnon-induced domain-wall motion in a magnetic insulator channel.

Advancing the development of spin-wave devices requires high-quality low-damping magnetic materials where magnon spin currents can efficiently propagate and effectively interact with local magnetic textures. Here we show that magnetic domain walls can modulate spin-wave transport in perpendicularly magnetized channels of Bi-doped yttrium iron garnet. Conversely, we demonstrate that the magnon spin current can drive domain-wall motion in the Bi-doped yttrium iron garnet channel device by means of magnon spin-transfer torque. The domain wall can be reliably moved over 15-20 µm distances at zero applied magnetic field by a magnon spin current excited by a radio-frequency pulse as short as 1 ns. The required energy for driving the domain-wall motion is orders of magnitude smaller than those reported for metallic systems. These results facilitate low-switching-energy magnonic devices and circuits where magnetic domains can be efficiently reconfigured by magnon spin currents flowing within magnetic channels.

Intrarenal Pressure with Vacuum-Assisted Ureteral Access Sheaths Using an In Situ Cadaveric Porcine Model.

Introduction: Vacuum-assisted ureteral access sheaths (V-UASs) are a new tool designed to evacuate dust or small fragments during retrograde intrarenal surgery (RIRS). There are reports of increased stone-free rates, decreased infections, and decreased operative time with V-UAS usage. The optimal technique and setting for V-UAS has yet to be described. Herein, we investigate real-time intrarenal pressure (IRP) throughout a range of settings using V-UAS in a porcine RIRS model. Materials and Methods: Ureteroscopy was performed in three female porcine cadaver kidneys through a ClearPetra V-UAS. IRP was recorded through a percutaneous catheter at different inflow pressures, sheath sizes, sheath distance from the ureteropelvic junction, and suction settings. Magnitude of change in delta IRP (dIRP) was compared at various settings. Results: There was no statistical difference in IRP when comparing no suction with vent inactivated. As expected, IRP decreased with larger sheath size and lower irrigation pressures. Average IRP dropped ∼18 mm Hg with suction activation (42.30 mm Hg, vent inactivated; 24.45 mm Hg IRP, suction activated; p < 0.0001). Irrigation pressure and sheath size did not make a difference in the dIRP. dIRP was significantly greater at lower suction settings compared with max suction (25.44 dIRP at 200 mm Hg suction, 10.26 mm Hg dIRP at max suction, p = 0.04). In a subset of observations, IRP paradoxically increased to higher than IRP with no suction at all after >5 seconds of activated suction. Conclusion: Use of V-UAS during RIRS can lower mean IRP; however, this effect could reverse with extended suctioning especially under conditions of high vacuum (>200 mm Hg) owing to outflow tract collapse. Our results suggest urologists should use lower suction settings and short, <5-second bursts to maximize therapeutic benefit, and minimize potential shortcomings of V-UAS during RIRS.

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

OBJECTIVES: To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events. MATERIALS AND METHODS: This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm2/m2]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m2]), visceral adipose index (VAI [cm2/m2]), and subcutaneous adipose index (SAI [cm2/m2]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy. Chemotherapy-associated adverse events (AE) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0.) Changes in body composition were quantified. Predictors of change in body composition were evaluated with multivariable linear regression. Associations between baseline or change in body composition and AEs were estimated with multivariable logistic regression adjusting for age, comorbidity, performance status, stage, and number/type of chemotherapy cycles. RESULTS: 141 patients (median age, 30 years [IQR 25-39]) including 86 patients (61%) with non-seminomatous GCT were included. Patients received a median of 3 cycles of cisplatin-based chemotherapy, and 124 patients (88%) completed planned chemotherapy. Median observed changes in SMI, SMD, and SMG were -6% (P<0.0001), -2% (P=0.07), and -7% (P<0.0001), respectively, while FMI increased 5.3% (P<0.0001). Overall, 120 patients (85%) experienced at least one AE including one or more ≥grade 3 AE in 57 patients (48%). Decrease in SMI (OR: 0.89, P=0.02), decrease in SMG (OR: 0.88, P=0.01,) and post-chemotherapy SMG (OR: 0.94, P=0.05) were independently associated with higher incidence of AEs, while pre-chemotherapy skeletal muscle parameters and post-chemotherapy SMI and SMD were not associated with AEs (P>0.05 for all). Preoperative adipose tissue or change in adiposity was not associated with incidence of AEs. CONCLUSIONS: In men with GCT receiving cytotoxic chemotherapy, a decrease in skeletal muscle mass and quality during chemotherapy were associated with a higher incidence of chemotherapy-associated AEs. Adipose tissue was not associated with the incidence of AEs.

Evaluating the extent of change in near point of convergence in traumatic brain injury: a systematic review and meta-analysis.

OBJECTIVE: Traumatic brain injury (TBI) causes significant impact on visual system. This study reports the impact of TBI on the near point of convergence (NPC) measure in individuals with mild TBI. METHODS: A systematic review and meta-analysis were conducted for studies that quantified NPC changes in mild TBI. The relevant studies were searched using search engines such as PubMed, EMBASE, Medline and Google Scholar. Thirty studies fulfilled the criteria for systematic review while twelve studies were included in the meta-analysis from 444 patients with mild TBI and 881 controls. RESULTS: This study showed a large and significant impact of head injury on the clinical measure of NPC in patients with mild TBI with a combined effect size of 0.98(95% CI: 0.67-1.29) and significantly moderate heterogeneity (Q(18) = 60.84,P = .001,I2 = 72.06%). Moderator analysis and subgroup analysis showed no difference in effect size with age and post-injury period. CONCLUSIONS: This study demonstrated that NPC is largely affected by the impact of TBI. Given the ease with which it can be measured and without the need of specialists and dedicated equipment, NPC measure might provide a supplementary measure of oculomotor function in addition to less sensitive and more subjective questionnaires and personal reports.

Strategies to Optimize Nephrolithiasis Emergency Care (STONE): Prospective Evaluation of an Emergency Department Clinical Pathway.

OBJECTIVE: To convene a multi-disciplinary panel to develop a pathway for Emergency Department (ED) patients with suspected nephrolithiasis and then prospectively evaluate its effect on patient care. MATERIALS AND METHODS: The STONE Pathway was developed and linked to order sets within our Electronic Health Record in April 2019. Records were prospectively reviewed for ED patients who underwent ultrasound or Computerized Tomography (CT) to evaluate suspected nephrolithiasis between January 2019 and August 2019 within our institution. The primary outcome measure was the proportion of patients whose ED CT was low dose (<4 mSv). Secondary outcome measures included receipt of pathway-concordant pain medications and urine strainers. Order set utilization was evaluated as a process measure. Balance measures assessed included repeat ED visits, imaging, hospitalizations, and a urologic clinic visit or surgery within 30 days of discharge. RESULTS: 441 patients underwent ED imaging, of whom 261 (59%) were evaluated for suspected nephrolithiasis. The STONE Pathway was used in 50 (30%) eligible patients. Patients treated with the Pathway were more likely to undergo low-dose CTs (49% vs 23%, P <.001), and receive guideline-concordant pain medications such as NSAIDs (90% vs 62%, P <.001), and were less likely to return to the ED within 30 days (13% vs 2%, P = .01). These measures demonstrated special cause variation following Pathway release. CONCLUSION: Clinical pathways increase compliance with evidence-based practices for pain control and imaging in nephrolithiasis emergency care and may improve the delivery of value-based care.

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy.

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

Inpatient Opioid Use Poorly Predicts Discharge Opioid Prescriptions Following Nephrectomy.

INTRODUCTION: The overprescribing of opioids after urological surgery places patients at risk for opioid overuse and dependency. However, few guidelines exist to help urologists consistently prescribe appropriate quantities of pain medications. We sought to characterize the variation in opioid prescribing habits at time of discharge following nephrectomy. METHODS: We performed a retrospective review of patients who underwent partial or radical nephrectomy between November 2016 and May 2018 at an academic medical center. We reviewed patient, procedure and provider level variables potentially associated with high opioid use. Daily inpatient opioid use and discharge opioid prescriptions were tabulated in oral morphine equivalents. RESULTS: We identified 173 eligible patients who used a daily average of 36 oral morphine equivalents during their hospitalization weaning to 27 oral morphine equivalents on the day of discharge. All but 2 patients were prescribed opioids at discharge with an average of 367 oral morphine equivalents per prescription (SD 284). On multiple linear regression preoperative opioid use, open vs minimally invasive approach, length of stay and last day opioid use were associated with discharge oral morphine equivalents (R2=0.51, p <0.05). CONCLUSIONS: Patients were discharged with excessive opioids with an average discharge prescription equivalent to 13.6 times the last inpatient day's use. When combined with other potential predictors of discharge opioid prescriptions inpatient use accounts for less than 50% of the variance between prescriptions. Systems are needed to help minimize variability in opioid prescribing practices and reduce the overall quantity prescribed.

High Burden of In-Person Kidney Cancer Surveillance in a Low Resource Population.

INTRODUCTION: Postoperative kidney cancer surveillance is predominantly based on imaging and laboratory evaluation rather than physical exam. We sought to characterize the burden of kidney cancer surveillance in a low resource population with an aim to identify opportunities for telehealth implementation. METHODS: We retrospectively reviewed patients who underwent partial or radical nephrectomy between November, 2016 and May, 2018 at an academic medical center. We reviewed patient demographic characteristics, travel distance to hospital, and Center for Medicare & Medicaid Services designation of home ZIP code as low income area or health professional shortage area. Followup visits were reviewed for imaging and laboratory studies as well as new physical exam findings. RESULTS: We identified 156 patients who attended 234 followup visits at mean 2.4 months (SD=2.9 months) postoperatively. Patient home ZIP codes were designated as low income area or health professional shortage area in 93 (59.6%) cases. One-way travel was mean 194 miles (SD=438 miles) per visit. When intended, laboratory or imaging studies were not obtained ahead of followup visits in 34 of 196 cases (17%). Based on the absence of new physical exam findings or procedures performed 201 (86%) visits could have potentially been performed remotely. CONCLUSIONS: Patients living in low income areas and health professional shortage areas are asked to travel long distances to perform kidney cancer surveillance often to review data that could be obtained remotely. Necessary imaging or laboratory studies are frequently not obtained ahead of appointments, further diminishing visit value. Kidney cancer surveillance may offer a promising opportunity for telehealth implementation within urology.

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.

Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.

A biocompatible reverse thermoresponsive polymer for ocular drug delivery.

Age-related macular degeneration (AMD) is a leading cause of vision loss, the treatment of which may require monthly intravitreal injections. This is a burden on patients and health services, and new delivery modalities that reduce injection frequency are required. To that end, we investigated the suitability of a novel reverse thermoresponsive polymer (RTP) as an ocular drug-delivery vehicle. In this work, we detail the structure and synthesis of a novel RTP, and determine drug release curves for two drugs commonly used in the treatment of AMD, bevacizumab and aflibercept. Biocompatibility of the RTP was assessed in vitro in human and rat cell lines and in vivo following intravitreal injection in rats. Bevacizumab demonstrated a more appropriate release profile than aflibercept, with 67% released within 14 days and 78% released in total over a 183-day period. No toxic effects of RTP were seen in human or rat cells in up to 14 days of co-culture with RTP. Following intravitreal injection, intraocular pressure was unaffected by the presence of RTP and no changes in retinal function or structure were observed at 1 week or 1 month post-injection. RTP injection did not cause inflammation, gliosis or apoptosis in the retina. This work demonstrates the potential suitability of the novel RTP as a sustained-release vehicle for ocular drug delivery for anti-neovascular therapies. Optimization of polymer chemistry for optimal drug loading and release is needed.