RAD18 opposes transcription-associated genome instability through FANCD2 recruitment.

DNA replication is a vulnerable time for genome stability maintenance. Intrinsic stressors, as well as oncogenic stress, can challenge replication by fostering conflicts with transcription and stabilizing DNA:RNA hybrids. RAD18 is an E3 ubiquitin ligase for PCNA that is involved in coordinating DNA damage tolerance pathways to preserve genome stability during replication. In this study, we show that RAD18 deficient cells have higher levels of transcription-replication conflicts and accumulate DNA:RNA hybrids that induce DNA double strand breaks and replication stress. We find that these effects are driven in part by failure to recruit the Fanconi Anemia protein FANCD2 at difficult to replicate and R-loop prone genomic sites. FANCD2 activation caused by splicing inhibition or aphidicolin treatment is critically dependent on RAD18 activity. Thus, we highlight a RAD18-dependent pathway promoting FANCD2-mediated suppression of R-loops and transcription-replication conflicts.

Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

ARID1A regulates R-loop associated DNA replication stress.

ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

Adolescent Kidney Outcomes after Extremely Preterm Birth and Neonatal Acute Kidney Injury: There May be More to the Story.

OBJECTIVE: Among children born extremely preterm (EP), the antecedents of chronic kidney disease (CKD), including neonatal acute kidney injury (nAKI), are not well characterized. STUDY DESIGN: This was a retrospective cohort pilot study. Participants (n = 36) were adolescents born before 28 weeks of gestation enrolled at birth into the extremely low gestational age newborn study, between 2002 and 2004, at the University of North Carolina. Participants were stratified by the primary exposure to nAKI, defined using the modified Kidney Disease Improving Global Outcomes nAKI criteria. Baseline serum creatinine (SCr) was defined as the lowest SCr after 48 to 72 postnatal hours. The primary outcome was an abnormal kidney profile during adolescence, defined as having one or more of these outcomes: elevated blood pressure (>120/80 mm Hg), microalbuminuria (urine microalbumin/creatinine >30 µg/g), or an abnormal kidney volume measured by ultrasound (total kidney volume corrected for body surface area <10th%ile for age). RESULTS: Half of the participants had a history of nAKI. Thirteen had stage 1 nAKI, four had stage 2, and one had stage 3 nAKI. At 15 years of age, 50% were overweight/obese, 31% had elevated blood pressure (BP), 11% had abnormal kidney volumes, and 17% had microalbuminuria. The relative risk for having an abnormal kidney profile during adolescence among participants with a history of nAKI was 0.63 (95% confidence interval: 0.3-1.3, p = 0.2). CONCLUSION: In this sample of adolescents born EP, a history of nAKI was not associated with elevated BP, microalbuminuria, or abnormal kidney volume. Future studies are needed in larger samples to better characterize the relationship between nAKI and CKD in EP-born children. KEY POINTS: · Extremely preterm birth is associated with acute kidney injury.. · Extremely preterm birth is associated with chronic kidney disease.. · Neonatal acute kidney injury after extremely preterm birth was not associated with kidney outcomes..

Tongue cancer developing after haematopoietic stem cell transplantation for treatment of acute promyelocytic leukaemia: A case report.

Acute promyelocytic leukaemia (APL) is a form of acute myelogenous leukaemia. APL is characterised by anaemia due to suppression of normal haematopoiesis and infection. Haematopoietic stem cell transplantation (HSCT) is current option for the treatment of haematopoietic malignancies and is proving to be successful. Although HSCT has been effective for the treatment of haematopoietic malignant tumours, chronic graft-versushost disease (GVHD) but secondary cancers can occur, which is a serious complication and frequently involves the oral cavity and skin. Here, we report the case of tongue cancer occurring 17 years after transplantation in a patient who developed GVHD after haematopoietic stem cell transplantation and APL remission. To the best of our knowledge, this is the first report of secondary oral cancer after HSCT with APL as the primary disease.

Comparing internal versus external carotid artery branch delivery of intraarterial chemotherapy for the treatment of retinoblastoma.

PURPOSE: The goal of this study was to compare the efficacy of intraarterial chemotherapy (IAC) for retinoblastoma delivered via the ophthalmic artery (OA) division of the internal carotid artery (ICA) versus alternative branches of the external carotid artery (ECA). METHODS: We performed a retrospective chart review of patients receiving IAC for retinoblastoma at a single institution. Subjects were divided into three groups: those that received IAC solely through the OA branch of the ICA, those that initially received IAC through the OA branch of the ICA but were later switched to the ECA, and those that only received IAC through the ECA. The main outcomes compared included globe salvage rate and reduction in tumor thickness and size. RESULTS: A total of 30 eyes from 26 patients were included. A total of 91 (58%) sessions of IAC were performed through the OA division of the ICA and 65 (42%) were performed through branches of the ECA. Eleven eyes (37%) solely received IAC through the OA branch of the ICA, 16 eyes (53%) were converted to ECA treatment, and 3 eyes solely received IAC through branches of the ECA. Statistical analysis did not show any significant difference in globe salvage rate or reduction in tumor thickness and size. CONCLUSION: The use of alternative approaches for IAC when the OA branch of the ICA catheterization is not feasible allows for safe continued delivery of highly effective IAC, leading to similar outcomes in terms of globe salvage and reduction in tumor size.

Toward Decentralizing Antibiotic Susceptibility Testing via Ready-to-Use Microwell Array and Resazurin-Aided Colorimetric Readout.

In the face of the global threat from drug-resistant superbugs, there remains an unmet need for simple and accessible diagnostic tools that can perform important antibiotic susceptibility testing against pathogenic bacteria and guide antibiotic treatments outside of centralized clinical laboratories. As a potential solution to this important problem, we report herein the development of a microwell array-based resazurin-aided colorimetric antibiotic susceptibility test (marcAST). At the core of marcAST is a ready-to-use microwell array device that is preassembled with custom titers of various antibiotics and splits bacterial samples upon a simple syringe injection step to initiate AST against all antibiotics. We also employ resazurin, which changes from blue to pink in the presence of growing bacteria, to accelerate and enable colorimetric readout in our AST. Even with its simplicity, marcAST can accurately measure the minimum inhibitory concentrations of reference bacterial strains against common antibiotics and categorize the antibiotic susceptibilities of clinically isolated bacteria. With more characterization and refinement, we envision that marcAST can become a potentially useful tool for performing AST without trained personnel, laborious procedures, or bulky instruments, thereby decentralizing this important test for combating drug-resistant superbugs.

Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States.

RATIONALE & OBJECTIVE: Underlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes. STUDY DESIGN: Retrospective cohort study. SETTINGS & PARTICIPANTS: 4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States. PREDICTOR(S): Presence (vs absence) of pre-existing kidney disease. OUTCOME(S): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary). ANALYTICAL APPROACH: We used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations. RESULTS: Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]). LIMITATIONS: Potential residual confounding. CONCLUSIONS: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population.

Impaired salivary SIgA antibodies elicit oral dysbiosis and subsequent induction of alveolar bone loss.

OBJECTIVE: Secreted IgA (SIgA) plays a central role in preventing bacterial and viral infections on mucosal surfaces by neutralizing toxins and viruses and inhibiting bacterial attachment to epithelial cells. However, the role of salivary SIgA antibodies (Abs) in regulating oral flora is still unknown. This study aimed to evaluate the association among oral bacteria, their metabolites and periodontitis in IgA-deficient (IgA KO) and wild-type (WT) control mice. METHODS: Microcomputed tomography (micro-CT) analysis was used to assess alveolar bone resorption as a development of periodontitis. The bacterial profiles of saliva were determined using the next-generation sequencing assays. Furthermore, the metabolites in saliva were measured and compared using CE-TOFMS. RESULTS: Salivary microbiota of IgA KO mice revealed a remarkably decreased frequency of Streptococcus, and increased percentages of Aggregatibacer, Actinobacillus, and Prevotella at the genus level when compared with those of WT. Compared to WT control mice of the same age, the level of alveolar bone loss was significantly increased in IgA KO mice, and infiltration of osteoclasts was found on the surface of the alveolar bone. The metabolome profile indicated that the metabolites of IgA KO mice had greater variability in carbon metabolic, urea cycle, and lipid pathways than WT mice. CONCLUSION: These results suggest that salivary SIgA plays an important role in regulating and maintaining normal oral microflora to prevent the development of periodontal disease.

A novel OCT signature in leukemic papillopathy masquerading as autoimmune or infectious uveitis.

PURPOSE: With therapeutic advances, central nervous system (CNS) involvement in leukemia has become more common. Leukemic optic disc infiltration, often a clinical diagnosis, can present as an isolated finding in primary or relapsed CNS disease and therefore requires early recognition. Not previously well appreciated, we report here signs of intraocular inflammation accompanying leukemic optic disc infiltration, suggesting infectious or non-infectious uveitis as an alternative diagnosis. We describe a novel optical coherence tomography (OCT) sign favoring leukemic infiltration. METHODS: Retrospective consecutive case series of all leukemic patients with disc edema (5 patients, 6 eyes) presenting to the University of Michigan's Ocular Oncology Clinic between October 2019 and March 2020. RESULTS: We report five leukemic patients (6 eyes) who were evaluated for disc edema and vitritis and eventually diagnosed with leukemic papillopathy. All five patients initially had a bland lumbar puncture (LP), and all four patients who underwent magnetic resonance imaging (MRI) had no retrobulbar nerve involvement. Clinical findings included preserved visual acuity (n = 5 eyes, 83%), anterior chamber (AC) cell (n = 3 eyes, 50%), vitreous cell (n = 6 eyes, 100%), and retinal whitening (n = 4 eyes, 66%). In five eyes (83%), a diagnosis of infectious or non-infectious uveitis was initially considered. The OCT finding of inner retinal thickening and loss of inner retinal lamination with largely preserved outer retinal architecture helped point towards a leukemic infiltrative process emanating from the disc and spreading retrograde through the nerve fiber layer. CONCLUSIONS: These cases highlight the difficulty of distinguishing intraocular inflammation associated with leukemic papillopathy from infectious or non-infectious uveitis, especially considering bland LP and negative retrobulbar MRI signal in all our patients. We propose juxtapapillary inner retinal infiltration with the loss of inner retinal lamination and relative preservation of outer retinal architecture on OCT imaging as a finding that supports the diagnosis of leukemic papillopathy.

CDDO-Me, Sulforaphane and tBHQ attenuate the RANKL-induced osteoclast differentiation via activating the NRF2-mediated antioxidant response.

Metabolic bone diseases are global public health concerns and are primarily caused by uncontrolled osteoclast (OC) formation and activation. During OC differentiation, intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can serve as the signaling molecules to promote osteoclastic genes expression. Nuclear factor erythroid-2 related factor 2 (NRF2), a master mediator of cellular antioxidant response, also plays a critical role in OC differentiation through the regulation of redox homeostasis. In this study, we investigated the effects of three NRF2 inducers on osteoclastogenesis, including Bardoxolone methyl (CDDO-Me), Sulforaphane (SFN), and tert-butylhydroquinone (tBHQ). By treating RAW cells with three compounds, we found that NRF2 was activated and its downstream antioxidant genes were upregulated, and the RANKL-induced intracellular ROS production and osteoclastogenesis were impaired. Additionally, the expression of nuclear factor of activated T cells c1 (NFATC1), C-FOS and tumor necrosis factor alpha (TNFα) were inhibited after acute exposures (6 h) to the three compounds. Furthermore, suppressed the expression of osteoclast differentiation-associated genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase-9 (MMP-9) and dendritic cell-specific transmembrane protein (DC-STAMP) were observed after prolonged exposures (5 days) to the compounds. Taken together, these results suggest that CDDO-Me, SFN and tBHQ attenuate RANKL-induced osteoclastogenesis via activation of NRF2-mediated antioxidant response. Among these compounds, relatively low concentrations of CDDO-Me showed stronger active and inhibitory effects on antioxidant response and osteoclastogenesis, respectively.

Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.

Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.

At What Cost to Clinical Trial Enrollment? A Retrospective Study of Patient Travel Burden in Cancer Clinical Trials.

BACKGROUND: Recent literature suggests that living in a rural setting may be associated with adverse cancer outcomes. This study examines the burden of travel from home to cancer center for clinical trial (CT) enrollees. MATERIALS AND METHODS: Patients from the University of California San Francisco Clinical Trial Management System database who enrolled in a cancer CT for a breast, genitourinary, or gastrointestinal malignancy between 1993 and 2014 were included. Cancer type, household zip code, race/ethnicity, phase of study, study sponsor, and year of signed consent were exported. Distance traveled from home to center was calculated using a GoogleMaps application programming interface. The relationships of distance with phase of CT, household income, and race/ethnicity were examined. RESULTS: A total of 1,600 patients were enrolled in breast (55.8%), genitourinary (29.4%), or gastrointestinal (14.9%) cancer CTs. The overall median unidirectional distance traveled from home to study site was 25.8 miles (interquartile range [IQR] 11.5-75.3). Of the trial sponsors examined, principal investigator (56.4%), industry (22.2%), cooperative group (11.6%), and National Institutes of Health (NIH; 9.8%), the longest distance traveled was for NIH-sponsored trials, with a median of 39.4 miles (p < .001). Phase I (8.4%) studies had the longest distance traveled, with a median of 41.2 miles (IQR 14.5-101.0 miles; p = .001). White patients (83%) traveled longer compared with black patients (4.4%), with median distances of 29.9 and 13.9 miles, respectively (p < .001). Patients from lower-income areas (n = 799) traveled longer distances compared with patients from higher-income areas (n = 773; 58.3 vs. 17.8 miles, respectively; p < .001). A multivariable linear model where log10 (distance) was the outcome and adjusting for the exported variables and income revealed that cancer type, year of consent, race/ethnicity, and income were significantly associated with distance traveled. CONCLUSION: This study found that the burden of travel is highest among patients enrolled in NIH-sponsored trials, phase I studies, or living in low-income areas. These data suggest that travel burden for cancer CT participants may be significant. IMPLICATIONS FOR PRACTICE: This study is one of the first to measure travel distance for patients in cancer clinical trials using a real-world GoogleMaps calculator. Out-of-pocket expenses such as travel are not typically covered by health care payers; therefore, patients may face considerable cost to attend each study visit. Using a single-center clinical trials enrollment database, this study found that the burden of travel is highest for patients enrolled in National Institutes of Health-sponsored trials and phase I studies, as well as for patients living in low-income areas. Results suggest that a significant proportion of patients enrolled in clinical trials face a substantial travel burden.

A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration-Resistant Prostate Cancer.

LESSONS LEARNED: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space. BACKGROUND: Selinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO-1), leading to nuclear accumulation of tumor suppressor proteins. METHODS: This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide. RESULTS: Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had ≥50% prostate-specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3-4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability. CONCLUSION: Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents.

Immune Response and Mortality Risk Relate to Distinct Lung Microbiomes in Patients with HIV and Pneumonia.

RATIONALE: The potential role of the airway microbiota in dictating immune responses and infection outcomes in HIV-associated pneumonia is largely unknown. OBJECTIVES: To investigate whether microbiologically and immunologically distinct subsets of patients with HIV and pneumonia exist and are related to mortality. METHODS: Bronchoalveolar lavage samples from Ugandan patients with HIV and pneumonia (n = 182) were obtained at study enrollment (following antibiotic treatment); patient demographics including 8- and 70-day mortality were collected. Lower airway bacterial community composition was assessed via amplification and sequencing of the V4 region of the 16S ribosomal RNA gene. Host immune response gene expression profiles were generated by quantitative polymerase chain reaction using RNA extracted from bronchoalveolar lavage fluid. Liquid and gas chromatography mass spectrometry was used to profile serum metabolites. MEASUREMENTS AND MAIN RESULTS: Based on airway microbiome composition, most patients segregated into three distinct groups, each of which were predicted to encode metagenomes capable of producing metabolites characteristically enriched in paired serum samples from these patients. These three groups also exhibited differences in mortality; those with the highest rate had increased ceftriaxone administration and culturable Aspergillus, and demonstrated significantly increased induction of airway T-helper cell type 2 responses. The group with the lowest mortality was characterized by increased expression of T-cell immunoglobulin and mucin domain 3, which down-regulates T-helper cell type 1 proinflammatory responses and is associated with chronic viral infection. CONCLUSIONS: These data provide evidence that compositionally and structurally distinct lower airway microbiomes are associated with discrete local host immune responses, peripheral metabolic reprogramming, and different rates of mortality.

The Evolving Role of Rituximab in Adult Minimal Change Glomerulopathy.

BACKGROUND: Minimal-change glomerulopathy is defined histologically by the presence of normal glomeruli on light microscopy and diffuse podocyte effacement on electron microscopy. Although effective in children, corticosteroid treatment in adults is more variable and time to response can be prolonged. Data to support rituximab use in adults with corticosteroid-dependent or resistant minimal-change glomerulopathy are limited. Here, we describe the clinical course of adults with corticosteroid-dependent or -resistant minimal-change glomerulopathy who received rituximab. METHODS: Demographic and clinical data were collected and analyzed from all adult patients with native kidney, biopsy-proven, minimal-change glomerulopathy who were administered rituximab between 2009 and 2014 and cared for at the UNC Kidney Center. RESULTS: Ten patients with corticosteroid-resistant (n = 5) or corticosteroid-dependent (n = 5) idiopathic minimal-change glomerulopathy were treated with rituximab between 2009 and 2014. Rituximab treatment induced remission in all 10 patients with a median time to remission of 2 months. The median time from rituximab to corticosteroid discontinuation was 3.5 months. The median remission time was 29 months and follow-up time was 39.5 months. No serious adverse events attributable to rituximab were observed. CONCLUSION: Rituximab induced remission in all patients with corticosteroid-dependent or -resistant minimal-change glomerulopathy, and may hold great therapeutic potential with good efficacy and minimal toxicity. Mounting evidence implies that a well-conducted randomized controlled clinical trial using rituximab in adults with minimal-change glomerulopathy in both corticosteroid-resistant and corticosteroid-dependent patients is warranted.

Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease are at increased risk of cystic kidney disease that requires imaging monitoring in many cases. However, these same patients often have contraindications to contrast-enhanced computed tomography and magnetic resonance imaging. This study evaluates the accuracy of contrast-enhanced ultrasound (CEUS), which is safe for patients with chronic kidney disease, for the characterization of kidney lesions in patients with and without chronic kidney disease. METHODS: We performed CEUS on 44 patients, both with and without chronic kidney disease, with indeterminate or suspicious kidney lesions (both cystic and solid). Two masked radiologists categorized lesions using CEUS images according to contrast-enhanced ultrasound adapted criteria. CEUS designation was compared to histology or follow-up imaging in cases without available tissue in all patients and the subset with chronic kidney disease to determine sensitivity, specificity and overall accuracy. RESULTS: Across all patients, CEUS had a sensitivity of 96% (95% CI: 84%, 99%) and specificity of 50% (95% CI: 32%, 68%) for detecting malignancy. Among patients with chronic kidney disease, CEUS sensitivity was 90% (95% CI: 56%, 98%), and specificity was 55% (95% CI: 36%, 73%). CONCLUSIONS: CEUS has high sensitivity for identifying malignancy of kidney lesions. However, because specificity is low, modifications to the classification scheme for contrast-enhanced ultrasound could be considered as a way to improve contrast-enhanced ultrasound specificity and thus overall performance. Due to its sensitivity, among patients with chronic kidney disease or other contrast contraindications, CEUS has potential as an imaging test to rule out malignancy. TRIAL REGISTRATION: This trial was registered in clinicaltrials.gov, NCT01751529 .

A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound.

Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity ( p = 0.001) and time-to-80% on wash-out ( p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes.

Associations of Source-Specific Fine Particulate Matter With Emergency Department Visits in California.

While many studies have investigated the health effects associated with acute exposure to fine particulate matter (particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5)), very few have considered the risks of specific sources of PM2.5 We used city-specific source apportionment in 8 major metropolitan areas in California from 2005-2009 to examine the associations of source-specific PM2.5 exposures from vehicular emissions, biomass burning, soil, and secondary nitrate and sulfate sources with emergency department visits (EDVs) for cardiovascular and respiratory diseases, including 7 subclasses. Using a case-crossover analysis, we observed associations of vehicular emissions with all cardiovascular EDVs (excess risk = 1.6%, 95% confidence interval: 0.9, 2.4 for an interquartile-range increment of 2.8 µg/m(3)) and with several subclasses of disease. In addition, vehicular emissions, biomass burning, and soil sources were associated with all respiratory EDVs and with EDVs for asthma. The soil source, which includes resuspended road dust, generated the highest risk estimate for asthma (excess risk = 4.5%, 95% confidence interval: 1.1, 8.0). Overall, our results provide additional evidence of the public health consequences of exposure to specific sources of PM2.5 and indicate that some sources of PM2.5 may pose higher risks than the overall PM2.5 mass.

Elastomeric and soft conducting microwires for implantable neural interfaces.

Current designs for microelectrodes used for interfacing with the nervous system elicit a characteristic inflammatory response that leads to scar tissue encapsulation, electrical insulation of the electrode from the tissue and ultimately failure. Traditionally, relatively stiff materials like tungsten and silicon are employed which have mechanical properties several orders of magnitude different from neural tissue. This mechanical mismatch is thought to be a major cause of chronic inflammation and degeneration around the device. In an effort to minimize the disparity between neural interface devices and the brain, novel soft electrodes consisting of elastomers and intrinsically conducting polymers were fabricated. The physical, mechanical and electrochemical properties of these materials were extensively characterized to identify the formulations with the optimal combination of parameters including Young's modulus, elongation at break, ultimate tensile strength, conductivity, impedance and surface charge injection. Our final electrode has a Young's modulus of 974 kPa which is five orders of magnitude lower than tungsten and significantly lower than other polymer-based neural electrode materials. In vitro cell culture experiments demonstrated the favorable interaction between these soft materials and neurons, astrocytes and microglia, with higher neuronal attachment and a two-fold reduction in inflammatory microglia attachment on soft devices compared to stiff controls. Surface immobilization of neuronal adhesion proteins on these microwires further improved the cellular response. Finally, in vivo electrophysiology demonstrated the functionality of the elastomeric electrodes in recording single unit activity in the rodent visual cortex. The results presented provide initial evidence in support of the use of soft materials in neural interface applications.