Publications by authors named "Eric Li"

74 Publications

Overactive bladder phenotypes: development and preliminary data.

Can J Urol 2021 Jun;28(3):10699-10704

Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Introduction: The purpose of this study is to develop overactive bladder (OAB) phenotypes that can be used to develop diagnostic and treatment pathways and offer clues to the underlying etiologies of patients with OAB.

Materials And Methods: This is a retrospective, multicenter study of patients with lower urinary tract symptoms (LUTS). Evaluation included a 24-hour bladder diary (24HBD), the lower urinary tract symptoms score (LUTSS) questionnaire, uroflowmetry (Q), and post-void residual urine (PVR) measurement. Patients completed the 24HBD and LUTSS on a smartphone application or paper. Those with an OAB symptom sub-score (OABSS) ≥ 8 were included. An expert panel developed a phenotype classification system based on variables considered to be important for treatment.

Results: The following variables were selected for inclusion in the phenotype modeling: 24-hour voided volume (24HV), maximum voided volume (MVV), Qmax and PVR. Subjects were divided into three phenotypes based on the 24HV: polyuria (24HV > 2.5 L), normal (24 HV 1-2.5 L), and oliguria (24HV < 1 L). Each phenotype was subdivided based on MVV, Qmax & PVR, resulting in 18 sub-types. Five hundred thirty-three patients, 348 men and 185 women, completed the LUTSS and 24HBD. OAB was present in 399 (75%) - 261 men and 138 women. The prevalence of the primary phenotypes was polyuria (25%), normal (63%), and oliguria (11%).

Conclusions: Classification of OAB variants into phenotypes based on 24HV, MVV, Qmax, and PVR provides the substrate for further research into the diagnosis, etiology, treatment outcomes and development of granular diagnostic and treatment algorithms.
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June 2021

Rural use of health service and telemedicine during COVID-19: The role of access and eHealth literacy.

Health Informatics J 2021 Apr-Jun;27(2):14604582211020064

University of British Columbia-Okanagan, Canada.

The COVID-19 pandemic has driven a greater reliance on telemedicine, yet rural access, use, and satisfaction with telemedicine and the role of eHealth literacy are unknown. Using a cross-sectional design, 279 (70.6% female) western rural Canadians completed an online survey. The majority of participants reported access to telemedicine, but nearly 1/5 lacked access to online or virtual mental health services. The majority of participants had used health care services following the declared COVID-19 pandemic in North America, and just under half had used telemedicine. Telemedicine satisfaction scores were higher among participants who had used video ( = 4.18) compared to those who used phone alone ( = 3.79) ( = 0.031). Telemedicine satisfaction and eHealth literacy were correlated ( = 0.26,  = 0.005). Participants did not want telemedicine to replace in-person consultations. Telemedicine practice requires that rural residents have the resources, ability and willingness to engage with remote care.
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http://dx.doi.org/10.1177/14604582211020064DOI Listing
May 2021

The Relationship of Olecranon Apophyseal Ossification and Sanders Hand Scores with the Timing of Peak Height Velocity in Adolescents.

J Bone Joint Surg Am 2021 May 11. Epub 2021 May 11.

Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, Connecticut.

Background: The onset of peak height velocity (PHV) guides the timing of interventions in the growing child. The purpose of the present study was to validate the Diméglio olecranon grading system and to compare these scores with the Risser/triradiate closure (TRC), proximal humerus, and Sanders hand scores.

Methods: Eighty children with annual serial radiographs were selected from the Bolton-Brush collection. The olecranon apophysis was graded with use of lateral radiographs of the elbow. The mean age to PHV was determined for each stage, and reliability was calculated with use of an intraclass correlation coefficient (ICC). Olecranon stage was combined with age, sex, and height in a generalized estimating equation (GEE) model to predict PHV. Predictive performance of this model was evaluated with use of tenfold cross-validation such that the model was trained on 90% of the radiographs and was asked to predict the PHV of the remaining 10%.

Results: PHV is closely associated with olecranon stage, with stage 1 occurring 3.0 years before PHV and stage 7 occurring 3.4 years after PHV. Stage 5 was found to occur at PHV. Scoring system reliability was high across an array of observers (ICC = 0.85 ± 0.07). The GEE model showed that this olecranon system outperforms the Risser/TRC system in predicting PHV and is comparable with the humerus and Sanders hand systems. When combined with age and sex, the olecranon system successfully predicted PHV such that 62% of PHV predictions were accurate within 6 months and 90% of PHV predictions were accurate within a year.

Conclusions: Our data show that stage 5 occurs at PHV, contrary to previously published data. When combined with age and sex, the olecranon system successfully predicts PHV within a year in 90% of cases, establishing a single lateral view of the olecranon as a simple alternative to more complex grading systems. Last, we describe novel 3 variations in olecranon morphology and provide a guide for accurate olecranon staging.

Clinical Relevance: Understanding PHV is critical in the treatment of many pediatric orthopaedic disorders. The revised olecranon staging system will allow for more accurate determination of this variable.
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http://dx.doi.org/10.2106/JBJS.20.01856DOI Listing
May 2021

Subgingival microbiome of deep and shallow periodontal sites in patients with rheumatoid arthritis: a pilot study.

BMC Oral Health 2021 05 8;21(1):248. Epub 2021 May 8.

Division of Infectious Diseases and Global Medicine, Department of Medicine, College of Medicine, University of Florida, FL, Gainesville, USA.

Background: Subgingival microbiome in disease-associated subgingival sites is known to be dysbiotic and significantly altered. In patients with rheumatoid arthritis (RA), the extent of dysbiosis in disease- and health-associated subgingival sites is not clear.

Methods: 8 RA and 10 non-RA subjects were recruited for this pilot study. All subjects received full oral examination and underwent collection of subgingival plaque samples from both shallow (periodontal health-associated, probing depth ≤ 3mm) and deep subgingival sites (periodontal disease-associated, probing depth ≥ 4 mm). RA subjects also had rheumatological evaluation. Plaque community profiles were analyzed using 16 S rRNA sequencing.

Results: The phylogenetic diversity of microbial communities in both RA and non-RA controls was significantly higher in deep subgingival sites compared to shallow sites (p = 0.022), and the overall subgingival microbiome clustered primarily according to probing depth (i.e. shallow versus deep sites), and not separated by RA status. While a large number of differentially abundant taxa and gene functions was observed between deep and shallow sites as expected in non-RA controls, we found very few differentially abundant taxa and gene functions between deep and shallow sites in RA subjects. In addition, compared to non-RA controls, the UniFrac distances between deep and shallow sites in RA subjects were smaller, suggesting increased similarity between deep and shallow subgingival microbiome in RA. Streptococcus parasanguinis and Actinomyces meyeri were overabundant in RA subjects, while Gemella morbillorum, Kingella denitrificans, Prevotella melaninogenica and Leptotrichia spp. were more abundant in non-RA subjects.

Conclusions: The aggregate subgingival microbiome was not significantly different between individuals with and without rheumatoid arthritis. Although the differences in the overall subgingival microbiome was driven primarily by probing depth, in contrast to the substantial microbiome differences typically seen between deep and shallow sites in non-RA patients, the microbiome of deep and shallow sites in RA patients were more similar to each other. These results suggest that factors associated with RA may modulate the ecology of subgingival microbiome and its relationship to periodontal disease, the basis of which remains unknown but warrants further investigation.
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http://dx.doi.org/10.1186/s12903-021-01597-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105973PMC
May 2021

Modification and application of the proximal humerus ossification system to adolescent idiopathic scoliosis patients.

Spine Deform 2021 May 3. Epub 2021 May 3.

Division of Orthopedics, Texas Children's Hospital, Department of Orthopedics, Baylor College of Medicine, Houston, TX, 77030, USA.

Purpose: We have previously demonstrated that proximal humeral ossification patterns are reliable for assessing peak height velocity in growing patients. Here, we sought to modify the system by including medial physeal closure and evaluate whether this system combined with the Cobb angle correlates with progression to surgery in patients with adolescent idiopathic scoliosis.

Methods: We reviewed 616 radiographs from 79 children in a historical collection to integrate closure of the medial physis into novel stages 3A and 3B. We then analyzed radiographs from the initial presentation of 202 patients with adolescent idiopathic scoliosis who had either undergone surgery or completed monitoring at skeletal maturity. Summary statistics for the percentage of patients who progressed to the surgical range were calculated for each category of humerus and Cobb angle.

Results: The intra-observer and inter-observer ICC for assessment of the medial physis was 0.6 and 0.8, respectively. Only 3.4% of radiographs were unable to be assessed for medial humerus closure. The medial humerus physis begins to close about 1 year prior to the lateral physis and patients with a closing medial physis, but an open lateral physis were found to be the closest to PHV (0.7 years). Stratifying patients by Cobb angle and modified humerus stage yield categories with low and high risks of progression to the surgical range.

Conclusion: The medial humerus can be accurately evaluated and integrated into a new modified proximal humerus ossification system. Patients with humerus stage 3A or below have a higher rate of progression to the surgical range than those with humerus stage 3B or above.
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http://dx.doi.org/10.1007/s43390-021-00338-yDOI Listing
May 2021

Computational Identification of Sex-Biased Biomarker MicroRNAs and Genes Associated with Immune Infiltration in Breast Cancer.

Genes (Basel) 2021 Apr 14;12(4). Epub 2021 Apr 14.

Department of Biology, Eastern Michigan University, 441 Mark Jefferson Hall, Ypsilanti, MI 48197, USA.

MicroRNAs (miRNAs) perform their functions through targeting messenger RNAs (mRNAs). X chromosome-located (X-linked) miRNAs have a broad role in cell lineage determination, immune regulation, and oncogenesis. The regulating roles of miRNAs in cancer and immunity are often altered when aberrant expression happens. Sex-biased genes could contribute to cancer sex bias in the context of their expression change due to targeting miRNAs. How biological roles and associations with immune cell abundance levels for sex-biased gene-miRNA pairs in gender-related cancer (e.g., breast cancer) change due to the alteration of their expression pattern to identify candidate therapeutic markers has not been investigated thoroughly. Upon analyzing anti-correlated genes and miRNAs within significant clusters of 12 The Cancer Genome Atlas (TCGA) cancer types and the list of sex-biased genes and miRNAs reported from previous studies, 125 sex-biased genes (11 male-biased and 114 female-biased) were identified in breast cancer (BC). Seventy-three sex-biased miRNAs (40 male-biased and 33 female-biased) were identified across 5 out of 12 cancers (head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and lung adenocarcinoma (LUAD)). Correlation between the BC sex-biased genes and tumor infiltrating immune cell types was further evaluated. We found eight genes having high correlation with immune infiltration. Fifteen candidate female-biased BC genes targeted by 3 X-linked miRNAs (, and ) were pinpointed in this study. Our computational result indicates that many identified female-biased genes which have positive associations with immune cell abundance levels could serve as alternative therapeutic markers. Our analysis suggests that female-biased expression of BC candidate genes is likely influenced by their targeting miRNA(s).
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http://dx.doi.org/10.3390/genes12040570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070832PMC
April 2021

Efficacy and Adverse Events of Docetaxel for Metastatic, Hormone-sensitive Prostate Cancer Among Elderly Men: A Post Hoc Analysis of the CHAARTED Trial.

Clin Genitourin Cancer 2021 Mar 19. Epub 2021 Mar 19.

Northwestern University, Feinberg School of Medicine, Department of Medicine, Chicago, IL. Electronic address:

Background: Combination therapy with docetaxel and androgen deprivation therapy (ADT) prolongs overall survival (OS) in men with metastatic hormone-sensitive prostate cancer. We assessed the benefits and adverse effects of docetaxel and ADT in relation to advancing age.

Methods: We performed a post hoc analysis of the CHAARTED trial comparing docetaxel and ADT vs. ADT alone (n = 773). Patients were stratified in age groups <60, 60-70, and >70 years old. Multivariable-adjusted progression-free survival (PFS) and OS were assessed using Kaplan-Meier curves and compared using multivariable Cox regressions with calculated interaction terms between age group and treatment arm. In the combination arm, the incidence of ≥1 adverse event (grade ≥3) and the number of adverse events per patient were compared for each age group using multivariable logistic and linear regressions, respectively.

Results: After adjusting for clinical variables, docetaxel's effect did not vary by age group for PFS and OS. There was no significant difference in the odds ratio of ≥1 adverse event (P > .1 for age groups 60-70 and >70 years old compared with <60 years old). However, men age >70 years old experienced +0.37 more adverse events per patient compared with men age <60 years old (95% CI, 0.11-0.64; P = .006).

Conclusions: PFS and OS were similar across age groups for the combination of docetaxel and ADT compared with ADT. Older men experienced a modest increase in adverse events per patient, highlighting the importance of balancing treatment benefits and adverse effects in this age group.
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http://dx.doi.org/10.1016/j.clgc.2021.03.016DOI Listing
March 2021

Cause of death during prostate cancer survivorship: A contemporary, US population-based analysis.

Cancer 2021 Apr 21. Epub 2021 Apr 21.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: More than 3.6 million men in the United States harbor a diagnosis of prostate cancer (PCa). The authors sought to provide in-depth analyses of the causes of death for contemporary survivors.

Methods: The authors performed a population-based cohort study in the United States (2000-2016) to assess causes of death for men diagnosed with PCa stratified by demographics and tumor stage. Using general population data, they calculated standardized mortality ratios (SMRs) as observed-to-expected death ratios.

Results: In total, 752,092 men with PCa, including 200,302 who died (27%), were assessed. A total of 29,048 men with local/regional disease (17%) died of PCa, whereas more than 4-fold men died of other causes (n = 143,719 [83%]). SMRs for death from noncancer causes (0.77; 95% confidence interval [CI], 0.77-0.78) suggested that these men were less likely than the general population to die of most other causes. The most common noncancer cause of death was cardiac-related (23%; SMR, 0.76; 95% CI, 0.75-0.77). Among men with distant PCa, 90% of deaths occurred within 5 years of diagnosis. Although deaths due to PCa composed the majority of deaths (74%), SMRs suggested that men with distant PCa were at heightened risk for death from most other noncancer causes (1.50; 95% CI, 1.46-1.54) and, in particular, for cardiac-related death (SMR, 1.48; 95% CI, 1.41-1.54) and suicide (SMR, 2.32; 95% CI, 1.78-2.96). Further analyses demonstrated that causes of death varied by patient demographics.

Conclusions: Causes of death during PCa survivorship vary by patient and tumor characteristics. These data provide valuable information regarding health care prioritization during PCa survivorship.

Lay Summary: Men with early-stage prostate cancer are 4-fold more likely to die of other causes, whereas those with advanced prostate cancer are at increased risk for several causes not related to prostate cancer in comparison with the general population. These findings can help guide physicians taking care of men with a diagnosis of prostate cancer.
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http://dx.doi.org/10.1002/cncr.33584DOI Listing
April 2021

Early detection of SARS-CoV-2 and other infections in solid organ transplant recipients and household members using wearable devices.

Transpl Int 2021 Mar 18. Epub 2021 Mar 18.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.
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http://dx.doi.org/10.1111/tri.13860DOI Listing
March 2021

Plasma and urine pharmacokinetics of two formulations of dexamethasone in greyhound dogs.

J Vet Pharmacol Ther 2021 Mar 17. Epub 2021 Mar 17.

Greyhound Racing Victoria, Melbourne, Vic., Australia.

Dexamethasone, formulated as sodium phosphate and as phenylpropionate combined with sodium phosphate, was administered subcutaneously to six greyhounds. Plasma and urine were collected for up to 240 h and analysed with a limit of quantification (LOQ) of at least 100 pg/ml for dexamethasone. Dexamethasone, formulated as sodium phosphate, terminal half-life was 10.4 h in plasma and approximately 16 h in urine, and at 96 h, plasma hydrocortisone concentrations returned to background with dexamethasone levels around the LOQ. Dexamethasone, formulated as phenylpropionate combined with sodium phosphate, terminal half-life, was 25.6 h in plasma and approximately 26 h in urine, and at 96 h, plasma hydrocortisone concentrations returned to background with dexamethasone levels in three of the six greyhounds around the LOQ. Critical assessment of the pharmacokinetic and pharmacodynamic data indicated how it might be utilized for medication control in racing greyhounds.
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http://dx.doi.org/10.1111/jvp.12970DOI Listing
March 2021

Peyronie's disease: pharmacological treatments and limitations.

Expert Rev Clin Pharmacol 2021 Jun 25;14(6):703-713. Epub 2021 Mar 25.

Division of Urology, Rush University Medical Center, Chicago, Illinois, USA.

: Peyronie's disease (PD) is a disorder of the tunica albuginea from disordered and excessive deposition of collagen resulting in a palpable scar, pain, erect penile deformity and erectile dysfunction that significantly impacts patients both physically and emotionally.: Several treatment options have been described for PD, including shockwave therapy, traction therapy, both oral and intralesional pharmacological options, and surgery. This review seeks to examine the data for different types of non-surgical treatments for PD. We review how various treatment modalities impact several relevant clinical endpoints for Peyronie's disease, including effects on pain, penile curvature, plaque formation, and erectile function. We performed a literature search using PubMed and SCOPUS while referencing AUA, EAU, and CUA guidelines for management of Peyronie's Disease for studies published 1980-2020.: Intralesional collagenase injections have the strongest evidence and are the only FDA approved intralesional treatment for PD. Penile traction therapy (PTT) is low risk and may be beneficial in patients willing to invest significant time using the devices. Furthermore, oral combination therapy with other modalities may provide some benefit. Further investigation is required to better understand pathophysiology of PD and clarify the therapeutic utility of existing treatments, potentially with a multimodal strategy.
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http://dx.doi.org/10.1080/17512433.2021.1903873DOI Listing
June 2021

3D Culture Systems for Exploring Cancer Immunology.

Cancers (Basel) 2020 Dec 28;13(1). Epub 2020 Dec 28.

Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.

Cancer immunotherapy has revolutionized cancer treatment, spurring extensive investigation into cancer immunology and how to exploit this biology for therapeutic benefit. Current methods to investigate cancer-immune cell interactions and develop novel drug therapies rely on either two-dimensional (2D) culture systems or murine models. However, three-dimensional (3D) culture systems provide a potentially superior alternative model to both 2D and murine approaches. As opposed to 2D models, 3D models are more physiologically relevant and better replicate tumor complexities. Compared to murine models, 3D models are cheaper, faster, and can study the human immune system. In this review, we discuss the most common 3D culture systems-spheroids, organoids, and microfluidic chips-and detail how these systems have advanced our understanding of cancer immunology.
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http://dx.doi.org/10.3390/cancers13010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795162PMC
December 2020

Patient-Reported Outcome Measures (PROMs) to Support Adherence to Falls Prevention Clinic Recommendations: A Qualitative Study.

Patient Prefer Adherence 2020 30;14:2105-2121. Epub 2020 Oct 30.

Social & Economic Change Laboratory, Faculty of Management, University of British Columbia - Okanagan, Kelowna, British Columbia, Canada.

Purpose: We examined how patient-reported outcome measures (PROMs) support patients' adherence to fall prevention recommendations in a novel primary care setting - the Falls Prevention Clinic.

Patients And Methods: Using a patient-oriented qualitative study design, we recruited patient partners to our study team to assist in developing focus group prompts. A trained facilitator conducted five semi-structured interviews with a total of 21 Falls Prevention Clinic participants. A trained facilitator prompted participants about: their views on the EuroQol 5 domain - 5 level (EQ-5D-5L) PROM, their preferences for PROM administration and feedback, the presentation of PROM questionnaire data, the use of comparative data and the EQ-5D-5L in improving adherence to recommendations, and other information they would need to improve adherence. Participants' responses were coded according to three stages of qualitative analysis: open, axial and selective coding using an iterative and comparative approach.

Results: "Opportunity" and "Development" emerged as higher-level themes for the participants' perspectives on how the EQ-5D-5L may be helpful for their appointments. "Frequency" described how often the participants believed the EQ-5D-5L should be administered and feedback provided. "Challenges", "Benefits", "Patients' Understanding", "Relevance of Data", and "Usefulness of Data" provided insight on how PROMs data presentation was viewed by patients. "Performance", "Resources", "Knowledge", "Role in Behaviour Change" highlighted the participants' ideas for the role of the EQ-5D-5L and additional information in supporting their adherence to falls prevention recommendations. Participants emphasized that patients would value further support information to facilitate their adherence.

Conclusion: This patient-oriented qualitative study, among individuals at high risk of future falls, sheds light on the importance of timely, understandable feedback, integrated with other clinical feedback in supporting adherence.
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http://dx.doi.org/10.2147/PPA.S269202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608137PMC
October 2020

The effect of tumor location on overall survival for pT2-4 bladder and upper tract urothelial carcinoma following radical surgery.

Can Urol Assoc J 2021 May;15(5):E248-E255

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Introduction: Historically, staging and treatment for upper tract urothelial carcinoma were extrapolated from bladder urothelial carcinoma literature. However, embryological, genetic, and anatomical differences exist between them. We sought to explore the relationship between location of urothelial cancer and overall survival (OS).

Methods: Data was culled from the National Cancer Database from 2004-2015. Patients with pT2-pT4 treated with definitive surgery were included; those with metastatic disease or who received neoadjuvant or adjuvant treatment were excluded. Patients were stratified by tumor location and pathological stage. The primary outcome was OS. Secondary outcomes were predictors of mortality in each pT stage stratum.

Results: A total of 11 330 patients with bladder, 954 patients with ureteral, and 1943 patients with renal pelvis urothelial carcinoma were analyzed. Mean followup was 43.3, 39.4, and 41.4 months for bladder, ureteral, and renal pelvis, respectively. On univariable analysis, ureteral pT2 was associated with worse OS compared to both bladder (61.3 vs. 80.4 months, p=0.007) and renal pelvis (61.3 vs. 80.5 months, p=0.014). Renal pelvis pT3 was associated with improved OS compared to both bladder (42.5 vs. 28.6 months, p=0.003) and ureteral (42.5 vs. 25.7 months, p<0.001). Renal pelvis pT4 had decreased survival compared to bladder (11.4 vs. 17.7 months, p<0.001). On multivariable Cox regression, only renal pelvis pT3 was associated with a 20% decreased risk of mortality compared to bladder pT3 (hazard ratio 0.80, 95% confidence interval 0.72-0.88, p<0.001).

Conclusions: Renal pelvis pT3 is associated with lower mortality. Mutational and embryological differences may play a role in this disparity.
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http://dx.doi.org/10.5489/cuaj.6698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095283PMC
May 2021

Chronic leukaemias in the community.

Aust Prescr 2020 08 3;43(4):126-130. Epub 2020 Aug 3.

Patients with chronic myeloid leukaemia and chronic lymphocytic leukaemia are now predominantly managed in an outpatient setting, with infrequent need for hospital-based therapy. New targeted oral treatments have transformed survival outcomes. An increasing number of patients now have a life expectancy approaching that of the general population. Suboptimal drug adherence is common and a key reason for therapy failure and poor clinical outcomes. The pharmacokinetics of new oral targeted drugs are significantly impacted by drug–drug interactions and an altered gastric pH. Long-term use of some of the new oral drugs is associated with complications, including cardiovascular events and infections, which can be fatal if not recognised.
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http://dx.doi.org/10.18773/austprescr.2020.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450777PMC
August 2020

Survival following upfront chemotherapy for treatment-naïve metastatic prostate cancer: a real-world retrospective cohort study.

Prostate Cancer Prostatic Dis 2021 03 1;24(1):261-267. Epub 2020 Sep 1.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Upfront chemotherapy prolongs overall survival for men with metastatic, hormone-sensitive prostate cancer (mHSPC) based on data from clinical trials. We sought to assess the association between upfront chemotherapy and overall survival in men with mHSPC in a real-world cohort.

Methods: We performed a retrospective cohort study of men with de novo, treatment-naïve metastatic prostate cancer from a large, national cancer database in the United States (2014-2015). Men in the upfront chemotherapy group received chemotherapy within 4 months of diagnosis (n = 1033, 28%) versus no chemotherapy or chemotherapy later than 12 months after diagnosis (controls; n = 2704, 72%). Overall survival was assessed using Kaplan-Meier estimates and compared using multivariable Cox regression analysis.

Results: After a median follow-up of 23 months, median overall survival was 35.7 months in the upfront chemotherapy group and 32.5 months for controls (log-rank p < 0.001). After adjusting for patient and clinical variables, upfront chemotherapy was associated with longer overall survival (hazard ratio 0.78, 95% confidence interval 0.68-0.89, p < 0.001). In exploratory analyses, the association between upfront chemotherapy and overall survival did not differ by age groups, race, or number of comorbidities (all interaction p > 0.2).

Conclusions: In this real-world cohort, upfront chemotherapy for mHSPC was associated with longer overall survival. These data support the continued use of chemotherapy for men with mHSPC regardless of race or age if they are fit for chemotherapy and underscore the importance of evaluating cancer therapeutics outside of clinical trials to demonstrate treatment efficacy in populations that may be underrepresented in clinical trials.
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http://dx.doi.org/10.1038/s41391-020-00278-0DOI Listing
March 2021

A single variant sequencing method for sensitive and quantitative detection of HIV-1 minority variants.

Sci Rep 2020 05 18;10(1):8185. Epub 2020 May 18.

Division of Infectious Disease and Global Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.

HIV drug resistance is a major threat to achieving long-term viral suppression in HIV-positive individuals. Drug resistant HIV variants, including minority variants, can compromise response to antiretroviral therapy. Many studies have investigated the clinical relevance of drug resistant minority variants, but the level at which minority variants become clinically relevant remains unclear. A combination of Primer-ID and deep sequencing is a promising approach that may quantify minority variants more accurately compared to standard deep sequencing. However, most studies that used the Primer-ID method have analyzed clinical samples directly. Thus, its sensitivity and quantitative accuracy have not been adequately validated using known controls. Here, we constructed defined proportions of artificial RNA and virus quasispecies and measured their relative proportions using the Primer-ID based, quantitative single-variant sequencing (qSVS) assay. Our results showed that minority variants present at 1% of quasispecies were detected reproducibly with minimal variations between technical replicates. In addition, the measured frequencies were comparable to the expected frequencies. These data validate the accuracy and reproducibility of the qSVS assay in quantifying authentic HIV minority variants, and support the use of this approach to examine the impacts of minority HIV variants on virologic response and clinical outcome.
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http://dx.doi.org/10.1038/s41598-020-65085-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234988PMC
May 2020

PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Nat Immunol 2020 04 9;21(4):442-454. Epub 2020 Mar 9.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1 T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4 T cells, which prevented activation, reduced T1-polarization and directed T17-differentiation. PD-L1 signaling also induced an anergic T-betIFN-γ phenotype in CD8 T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1 T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1 T cells engaged PD-1 macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1 T cells have diverse tolerogenic effects on tumor immunity.
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http://dx.doi.org/10.1038/s41590-020-0620-xDOI Listing
April 2020

The Proximal Humeral Ossification System Improves Assessment of Maturity in Patients with Scoliosis.

J Bone Joint Surg Am 2019 Oct;101(20):1868-1874

Division of Orthopaedics and Scoliosis, Texas Children's Hospital, Houston, Texas.

Background: We recently developed a classification system to assess skeletal maturity by scoring proximal humeral ossification in a similar way to the canonical Risser sign. The purpose of the present study was to determine whether our system can be used to reliably assess radiographs of the spine for modern patients with idiopathic scoliosis, whether it can be used in combination with the Sanders hand system, and whether the consideration of patient factors such as age, sex, and standing height improves the accuracy of predictions.

Methods: We retrospectively reviewed 414 randomized radiographs from 216 modern patients with scoliosis and measured reliability with use of the intraclass correlation coefficient (ICC). We then analyzed 606 proximal humeral radiographs for 70 children from a historical collection to determine the value of integrating multiple classification systems. The age of peak height velocity (PHV) was predicted with use of linear regression models, and performance was evaluated with use of tenfold cross-validation.

Results: The proximal humeral ossification system demonstrated excellent reliability in modern patients with scoliosis, with an ICC of 0.97 and 0.92 for intraobserver and interobserver comparisons, respectively. The use of our system in combination with the Sanders hand system yielded 7 categories prior to PHV and demonstrated better results compared with either system alone. Linear regression algorithms showed that integration of the proximal part of the humerus, patient factors, and other classification systems outperformed models based on canonical Risser and triradiate-closure methods.

Conclusions: Humeral head ossification can be reliably assessed in modern patients with scoliosis. Furthermore, the system described here can be used in combination with other parameters such as the Sanders hand system, age, sex, and height to predict PHV and percent growth remaining with high accuracy.

Clinical Relevance: The proximal humeral ossification system can improve the prediction of PHV in patients with scoliosis on the basis of a standard spine radiograph without a hand radiograph for the determination of bone age. This increased accuracy for predicting maturity will allow physicians to better assess patient maturity relative to PHV and therefore can help to guide treatment decision-making without increasing radiation exposure, time, or cost. The present study demonstrates that assessment of the proximal humeral physis is a viable and valuable aid in the determination of skeletal maturity as obtained from radiographs of the spine that happen to include the shoulder in adolescent patients with idiopathic scoliosis.
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http://dx.doi.org/10.2106/JBJS.19.00296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515481PMC
October 2019

Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury.

J Lipid Res 2019 12 4;60(12):2034-2049. Epub 2019 Oct 4.

Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY

Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 () mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and was attenuated in and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including and ) in versus WT mice fed EtOH. mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.
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http://dx.doi.org/10.1194/jlr.RA119000200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889711PMC
December 2019

Upper versus lower airway microbiome and metagenome in children with cystic fibrosis and their correlation with lung inflammation.

PLoS One 2019 19;14(9):e0222323. Epub 2019 Sep 19.

Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida College of Medicine, Gainesville, FL, United States of America.

Objective: Airways of children with cystic fibrosis (CF) harbor complex polymicrobial communities which correlates with pulmonary disease progression and use of antibiotics. Throat swabs are widely used in young CF children as a surrogate to detect potentially pathogenic microorganisms in lower airways. However, the relationship between upper and lower airway microbial communities remains poorly understood. This study aims to determine (1) to what extent oropharyngeal microbiome resembles the lung microbiome in CF children and (2) if lung microbiome composition correlates with airway inflammation.

Method: Throat swabs and bronchoalveolar lavage (BAL) were obtained concurrently from 21 CF children and 26 disease controls. Oropharyngeal and lung microbiota were analyzed using 16S rRNA deep sequencing and correlated with neutrophil counts in BAL and antibiotic exposure.

Results: Oropharyngeal microbial communities clustered separately from lung communities and had higher microbial diversity (p < 0.001). CF microbiome differed significantly from non-CF controls, with a higher abundance of Proteobacteria in both upper and lower CF airways. Neutrophil count in the BAL correlated negatively with the diversity but not richness of the lung microbiome. In CF children, microbial genes involved in bacterial motility proteins, two-component system, flagella assembly, and secretion system were enriched in both oropharyngeal and lung microbiome, whereas genes associated with synthesis and metabolism of nucleic acids and protein dominated the non-CF controls.

Conclusions: This study identified a unique microbial profile with altered microbial diversity and metabolic functions in CF airways which is significantly affected by airway inflammation. These results highlight the limitations of using throat swabs as a surrogate to study lower airway microbiome and metagenome in CF children.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222323PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752789PMC
March 2020

Pharmacological antagonism of histamine H2R ameliorated L-DOPA-induced dyskinesia via normalization of GRK3 and by suppressing FosB and ERK in PD.

Neurobiol Aging 2019 09 19;81:177-189. Epub 2019 Jun 19.

Biomaterials and Advanced Drug Delivery Laboratory, School of Medicine, Stanford University, Palo Alto, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco. Electronic address:

Parkinson's disease (PD) is often managed with L-3,4-dihydroxyphenylalanine (L-DOPA), which is still the gold standard to relieve the clinical motor symptoms of PD. However, chronic use of L-DOPA leads to significant motor complications, especially L-DOPA-induced dyskinesia (LID), which limit the therapeutic benefit. Few options are available for the pharmacological management of LID partly due to the inadequacy of our mechanistic understanding of the syndrome. We focused on the role of the histamine (HA) H2 receptor (H2R) in the striatum, which others have shown to be involved in the development of LID. We generated LID in a hemiparkinsonian mouse model and tested the signaling effects of ranitidine, an H2R antagonist. We used histidine decarboxylase deficient mice (Hdc-Ko) which lacks HA to study the role of G-protein-coupled receptor kinases (GRKs) in HA deficiency. Loss of HA in Hdc-Ko mice did not result in the downregulation of GRKs, especially GRK3 and GRK6, which were previously found to be reduced in hemiparkinsonian animal models. Ranitidine, when given along with L-DOPA, normalized the expression of GRK3 in the dopamine-depleted striatum thereby inhibiting LID in mice. The extracellular signal regulated kinase and ΔFosB signaling pathways were attenuated in the lesioned striatum when ranitidine was combined with L-DOPA than L-DOPA alone. These results demonstrate that ranitidine inhibits LID by normalizing the levels of GRK3, extracellular signal regulated kinase activation, and FosB accumulation in the dopamine-depleted striatum via HA H2R antagonism.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.06.004DOI Listing
September 2019

Long term results of augmentation cystoplasty and urinary diversion in multiple sclerosis.

Can J Urol 2019 06;26(3):9774-9780

Department of Urology, Bezmialem Vakif University, Istanbul, Turkey.

Introduction: There is a paucity of data about augmentation cystoplasty (AC) in multiple sclerosis (MS) patients with refractory lower urinary tract symptoms (LUTS). The aim of this study is to evaluate the long term outcomes and morbidity of these procedures in MS patients.

Materials And Methods: This is a retrospective observational study of consecutive patients (1984-2017) with MS and refractory LUTS who underwent AC with or without a continent/incontinent abdominal stoma or urinary diversion. Pre and postoperative evaluations included routine labs, videourodynamic studies (VUDS), cystoscopy, and upper tract imaging. Long term outcomes and complications were assessed by validated questionnaires and/or chart review.

Results: There were 17 patients (12 women, 5 men) ranging in age from 34-77 years. Thirteen patients were wheelchair-bound (10 quadriplegics, 3 paraplegics). Indications included neurogenic detrusor overactivity (NDO) in two, low bladder compliance (LBC) in 13 and both NDO and LBC in two. One patient committed suicide at 3 months, and one was lost to follow up. Of the remaining 15, median follow up was 13 years (range 4-22), and 11 were followed up until death. Overall, 14/15 (93%) had a successful outcome based on the Patient Global Impression of Improvement (PGI-I). With respect to incontinence, 14/15 (93%) had a successful outcome based on the Simplified Urinary Incontinence Score (SUIS). Median bladder capacity increased from 180 mL to 605 mL (p < 0.001). Median maximum detrusor pressure decreased from 63 cm H₂ O to 18 cm H₂O (p < 0.003). Two patients underwent stomal stenosis revisions, four patients had pyelonephritis, and two patients developed de novo bladder stones.

Conclusions: AC is a major surgical procedure with high potential morbidity, but these data suggest that AC is efficacious in the long term with acceptable morbidity and mortality. We believe it is an underutilized procedure for refractory LUTS in MS patients.
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June 2019

Plasma and urine pharmacokinetics of intravenously administered flunixin in greyhound dogs.

J Vet Pharmacol Ther 2019 Sep 14;42(5):505-510. Epub 2019 May 14.

Greyhound Racing Victoria, Melbourne, Victoria, Australia.

Medication control in greyhound racing requires information from administration studies that measure drug levels in the urine as well as plasma, with time points that extend into the terminal phase of excretion. To characterize the plasma and the urinary pharmacokinetics of flunixin and enable regulatory advice for greyhound racing in respect of both medication and residue control limits, flunixin meglumine was administered intravenously on one occasion to six different greyhounds at the label dose of 1 mg/kg and the levels of flunixin were measured in plasma for up to 96 hr and in urine for up to 120 hr. Using the standard methodology for medication control, the irrelevant plasma concentration was determined as 1 ng/ml and the irrelevant urine concentration was determined as 30 ng/ml. This information can be used by regulators to determine a screening limit, detection time and a residue limit. The greyhounds with the highest average urine pH had far greater flunixin exposure compared with the greyhounds that had the lowest. This is entirely consistent with the extent of ionization predicted by the Henderson-Hasselbalch equation. This variability in the urine pharmacokinetics reduces with time, and at 72 hr postadministration, in the terminal phase, the variability in urine and plasma flunixin concentrations are similar and should not affect medication control.
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http://dx.doi.org/10.1111/jvp.12775DOI Listing
September 2019

QuBiT: a quantitative tool for analyzing epithelial tubes reveals unexpected patterns of organization in the trachea.

Development 2019 05 16;146(12). Epub 2019 May 16.

Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA

Biological tubes are essential for animal survival, and their functions are dependent on tube shape. Analyzing the contributions of cell shape and organization to the morphogenesis of small tubes has been hampered by the limitations of existing programs in quantifying cell geometry on highly curved tubular surfaces and calculating tube-specific parameters. We therefore developed QuBiT (Quantitative Tool for Biological Tubes) and used it to analyze morphogenesis of the embryonic trachea (airway). In the main tube, we find previously unknown anterior-to-posterior (A-P) gradients of cell apical orientation and aspect ratio, and periodicity in the organization of apical cell surfaces. Inferred cell intercalation during development dampens an A-P gradient of the number of cells per cross-section of the tube, but does not change the patterns of cell connectivity. Computationally 'unrolling' the apical surface of wild-type trachea and the hindgut reveals previously unrecognized spatial patterns of the apical marker Uninflatable and a non-redundant role for the Na/K ATPase in apical marker organization. These unexpected findings demonstrate the importance of a computational tool for analyzing small diameter biological tubes.
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http://dx.doi.org/10.1242/dev.172759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602340PMC
May 2019

Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions.

Cell 2019 04 28;177(2):478-491.e20. Epub 2019 Mar 28.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Center for Brain Science, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Biozentrum, University of Basel, CH-4056 Basel, Switzerland; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; FAS Center for Systems Biology, Harvard University, MA 02138, USA; Allen Discovery Center for Cell Lineage Tracing, Seattle, WA 98104, USA. Electronic address:

Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.
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http://dx.doi.org/10.1016/j.cell.2019.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494450PMC
April 2019

A Novel Na-K-Cl Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke.

Stroke 2019 04;50(4):1021-1025

From the Department of Neurology (H.H., M.I.H.B., T.J., S. Song, S. Shankar, T.T., E.L., B.J.M, D.S.), University of Pittsburgh, PA.

Background and Purpose- Inhibition of brain NKCC1 (Na-K-Cl cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.
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http://dx.doi.org/10.1161/STROKEAHA.118.024287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608592PMC
April 2019

Current guidelines and treatment paradigms for nocturnal polyuria: A "NEW" disease state for US physicians, patients and payers.

Int J Clin Pract 2019 Aug 22;73(8):e13337. Epub 2019 Apr 22.

Department of Urology, State University of New York Downstate Medical Center, Brooklyn, New York.

Nocturia is one of the most bothersome symptoms encountered in urology, and its prevalence rises with age. Causes include both urological and non-urological aetiologies, often in combination. The effects of nocturia on a patient's quality of life can be detrimental. The initial approach to managing this condition includes appropriately classifying nocturia based on the results of a 24-hour bladder diary. Broadly, the categories under which nocturia can be classified include: low nocturnal or global bladder capacity, nocturnal polyuria, global polyuria and mixed.Based on the type of nocturia and possible underlying causes, clinicians can appropriately discuss with patients the treatment plans that may include a combination of behavioural, pharmacologic, and invasive therapy. The available literature on the management of nocturia was reviewed. Findings were incorporated into a practice-based approach for its workup and treatment.
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http://dx.doi.org/10.1111/ijcp.13337DOI Listing
August 2019

Inflammatory Bowel Disease and the Risk of Prostate Cancer.

Eur Urol 2019 05 4;75(5):846-852. Epub 2018 Dec 4.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Background: There are limited data examining the risk of prostate cancer (PCa) in patients with inflammatory bowel disease (IBD).

Objective: To compare the incidence of PCa between men with and those without IBD.

Design, Setting, And Participants: This was a retrospective, matched-cohort study involving a single academic medical center and conducted from 1996 to 2017. Male patients with IBD (cases=1033) were randomly matched 1:9 by age and race to men without IBD (controls=9306). All patients had undergone at least one prostate-specific antigen (PSA) screening test.

Outcome Measurements And Statistical Analysis: Kaplan-Meier and multivariable Cox proportional hazard models, stratified by age and race, evaluated the relationship between IBD and the incidence of any PCa and clinically significant PCa (Gleason grade group ≥2). A mixed-effect regression model assessed the association of IBD with PSA level.

Results And Limitations: PCa incidence at 10yr was 4.4% among men with IBD and 0.65% among controls (hazard ratio [HR] 4.84 [3.34-7.02] [3.19-6.69], p<0.001). Clinically significant PCa incidence at 10yr was 2.4% for men with IBD and 0.42% for controls (HR 4.04 [2.52-6.48], p<0.001). After approximately age 60, PSA values were higher among patients with IBD (fixed-effect interaction of age and patient group: p=0.004). Results are limited by the retrospective nature of the analysis and lack of external validity.

Conclusions: Men with IBD had higher rates of clinically significant PCa when compared with age- and race-matched controls.

Patient Summary: This study of over 10000 men treated at a large medical center suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population.
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http://dx.doi.org/10.1016/j.eururo.2018.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542355PMC
May 2019

Two herpesviral noncoding PAN RNAs are functionally homologous but do not associate with common chromatin loci.

PLoS Pathog 2018 11 1;14(11):e1007389. Epub 2018 Nov 1.

Department of Molecular Biophysics and Biochemistry, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.

During lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV), a nuclear viral long noncoding RNA known as PAN RNA becomes the most abundant polyadenylated transcript in the cell. Knockout or knockdown of KSHV PAN RNA results in loss of late lytic viral gene expression and, consequently, reduction of progeny virion release from the cell. Here, we demonstrate that knockdown of PAN RNA from the related Rhesus macaque rhadinovirus (RRV) phenocopies that of KSHV PAN RNA. These two PAN RNA homologs, although lacking significant nucleotide sequence conservation, can functionally substitute for each other to rescue phenotypes associated with the absence of PAN RNA expression. Because PAN RNA is exclusively nuclear, previous studies suggested that it directly interacts with host and viral chromatin to modulate gene expression. We studied KSHV and RRV PAN RNA homologs using capture hybridization analysis of RNA targets (CHART) and observed their association with host chromatin, but the loci differ between PAN RNA homologs. Accordingly, we find that KSHV PAN RNA is undetectable in chromatin following cell fractionation. Thus, modulation of gene expression at specific chromatin loci appears not to be the primary, nor the pertinent function of this viral long noncoding RNA. PAN RNA represents a cautionary tale for the investigation of RNA association with chromatin whereby cross-linking of DNA spatially adjacent to an abundant nuclear RNA gives the appearance of specific interactions. Similarly, PAN RNA expression does not affect viral transcription factor complex expression or activity, which is required for generation of the late lytic viral mRNAs. Rather, we provide evidence for an alternative model of PAN RNA function whereby knockdown of KSHV or RRV PAN RNA results in compromised nuclear mRNA export thereby reducing the cytoplasmic levels of viral mRNAs available for production of late lytic viral proteins.
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http://dx.doi.org/10.1371/journal.ppat.1007389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233925PMC
November 2018