Publications by authors named "Richard Lee"

1,785 Publications

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Effect of varicoceles on spermatogenesis.

Semin Cell Dev Biol 2021 May 6. Epub 2021 May 6.

Department of Urology, Weill Cornell Medicine, New York-Presbyterian Hospital, 525 East 68th Street, Starr 900, New York, NY 10065, United States. Electronic address:

Varicoceles are dilated veins within the spermatic cord and a relatively common occurrence in men. Fortunately, the large majority of men are asymptomatic, however, a proportion of men with varicoceles can suffer from infertility and testosterone deficiency. Sperm and testosterone are produced within the testis, and any alteration to the testicular environment can negatively affect the cells responsible for these processes. The negative impact of varicoceles on testicular function occurs mainly due to increased oxidative stress within the testicular parenchyma which is thought to be caused by scrotal hyperthermia, testicular hypoxia, and blood-testis barrier disruption. Management of varicoceles involves ligation or percutaneous embolization of the dilated veins. Repair of varicoceles can improve semen parameters and fertility, along with serum testosterone concentration. In this review, we discuss the pathophysiology of varicoceles, their impact on testicular function, and management.
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http://dx.doi.org/10.1016/j.semcdb.2021.04.005DOI Listing
May 2021

Senescence mechanisms and targets in the heart.

Cardiovasc Res 2021 May 7. Epub 2021 May 7.

Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA 02138.

Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence, the senescent state can also be induced by oxidative stress, metabolic dysfunction, and epigenetic regulation, among other stressors. It is critical that we understand the molecular pathways that lead to cellular senescence and the consequences of cellular senescence in order to develop new therapeutic approaches to treat cardiovascular disease. In this review, we discuss molecular mechanisms of cellular senescence, explore how cellular senescence of different cardiac cell types (including cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, valve interstitial cells) can lead to cardiovascular disease, and highlight potential therapeutic approaches that target molecular mechanisms of cellular senescence to prevent or treat cardiovascular disease.
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http://dx.doi.org/10.1093/cvr/cvab161DOI Listing
May 2021

Asian-Americans Remain Low Utilizers of County Mental Health Services.

CNS Spectr 2021 Apr;26(2):141-163

University of California, Riverside School of Medicine, Riverside, CA, USA.

The National Latino and Asian American Study (NLAAS, 2002-2003, n =2095) indicated that Asian-Americans (AA) use mental health services less frequently than the general population (8.6% vs. 17.95%). Even AA who have been diagnosed with mental health disorders use mental health services less frequently than their non-AA counterparts (34.1% versus 41.1%)2. AA in Riverside County count for 7.4% of the population, or about 181,356 individuals, according to the 2018 census estimates. The objective of the study is to examine and compare rates of utilization of mental health services by AA specifically in the Riverside County setting. This study utilizes data on patients' ethnicity, age, gender, and diagnosis as collected annually by the Riverside County Department of Mental Health from the fiscal year of 2017-2018. It compares the prevalence of psychiatric disorders and the rate of utilization of mental health services by AA in the county to the data collected by the NLAAS. The total number of AA using mental health services in Riverside County is 669, which totals 1.73% of all individuals accessing the same services. The number of AA using mental health services represented 0.45% of the total AA population in Riverside County. AA in Riverside County are utilizing MH services even less than the national rates (0.45% vs 8.6% nationally from NLAAS data). The gap in care illustrated by these results exemplifies not only the disparity in utilization of MH services seen in this particular ethnic group, but portrays the stagnant results from Riverside County s attempts to address this issue. Possible reasons for the disparity include lack of access, stigma, recovery, migration, and a lack of culturally-competent care. A reimagined outreach initiative may help to better address this issue. Riverside County already has implemented an AA Task Force, holds health fairs at local churches in the communities, supports a UCR School of Medicine student-run free clinic, and is active in NAMI events.
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http://dx.doi.org/10.1017/S1092852920002242DOI Listing
April 2021

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

Lancet Gastroenterol Hepatol 2021 Apr 26. Epub 2021 Apr 26.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes.

Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495.

Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016).

Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment.

Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.
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http://dx.doi.org/10.1016/S2468-1253(21)00074-1DOI Listing
April 2021

Reversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent nephropathy.

Lab Invest 2021 Apr 28. Epub 2021 Apr 28.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/ob mouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.
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http://dx.doi.org/10.1038/s41374-021-00592-8DOI Listing
April 2021

Cold hardening improves larval tick questing under low temperatures at the expense of longevity.

Comp Biochem Physiol A Mol Integr Physiol 2021 Apr 23:110966. Epub 2021 Apr 23.

Department of Biology, Miami University, Oxford, OH 45056, United States of America.

Questing in ticks is essential for locating a host, and this behavioral response can occur at regionally specific low temperatures for most tick species. Little is known about the dynamics between tick questing behavior and temperature in ticks, specifically how this may impact other aspects of tick biology. Here, we examine whether cold hardening increases questing in three larval tick species (Ixodes uriae, Dermacentor variabilis, and Amblyomma americanum) at low temperatures and whether cold hardening impacts longevity. Rapid cold hardening and prolonged cold acclimation benefitted ticks by decreasing the temperature of chill coma onset, and increased survival, activity, and questing in ticks at low temperatures. Oxygen consumption increased at low temperatures following acclimation in larvae, suggesting this process has a distinct metabolic expense. This increased metabolism associated with hardening led to a substantial reduction in larval longevity as nutrient reserves are limited and cannot be replenished until a host is located. These studies suggest that tick larvae, and likely other developmental stages, require a delicate balance between the need for questing at low temperatures and survival until the first blood meal.
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http://dx.doi.org/10.1016/j.cbpa.2021.110966DOI Listing
April 2021

Decreasing Failure-to-Rescue From Severe Maternal Morbidity at Cesarean Delivery: Recent US Trends.

JAMA Surg 2021 Apr 21. Epub 2021 Apr 21.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles.

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http://dx.doi.org/10.1001/jamasurg.2021.0600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060881PMC
April 2021

Treatment Outcomes of Slow Coagulation Transscleral Cyclophotocoagulation In Pseudophakic Patients with Medically Uncontrolled Glaucoma.

Am J Ophthalmol 2021 Apr 11. Epub 2021 Apr 11.

Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Fl 33136, USA. Electronic address:

Purpose: Reporting treatment outcomes of slow coagulation transscleral cyclophotocoagulation (TSCPC) as an initial surgical intervention in pseudophakic glaucomatous patients.

Design: Retrospective case series.

Methods Setting: Single academic center.

Study Population: Seventy-four pseudophakic patients (mean age of 82.6 ±12.5 years and mean follow-up of 18.7±9.1 months) with a diagnosis of glaucoma and no previous glaucoma surgeries.

Intervention: Slow coagulation continuous-wave TSCPC (1250-milliwatt power and 4-second duration) MAIN OUTCOME MEASURES: Primary outcome measure was surgical success defined as an IOP 6 - 21 mmHg with reduction ≥ 20% from baseline, no reoperation for glaucoma, and no loss of light-perception vision. Secondary outcome measures include glaucoma medication use, visual acuity (VA), and complications.

Results: IOP decreased from 27.5±9.8 mmHg preoperatively to 16.1±6.3 mm Hg postoperatively (P< 0.001). The preoperative number of glaucoma medications was 4.1±0.9 and 3.1±1.3 post-TSCPC (p< 0.001). The cumulative probability of success at 1 and 2 years were 60.6 % and 58.5%, respectively. When patients were divided into 2 groups based on their baseline IOP being > 21 mmHg (high group) or ≤ 21 mmHg (low group), success rates at 2 years were 64.9% and 45.5%, respectively (P = 0.144). Mean logMAR VA changed from 0.70 ± 0.64 to 1.04±0.87 at the last follow-up visit (P= 0.01). No serious complications were observed and most of the complications were mild and transient.

Conclusions: Slow coagulation TSCPC has good efficiency, especially in patients with baseline IOP > 21 mm Hg, and safety profile as an initial surgical intervention in pseudophakic glaucomatous patients.
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http://dx.doi.org/10.1016/j.ajo.2021.04.003DOI Listing
April 2021

Physical Activity and Sleep Measures Using a Fitness Tracking Device during Hematopoietic Cell Transplantation: A Pilot Study.

Transplant Cell Ther 2021 Feb 19. Epub 2021 Feb 19.

University Hospitals Seidman Cancer Center, Cleveland, Ohio; Case Western Reserve University, Cleveland, Ohio. Electronic address:

Patients undergoing hematopoietic cell transplantation (HCT) experience decline in their physical activity during their transplant admission. There is limited experience with prospective monitoring of transplant recipients. We therefore measured physical activity and sleep patterns of subjects undergoing autologous and allogeneic HCT. Eighty-three patients were consented for this study. Sixty-three patients competed the study and had their physical activity prospectively assessed using the fitness-tracking device Fitbit HR. Outcomes included adherence, physical activity, readmission, hematopoietic engraftment, and 100-day survival. Sixty percent of patients (n = 37) underwent autologous HCT, and 40% (n = 26) underwent allogenic HCT. Both groups had a comparable number of steps at admission to the hospital. The number of daily steps during the study period was lower in the allogeneic group (2159 versus 3008, P = .07), as was the minimum number of steps recorded over the transplant admission (allogeneic HCT = 395 versus autologous HCT = 848, P = .01). Patients undergoing allogeneic HCT were less active on the day before discharge (1956 steps versus 3183 steps, P = .08). In multivariate analysis, physical activity was not associated with HCT-related outcomes. Patients undergoing HCT experience significant decline in their physical activity during their transplant admission that does not recover by the time of discharge. This effect can be objectively measured using fitness tracking devices.
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http://dx.doi.org/10.1016/j.jtct.2021.02.015DOI Listing
February 2021

Adoption, Safety, and Retreatment Rates of Prostatic Urethral Lift for Benign Prostatic Enlargement.

J Urol 2021 Apr 1:101097JU0000000000001757. Epub 2021 Apr 1.

Department of Urology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York.

Purpose: Novel minimally invasive therapies like the prostatic urethral lift are among the many endoscopic options for the treatment of benign prostatic enlargement and lower urinary tract symptoms (BPE/LUTS). To further understand the relative uptake, complications and retreatment rates of contemporary endoscopic procedures for BPE/LUTS across diverse practice types, we performed a retrospective study of inpatient and ambulatory surgery encounters in the Premier Healthcare database.

Materials And Methods: We included men who underwent endoscopic procedures for BPE/LUTS between 2000 and 2018. We determined the utilization of endoscopic therapies for BPE/LUTS, 30-day and 90-day readmission rates, and retreatment rate. Multivariable logistic regression was used to assess the association of procedure type with outcomes for the 3 most commonly performed procedures.

Results: We identified 175,150 men treated with endoscopic surgery for BPE/LUTS. The annual percent utilization of the prostatic urethral lift increased from <1% in 2014 to 10.4% in 2018. Compared to transurethral resection of the prostate and prostate photovaporization, prostatic urethral lift was associated with a lower odds of readmission at 30 (OR 0.58, p <0.01) and 90 (OR 0.55, p <0.01) days and a higher odds of retreatment within 2 years of follow up (OR 1.78, p <0.01).

Conclusions: Providers have rapidly adopted prostatic urethral lift which accounted for more than 1 in 10 endoscopic procedures captured for BPE/LUTS in 2018. Men treated with prostatic urethral lift are readmitted less within 30 and 90 days but are more likely to be retreated within 2 years of their index procedure as compared to men treated with transurethral resection of the prostate or prostate photovaporization.
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http://dx.doi.org/10.1097/JU.0000000000001757DOI Listing
April 2021

Editorial: Machine Learning and Network-Driven Integrative Genomics.

Front Genet 2021 11;12:660201. Epub 2021 Mar 11.

Lieber Institute for Brain Development, Johns Hopkins Medical, Baltimore, MD, United States.

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http://dx.doi.org/10.3389/fgene.2021.660201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990759PMC
March 2021

Mistletoe Extract Viscum Fraxini-2 for Treatment of Advanced Hepatocellular Carcinoma: A Case Series.

Case Rep Oncol 2021 Jan-Apr;14(1):224-231. Epub 2021 Mar 1.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of death from cancer worldwide, and for advanced HCC the prognosis is poor. Preliminary studies indicate mistletoe extracts may have anticancer activity for HCC.

Methods: A prospective observational case series of advanced HCC patients that chose to take a mistletoe extract called viscum fraxini-2 (VF-2) alone for treatment. Time on treatment, imaging, and laboratory values were collected for descriptive analyses.

Results: A total of 12 patients with advanced HCC enrolled onto the protocol, and 10 patients had data available for evaluation. The majority were male (10/12) with a median age of 64 (SD 11). Most patients had received sorafenib therapy (9/12) and had varying Child-Pugh classes (A-4, B-6, C-2). Treatment with VF-2 ranged from 1 to 36 weeks with a mean of 12.3 weeks (SD 12). Six patients received 8 weeks of treatment, and 3 patients received 12 or more weeks of treatment. For patients that received at least 4 weeks of treatment, the average AFP value stabilized during the first 4 weeks of treatment. Two patients experienced an AFP decrease of >30%, approximately 37 and 40% decreases at the nadir. One patient had stable disease of 9 months. Major side effects were fever, fatigue, rash, and local injection site reaction of swelling, redness, and tenderness.

Conclusion: This case series of advanced HCC indicates that mistletoe extract VF-2 may have potential biological activity against HCC for selected patients. Research is needed to identify the active compound and predictive markers of response.
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http://dx.doi.org/10.1159/000511566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983630PMC
March 2021

E2F1 and E2F2-mediated repression of CPT2 establishes a lipid-rich tumor-promoting environment.

Cancer Res 2021 Mar 26. Epub 2021 Mar 26.

Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital.

Lipid metabolism rearrangements in nonalcoholic fatty-liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocarcinogenesis (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expression was increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 expression was also increased and positively correlated. E2f1-/- and E2f2-/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1-/- and E2f2-/- mice enhanced fatty-acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for fatty-acid oxidation (FAO) whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared to controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expression inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-Cpt2 axis provides a lipid-rich environment required for hepatocarcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2052DOI Listing
March 2021

Identification of an intraocular microbiota.

Cell Discov 2021 Mar 9;7(1):13. Epub 2021 Mar 9.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China.

The current dogma in ophthalmology and vision research presumes the intraocular environment to be sterile. However, recent evidence of intestinal bacterial translocation into the bloodstream and many other internal organs including the eyes, found in healthy and diseased animal models, suggests that the intraocular cavity may also be inhabited by a microbial community. Here, we tested intraocular samples from over 1000 human eyes. Using quantitative PCR, negative staining transmission electron microscopy, direct culture, and high-throughput sequencing technologies, we demonstrated the presence of intraocular bacteria. The possibility that the microbiome from these low-biomass communities could be a contamination from other tissues and reagents was carefully evaluated and excluded. We also provide preliminary evidence that a disease-specific microbial signature characterized the intraocular environment of patients with age-related macular degeneration and glaucoma, suggesting that either spontaneous or pathogenic bacterial translocation may be associated with these common sight-threatening conditions. Furthermore, we revealed the presence of an intraocular microbiome in normal eyes from non-human mammals and demonstrated that this varied across species (rat, rabbit, pig, and macaque) and was established after birth. These findings represent the first-ever evidence of intraocular microbiota in humans.
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http://dx.doi.org/10.1038/s41421-021-00245-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943566PMC
March 2021

A survey of cancer patients, caregivers, and providers regarding familiarity, importance, and utilization of supportive and integrative oncology services.

Support Care Cancer 2021 Mar 19. Epub 2021 Mar 19.

Case Western Reserve University School of Medicine Comprehensive Cancer Center, 2103 Cornell Rd, Cleveland, OH, 44106, USA.

Purpose: Supportive and integrative oncology services aim to improve the quality of life of cancer patients. This study characterizes the views of these services among cancer patients, caregivers, and providers at a comprehensive cancer center.

Methods: A cross-sectional survey was administered in 2017-2018. The survey asked about participants' familiarity, perceived importance, use, accessibility, and barriers to 19 supportive and integrative oncology services using a Likert scale. Data were analyzed using the Kruskal-Wallis test and a proportional odds regression model.

Results: A total of 976 surveys were obtained (604 patient surveys, 199 caregiver surveys, 173 provider surveys). Patients were mostly female (56.3%), ≥60 years old (59.4%), and Caucasian (66%). Providers were an even distribution of nurses, physicians, and advanced practice providers. Patients felt social work and nutrition services were the most familiar (36.4% and 34.8%) and the most important (46.3% and 54.5%). Caregivers were also most familiar with those two services, but felt that nutrition and learning resources were most important. Social work and nutrition were easiest to access and used the most by both patients and providers. There was a positive correlation between accessibility and perceived importance. Being unaware was the most common barrier identified by patients (38.4%), providers (67.1%), and caregivers (33.7%).

Conclusion: Social work and nutrition services were most familiar to respondents, and also generally the most important, accessible, and utilized. Lack of awareness was the most common barrier cited and suggests that increased efforts to educate patients and providers about other services available are needed.
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http://dx.doi.org/10.1007/s00520-021-06081-4DOI Listing
March 2021

Ibrutinib-related uveitis: A report of two severe cases.

Eur J Ophthalmol 2021 Mar 15:11206721211001268. Epub 2021 Mar 15.

Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Introduction: Ibrutinib is a small-molecule drug approved for the treatment of haematological disorders and is known to be associated with visual disturbances, but uveitis has not yet been reported as an adverse effect of this medication. We present two cases of ibrutinib-associated severe uveitis in patients with chronic lymphocytic leukaemia.

Case Description: Our first case is a 65-year-old woman who presented with acute onset of bilateral fibrinous anterior uveitis 1 day after starting ibrutinib. Her vision was hand movements in the right eye and 20/120 in the left with hyperaemic discs and subretinal fluid. Ibrutinib was stopped and she experienced a significant improvement under local and oral steroid treatment. The second case is a 64-year-old male with subacute onset of bilateral hypertensive anterior uveitis with pupillary seclusion and right eye hyphaema. He was on ibrutinib for the past 9 months. His vision at presentation was 20/80 and 20/60 for the right and left eye, respectively. He responded poorly to local steroid treatment until ibrutinib was stopped due to cardiac side-effects, after which his uveitis resolved and treatment was stopped.

Conclusion: The temporal association between changes in ibrutinib treatment and our patients' ocular inflammation suggests a causative link. Ibrutinib increases Th1-based immune responses which is proposed as a mechanism for drug-induced uveitis. Its antiplatelet effect may explain the fibrinous nature of the inflammation and hyphaema.
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http://dx.doi.org/10.1177/11206721211001268DOI Listing
March 2021

Re-intervention for bioprosthetic valve failure: Is less more, or just less?

Authors:
Richard Lee

J Thorac Cardiovasc Surg 2021 Feb 17. Epub 2021 Feb 17.

Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Georgia, Augusta University, Augusta, Ga. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.119DOI Listing
February 2021

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes.

Stem Cell Res Ther 2021 Mar 12;12(1):177. Epub 2021 Mar 12.

Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, 7 Divinity Ave, Cambridge, MA, 02138, USA.

Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.
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http://dx.doi.org/10.1186/s13287-021-02252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953594PMC
March 2021

Toward Precisely Controllable Acoustic Response of Shell-Stabilized Nanobubbles: High Yield and Narrow Dispersity.

ACS Nano 2021 03 8;15(3):4901-4915. Epub 2021 Mar 8.

Department of Radiology Case Western Reserve University, Cleveland, Ohio 44106, United States.

Understanding the pressure dependence of the nonlinear behavior of ultrasonically excited phospholipid-stabilized nanobubbles (NBs) is important for optimizing ultrasound exposure parameters for implementations of contrast enhanced ultrasound, critical to molecular imaging. The viscoelastic properties of the shell can be controlled by the introduction of membrane additives, such as propylene glycol as a membrane softener or glycerol as a membrane stiffener. We report on the production of high-yield NBs with narrow dispersity and different shell properties. Through precise control over size and shell structure, we show how these shell components interact with the phospholipid membrane, change their structure, affect their viscoelastic properties, and consequently change their acoustic response. A two-photon microscopy technique through a polarity-sensitive fluorescent dye, C-laurdan, was utilized to gain insights on the effect of membrane additives to the membrane structure. We report how the shell stiffness of NBs affects the pressure threshold () for the sudden amplification in the scattered acoustic signal from NBs. For narrow size NBs with 200 nm mean size, we find to be between 123 and 245 kPa for the NBs with the most flexible membrane as assessed using C-Laurdan, 465-588 kPa for the NBs with intermediate stiffness, and 588-710 kPa for the NBs with stiff membranes. Numerical simulations of the NB dynamics are in good agreement with the experimental observations, confirming the dependence of acoustic response to shell properties, thereby substantiating further the development in engineering the shell of ultrasound contrast agents. The viscoelastic-dependent threshold behavior can be utilized for significantly and selectively enhancing the diagnostic and therapeutic ultrasound applications of potent narrow size NBs.
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http://dx.doi.org/10.1021/acsnano.0c09701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992193PMC
March 2021

Disparities in Cancer Care and the Asian American Population.

Oncologist 2021 Mar 8. Epub 2021 Mar 8.

University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Asian Americans are the only racial/ethnic group in the U.S. for whom cancer is the leading cause of death in men and women, unlike heart disease for all other groups. Asian Americans face a confluence of cancer risks, with high rates of cancers endemic to their countries of origin due to infectious and cultural reasons, as well as increasing rates of "Western" cancers that are due in part to assimilation to the American diet and lifestyle. Despite the clear mortality risk, Asian Americans are screened for cancers at lower rates than the majority of Americans. Solutions to eliminate the disparity in cancer care are complicated by language and cultural concerns of this very heterogeneous group. This review addresses the disparities in cancer screening, the historical causes, the potential contribution of racism, the importance of cultural perceptions of health care, and potential strategies to address a very complicated problem. Noting that the health care disparities faced by Asian Americans may be less conspicuous than the structural racism that has inflicted significant damage to the health of Black Americans over more than four centuries, this review is meant to raise awareness and to compel the medical establishment to recognize the urgent need to eliminate health disparities for all. IMPLICATIONS FOR PRACTICE: Cancer is the leading cause of death in Asian Americans, who face cancers endemic to their native countries, perhaps because of infectious and cultural factors, as well as those faced by all Americans, perhaps because of "Westernization" in terms of diet and lifestyle. Despite the mortality rates, Asian Americans have less cancer screening than other Americans. This review highlights the need to educate Asian Americans to improve cancer literacy and health care providers to understand the important cancer risks of the fastest-growing racial/ethnic group in the U.S. Eliminating disparities is critical to achieving an equitable society for all Americans.
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http://dx.doi.org/10.1002/onco.13748DOI Listing
March 2021

New Endoscopic In-office Surgical Therapies for Benign Prostatic Hyperplasia: A Systematic Review.

Eur Urol Focus 2021 Mar 1. Epub 2021 Mar 1.

Department of Urology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA. Electronic address:

Context: In recent years, new technologies have been developed to treat benign prostatic enlargement (BPE). Three of these devices may be utilized in office and are promising additions.

Objective: To systematically review all clinical trials investigating prostatic urethral lift (PUL), water vapor thermal therapy (WVTT), and temporary implantable nitinol device (TIND), with emphasis on clinical efficacy and complications.

Evidence Acquisition: We performed a systematic review of PubMed/Medline database in November 2020 according to Preferred Reporting Items for Systematic Review and Meta-analysis guidelines.

Evidence Synthesis: Of 168 articles identified, 18 met the inclusion criteria. Evidence consisted of few randomized controlled trials, and multiple single-arm prospective and retrospective studies. Among the three modalities, PUL demonstrates rare occurrence of serious complications but higher retreatment rates at short- and long-term follow-up. WVTT offers lower retreatment rates with a similar safety profile. TIND studies report varying rates of retreatment and complications. All technologies offer low rates of erectile and ejaculatory dysfunction, although the risk appears to be highest for WVTT (<10.8%).

Conclusions: Among the emerging technologies introduced to treat BPE, the in-office PUL, WVTT, and TIND systems are valuable additions to the current surgical options. These systems offer unique advantages that should be considered in the shared decision-making process.

Patient Summary: In this report, we identified all clinical trials reporting on the efficacy and safety of the in-office prostatic urethral lift (PUL), water vapor thermal therapy (WVTT), and temporary implantable nitinol device (TIND) systems for the treatment of benign prostatic enlargement. We found that PUL and WVTT demonstrate acceptable outcomes in terms of functional improvement, retreatment, and complications. More data with longer follow-up are required to further evaluate TIND, but early results are promising.
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http://dx.doi.org/10.1016/j.euf.2021.02.013DOI Listing
March 2021

Uromodulin Isolation and Its -Glycosylation Analysis by NanoLC-MS/MS.

J Proteome Res 2021 May 2;20(5):2662-2672. Epub 2021 Mar 2.

Department of Urology and The Proteomics Center, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, United States.

The glycoprotein uromodulin (UMOD) is the most abundant protein in urine, and -glycans are critical for many biological functions of UMOD. Comprehensive glycan profiling of UMOD provides valuable information to understand the exact mechanisms of glycan-regulated functions. To perform comprehensive glycosylation analysis of UMOD from urine samples with limited volumes, we developed a streamlined workflow that included UMOD isolation from 5 mL of urine from 6 healthy adult donors (3 males and 3 females) and a glycosylation analysis using a highly sensitive and reproducible nanoLC-MS/MS based glycomics approach. In total, 212 -glycan compositions were identified from the purified UMOD, and 17% were high-mannose glycans, 2% were afucosylated/asialylated, 3% were neutral fucosylated, 28% were sialylated (with no fucose), 46% were fucosylated and sialylated, and 4% were sulfated. We found that isolation of UMOD resulted in a significant decrease in the relative quantity of high-mannose and sulfated glycans with a significant increase of neutral fucosylated glycans in the UMOD-depleted urine relative to the undepleted urine, but depletion had little impact on the sialylated glycans. To our knowledge, this is the first study to perform comprehensive -glycan profiling of UMOD using nanoLC-MS/MS. This analytical workflow would be very beneficial for studies with limited sample size, such as pediatric studies, and can be applied to larger patient cohorts not only for UMOD interrogation but also for global glycan analysis.
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http://dx.doi.org/10.1021/acs.jproteome.0c01053DOI Listing
May 2021

Expression of aquaporins in response to distinct dehydration stresses that confer stress tolerance in the Antarctic midge Belgica antarctica.

Comp Biochem Physiol A Mol Integr Physiol 2021 Jun 26;256:110928. Epub 2021 Feb 26.

Graduate School of Science, Osaka City University, Osaka, Japan. Electronic address:

Larvae of the Antarctic midge Belgica antarctica Jacobs (Diptera: Chironomidae) are highly tolerant of diverse environmental stresses, including freezing, severe desiccation, and osmotic extremes. Furthermore, dehydration confers subsequent desiccation and freeze tolerance. While a role for aquaporins-channels for water and other solutes-has been proposed in these dehydration processes, the types of aquaporins involved in dehydration-driven stress tolerance remain unknown. In the present study, we investigated expression of six aquaporins (Drip, Prip, Eglp1, Eglp2, Aqp12L, and Bib) in larvae of B. antarctica subjected to three different dehydration conditions: desiccation, cryoprotective dehydration, and osmotic dehydration. The expression of Drip and Prip was up-regulated under desiccation and cryoprotective dehydration, suggesting a role for these aquaporins in efficient water loss under these dehydration conditions. Conversely, expression of Drip and Prip was down-regulated under osmotic dehydration, suggesting that their expression is suppressed in larvae to combat dehydration. Larval water content was similarly decreased under all three dehydration conditions. Differences in responses of the aquaporins to the three forms of dehydration suggests distinct water management strategies associated with different forms of dehydration stress.
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http://dx.doi.org/10.1016/j.cbpa.2021.110928DOI Listing
June 2021

Malpractice litigation: The unmeasured complication.

J Thorac Cardiovasc Surg 2021 Feb 24. Epub 2021 Feb 24.

Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Georgia, Augusta University, Augusta, Ga.

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http://dx.doi.org/10.1016/j.jtcvs.2020.12.055DOI Listing
February 2021

Reelin Depletion Protects Against Atherosclerosis by Decreasing Vascular Adhesion of Leukocytes.

Arterioscler Thromb Vasc Biol 2021 Apr 25;41(4):1309-1318. Epub 2021 Feb 25.

Department of Molecular Genetics (L.C., X.X., J.H.), University of Texas (UT) Southwestern Medical Center, Dallas.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990715PMC
April 2021

Glucagon Like Peptide 1 Receptor Agonists for Targeted Delivery of Antisense Oligonucleotides to Pancreatic Beta Cell.

J Am Chem Soc 2021 Mar 24;143(9):3416-3429. Epub 2021 Feb 24.

Research and early Development, Discovery Sciences,, AstraZeneca, Gothenburg, Sweden.

The extra hepatic delivery of antisense oligonucleotides (ASOs) remains a challenge and hampers the widespread application of this powerful class of therapeutic agents. In that regard, pancreatic beta cells are a particularly attractive but challenging cell type because of their pivotal role in diabetes and the fact that they are refractory to uptake of unconjugated ASOs. To circumvent this, we have expanded our understanding of the structure activity relationship of ASOs conjugated to Glucagon Like Peptide 1 Receptor (GLP1R) agonist peptide ligands. We demonstrate the key role of the linker chemistry and its optimization to design maleimide based conjugates with improved efficacy. In addition, truncation studies and scoping of a diverse set of GLP1R agonists proved fruitful to identify additional targeting ligands efficacious including native hGLP1(7-36)NH. Variation of the carrier peptide also shed some light on the dramatic impact of subtle sequence differences on the corresponding ASO conjugate performance , an area which clearly warrant further investigations. We have confirmed the remarkable potential of GLP1R agonist conjugation for the delivery of ASOs to pancreatic beta cell by effectively knocking down islet amyloid polypeptide (IAPP) mRNA, a potential proapoptotic target, in mice.
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http://dx.doi.org/10.1021/jacs.0c12043DOI Listing
March 2021

Commentary: Are cardiac surgeons treating patients of lower socioeconomic status differently?

J Thorac Cardiovasc Surg 2020 Sep 9. Epub 2020 Sep 9.

Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Georgia, Augusta University, Augusta, Ga.

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http://dx.doi.org/10.1016/j.jtcvs.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015947PMC
September 2020

Commentary: Hypertrophic cardiomyopathy and the mitral valve-the debate continues.

J Thorac Cardiovasc Surg 2021 Jan 20. Epub 2021 Jan 20.

Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Georgia, Augusta University, Augusta, Ga. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.046DOI Listing
January 2021

Chimerism Assay Using Single Nucleotide Polymorphisms Adjacent and in Linkage-Disequilibrium Enables Sensitive Disease Relapse Monitoring after Hematopoietic Stem-Cell Transplantation.

Clin Chem 2021 Apr;67(5):781-787

Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, South Korea.

Background: Short tandem repeat (STR)-based chimerism analysis has been widely used for chimerism monitoring after hematopoietic stem-cell transplantation (HSCT), but technical artifacts can be problematic. We designed a chimerism assay using single nucleotide polymorphisms (SNPs) adjacent and in linkage-disequilibrium (CASAL), which doubly checked for SNP pairs, and thus could reduce background errors and increase analytical sensitivity.

Methods: CASAL targeted 84 SNP pairs within 10 bp distance and in perfect linkage-disequilibrium. Using undiluted and serially diluted samples, baseline error rates, and linearity was calculated. Clinical performance of CASAL was evaluated in comparison with a conventional STR assay, using 191 posttransplant samples from 42 patients with HSCT.

Results: CASAL had ∼10 times lower baseline error rates compared to that of ordinary next-generation sequencing. Limit of detection and quantification of CASAL were estimated to be 0.09 and 0.39%, respectively, with a linear range of 0.1-100%. CASAL correlated well with STR assay (r2 = 0.99) and the higher sensitivity enabled detection of low-level recipient chimerism and earlier prediction of relapse.

Conclusions: CASAL is a simple, analytically sensitive and accurate assay that can be used in clinical samples after HSCT with a higher performance compared to that of traditional assays. It should also be useful in other forensic and archeological testing.
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http://dx.doi.org/10.1093/clinchem/hvab010DOI Listing
April 2021

Combating Multidrug-Resistant Bacteria by Integrating a Novel Target Site Penetration and Receptor Binding Assay Platform Into Translational Modeling.

Clin Pharmacol Ther 2021 Apr 24;109(4):1000-1020. Epub 2021 Mar 24.

Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, New York, USA.

Multidrug-resistant bacteria are causing a serious global health crisis. A dramatic decline in antibiotic discovery and development investment by pharmaceutical industry over the last decades has slowed the adoption of new technologies. It is imperative that we create new mechanistic insights based on latest technologies, and use translational strategies to optimize patient therapy. Although drug development has relied on minimal inhibitory concentration testing and established in vitro and mouse infection models, the limited understanding of outer membrane permeability in Gram-negative bacteria presents major challenges. Our team has developed a platform using the latest technologies to characterize target site penetration and receptor binding in intact bacteria that inform translational modeling and guide new discovery. Enhanced assays can quantify the outer membrane permeability of β-lactam antibiotics and β-lactamase inhibitors using multiplex liquid chromatography tandem mass spectrometry. While β-lactam antibiotics are known to bind to multiple different penicillin-binding proteins (PBPs), their binding profiles are almost always studied in lysed bacteria. Novel assays for PBP binding in the periplasm of intact bacteria were developed and proteins identified via proteomics. To characterize bacterial morphology changes in response to PBP binding, high-throughput flow cytometry and time-lapse confocal microscopy with fluorescent probes provide unprecedented mechanistic insights. Moreover, novel assays to quantify cytosolic receptor binding and intracellular drug concentrations inform target site occupancy. These mechanistic data are integrated by quantitative and systems pharmacology modeling to maximize bacterial killing and minimize resistance in in vitro and mouse infection models. This translational approach holds promise to identify antibiotic combination dosing strategies for patients with serious infections.
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http://dx.doi.org/10.1002/cpt.2205DOI Listing
April 2021