Publications by authors named "Amanda Chung"

49 Publications

Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing.

Cell 2021 Apr 9;184(9):2503-2519.e17. Epub 2021 Apr 9.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142, USA. Electronic address:

A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.03.025DOI Listing
April 2021

Psychological Health of Surgeons in a Time of COVID-19: A Global Survey.

Ann Surg 2021 Jan 22. Epub 2021 Jan 22.

Department of Urology, National University Hospital, National University Health System, Singapore Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore Department of Psychological Medicine, National University of Singapore Department of Urology, CiptoMangunkusumo Hospital, Jakarta, Indonesia General Surgery and Digestive System Service, Alfredo Espinosa Hospital, Urduliz, Vizcaya, Spain Colorectal Unit, Vall d'Hebron University Hospital, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Luigi Vanvitelli University of Campania, Italy Department of Urology, Ng Teng Fong General Hospital, National University Health System, Singapore Wellcome EPSRC Centre for Interventional and Surgical Sciences (WEISS), University College London, London, United Kingdom Hospital Israelita Albert Einstein, Sao Paulo, Brazil; BP-a Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil Department of Urology, Kasturba Medical College Manipal, Manipal Academy of Higher Education, India Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR Eastern Health and Monash University Eastern Health Clinical School, Box Hill, VIC, Australia Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy SH Ho Urology Center, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China Department of Urology, Marmara University Research and Training Hospital, Turkey Conselleria de Sanidad Universal y salud Publica, Spain Hospital Universitario Parc Taulí Sabadell, Spain Escola Paulista de Medicina - Universidade Federal de São Paulo, Brazil Department of Surgery, Faculty of Medicine, Universiti Teknologi MARA, Malaysia Unit of Urological Robotic Surgery and Renal Transplantation, Careggi University Hospital, Florence, Italy Department of Urology, Campus Biomedico University of Rome, Italy Servicio de Urología, Hospital Universitario La Paz, Madrid, Spain Division of Urology, University Health Network, Department of Surgery, University of Toronto, Canada Macquarie University Hospital and Royal North Shore Hospital, Department of Urology, Sydney, New South Wales, Australia Department of Urology- Luzerner Kantonsspital- Luzern, CH, Switzerland Instituto de Investigación Sanitaria San Carlos, Hospital Clinico San Carlos, Madrid, Spain Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore (NUS).

Objective: To assess the degree of psychological impact among surgical providers during the COVID-19 pandemic.

Summary Background Data: The COVID-19 pandemic has extensively impacted global healthcare systems. We hypothesized that the degree of psychological impact would be higher for surgical providers deployed for COVID-19 work, certain surgical specialties, and for those who knew of someone diagnosed with, or who died, of COVID-19.

Methods: We conducted a global web-based survey to investigate the psychological impact of COVID-19. The primary outcomes were the Depression Anxiety Stress Scale-21 (DASS-21) and Impact of Event Scale-Revised (IES-R) scores.

Results: 4283 participants from 101 countries responded. 32.8%, 30.8%, 25.9% and 24.0% screened positive for depression, anxiety, stress and Post-Traumatic Stress Disorder (PTSD) respectively. Respondents who knew someone who died of COVID-19 were more likely to screen positive for depression, anxiety, stress and PTSD (OR 1.3, 1,6, 1.4, 1.7 respectively, all p < 0.05). Respondents who knew of someone diagnosed with COVID-19 were more likely to screen positive for depression, stress and PTSD (OR 1.2, 1.2 and 1.3 respectively, all p < 0.05). Surgical specialities that operated in the Head and Neck region had higher psychological distress among its surgeons. Deployment for COVID-19-related work was not associated with increased psychological distress.

Conclusions: The COVID-19 pandemic may have a mental health legacy outlasting its course. The long-term impact of this ongoing traumatic event underscores the importance of longitudinal mental health care for healthcare personnel, with particular attention to those who know of someone diagnosed with, or who died of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000004775DOI Listing
January 2021

Ectopic prostatic tissue in the perineum.

BMJ Case Rep 2020 Nov 4;13(11). Epub 2020 Nov 4.

Department of Urology, Northern Beaches Hospital, Frenchs Forest, New South Wales, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2020-239378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643483PMC
November 2020

Association between ureteric stent dwell time and urinary tract infection.

ANZ J Surg 2021 01 2;91(1-2):187-191. Epub 2020 Nov 2.

Department of Urology, Northern Beaches Hospital, Sydney, New South Wales, Australia.

Background: Ureteric stone obstruction commonly presents to the emergency department, with definitive management often involving ureteroscopy and laser lithotripsy. Insertion of a ureteric stent prior to staged lithotripsy is commonly performed in the public healthcare system. Foreign bodies in the urinary tract are also known to increase urinary tract infection (UTI) risk. This study aims to evaluate the association between stent dwell time and UTI prior to lithotripsy.

Methods: The medical records of all patients who were treated for ureteric stones with initial stent insertion and staged lithotripsy, from 1 January 2018 to 30 June 2019 at a single tertiary centre, by eight urologists were retrospectively reviewed. Demographic features, disease factors and urine culture data were collected and analysed.

Results: Of the 172 patients (median age 56.7 years) identified, one-third had a positive pre-stent urine culture. Twenty-three percent had a positive pre-lithotripsy urine culture with 38% of females compared with 15% of males having a positive culture (P = 0.001). Only 4.3% of patients had a pre-lithotripsy UTI when the stent dwell time was less than 1 month compared with 26.2% when ureteric stents were in situ for longer than 1 month (P = 0.021). The correlation between ureteric stent dwell time and pre-lithotripsy UTI was not linear. Patient comorbidities, stone size, burden and location were not statistically correlated to pre-lithotripsy UTI.

Conclusion: In delayed two-staged surgical management of acute urolithiasis, optimal ureteric stent dwell time is less than 1 month to reduce pre-lithotripsy UTI. Female gender is an independent risk factor for pre-lithotripsy UTI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ans.16414DOI Listing
January 2021

Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche.

Nat Biomed Eng 2020 11 5;4(11):1076-1089. Epub 2020 Oct 5.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid-polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-020-00623-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655681PMC
November 2020

Global Survey of the Roles and Attitudes Toward Social Media Platforms Amongst Urology Trainees.

Urology 2021 Jan 18;147:64-67. Epub 2020 Sep 18.

Department of Urology, La Paz University Hospital, Madrid, Spain, Autonomous University of Madrid, Madrid, Spain.

Objectives: To perform a global survey assessing the role of and the attitudes toward media platforms amongst training Urologists METHODS: We distributed a 21-item online survey on social medial (SoMe) and other media platforms to current Urology trainees by email via individual institutions and multiple Urological associations. The survey acquired data including baseline characteristics, the role of and attitudes toward SoMe and other media platforms in training and assessed the prevalence of Social Media Disorder (SMD) based on the validated 9-item SMD Scale. Stata IC was used for statistical analysis.

Results: Three hundred and seventy-two urology trainees in 6 continents participated in the survey. Overall, 99.4% used SoMe and 27.3% listened to healthcare-focused podcasts. Most trainees (85.5%) are using guideline apps for education purposes, with the top 3 most utilized apps being the EAU, AUA, and UpToDate applications. There was mixed sentiment regarding the impact of SoMe on the patient-physician relationship, wherein most felt it challenges the doctor's authority (56.7%) but also empowers the patient (62.7%) and encourages shared-care (57.3%). Unfortunately, 11.3% of urology trainees met criteria for SMD while 65.4% had not reviewed professional guidelines on appropriate SoMe use.

Conclusion: Despite practically all urology trainees using SoMe and guideline applications, the majority of trainees have not reviewed or have been educated on professional guidelines for SoMe usage. There is a small but significant number of trainees who are at risk for SMD which may be contributing to higher rates of physician burnout amongst urologists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2020.09.007DOI Listing
January 2021

Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute Phase Peyronie's Disease: A Multi-institutional Analysis.

Urology 2020 Nov 7;145:147-151. Epub 2020 Aug 7.

Department of Urology, Tulane University School of Medicine, New Orleans, LA. Electronic address:

Objective: To study, in a multi-institutional setting, the efficacy/safety outcomes in acute phase Peyronie's disease (PD) of multiple high-volume centers employing CCH to treat PD, which is defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis. It is a chronic condition that afflicts 3%-13% of the US male population. There is no current multi-institutional research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD.

Methods: Retrospective data were collected for consecutive patients with PD who underwent treatment with CCH between April 2014 and March 2018 at 5 institutions. 918 patients were included. Patients with duration of PD no longer than 6 months at presentation qualified as being in the acute phase of PD. Main outcomes of interest include the change in curvature after receiving CCH therapy, and frequency of serious treatment-related adverse events. Successful improvement in curvature is defined as an at least 20% decrease in penile curvature from baseline after CCH therapy.

Results: A total of 918 patients were included in the analysis, of which 134 (14.6%) qualified as acute phase PD (group 1) and the remaining 784 (85.4%) qualified as stable phase (group 2). Mean duration of PD was 4.44 ± 1.68 months for group 1, and 40.8 ± 61.2 months for group 2. There was no significant difference in final change in curvature between acute and stable phase of PD (13.5° vs 15.6°, P = .09). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (16 patients, 11.9%) and the stable phase (77 patients, 9.8%; P = .44). In our multivariate analysis, only number of CCH cycles received was predictive of improvement of curvature.

Conclusion: This large multi-institutional analysis confirms that CCH therapy is as safe and efficacious in acute phase PD as it is in stable phase PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2020.07.048DOI Listing
November 2020

Reductive cleavage of ,'-di--butyl-carbodi-imide generates -butyl-cyanamide ligands, (MeCNCN), that bind potassium both end-on and side-on in the same single crystal.

Acta Crystallogr E Crystallogr Commun 2020 Jul 9;76(Pt 7):1047-1050. Epub 2020 Jun 9.

Department of Chemistry, University of California, Irvine, CA 92697-2025, USA.

,'-Di--butyl-carbodi-imide, MeCN=C=NCMe, undergoes reductive cleavage in the presence of the Gd complex, [K(18-crown-6)][Gd(N)] ( = SiMe), to form a new type of ligand, the -butyl-cyanamide anion, (MeCNCN). This new ligand can bind metals with one or two donor atoms as demonstrated by the isolation of a single crystal containing potassium salts of both end-on and side-on bound -butyl-cyanamide anions, (MeCNCN). The crystal contains [K(18-crown-6)(HO)][NCNCMe-], in which one ( BuNCN) anion is coordinated end-on to potassium ligated by 18-crown-6 and water, as well as [K(18-crown-6)][η-NCNCMe], in which an 18-crown-6 potassium is coordinated side-on to the terminal N-C linkage. This single crystal also contains one equivalent of 1,3-di--butyl urea, (CHNO), which is involved in hydrogen bonding that may stabilize the whole assembly, namely, aqua-(-butyl-cyanamidato)(1,4,7,10,13,16-hexa-oxa-cyclo-octa-deca-ne)potas-sium(I)-(-butyl-cyanamidato)(1,4,7,10,13,16-hexa-oxa-cyclo-octa-deca-ne)potas-sium(I)-,'-di--butyl-carbodi-imide (1/1/1) [K(CHN)(CHO)]·[K(CHN)(CHO)(HO)]·CHN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1107/S205698902000732XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336795PMC
July 2020

Anatomic resolution of neurotransmitter-specific projections to the VTA reveals diversity of GABAergic inputs.

Nat Neurosci 2020 08 15;23(8):968-980. Epub 2020 Jun 15.

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

The ventral tegmental area (VTA) is important for reward processing and motivation. The anatomic organization of neurotransmitter-specific inputs to the VTA remains poorly resolved. In the present study, we mapped the major neurotransmitter projections to the VTA through cell-type-specific retrograde and anterograde tracing. We found that glutamatergic inputs arose from a variety of sources and displayed some connectivity biases toward specific VTA cell types. The sources of GABAergic projections were more widespread, displayed a high degree of differential innervation of subregions in the VTA and were largely biased toward synaptic contact with local GABA neurons. Inactivation of GABA release from the two major sources, locally derived versus distally derived, revealed distinct roles for these projections in behavioral regulation. Optogenetic manipulation of individual distal GABAergic inputs also revealed differential behavioral effects. These results demonstrate that GABAergic projections to the VTA are a major contributor to the regulation and diversification of the structure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-020-0657-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927312PMC
August 2020

Scaling up malaria elimination management and leadership: a pilot in three provinces in Zimbabwe, 2016-2018.

Malar J 2020 May 20;19(1):185. Epub 2020 May 20.

Ministry of Health and Child Care, Harare, Zimbabwe.

Background: Focus for improved malaria programme performance is often placed on the technical challenges, while operational issues are neglected. Many of the operational challenges that inhibit malaria programme effectiveness can be addressed by improving communication and coordination, increasing accountability, maintaining motivation, providing adequate training and supervision, and removing bureaucratic silos.

Methods: A programme of work was piloted in Zimbabwe with one malaria eliminating province, Matabeleland South in 2016-2017, and scaled up to include two other provinces, Matabeleland North and Midlands, in 2017-2018. The intervention included participatory, organization development and quality improvement methods.

Results: Workshop participants in Matabeleland South reported an improvement in data management. In Matabeleland North, motivation among nurses improved as they gained confidence in case management from training, and overall staff morale improved. There was also an improvement in data quality and data sharing. In Midlands, the poorly performing district was motivated to improve, and both participating districts became more goal-oriented. They also became more focused on monitoring their data regularly. Participants from all provinces reported having gained skills in listening, communicating, facilitating discussions, and making presentations. Participation in the intervention changed the mindset of malaria programme staff, increasing ownership and accountability, and empowering them to identify and solve problems, make decisions, and act within their sphere of influence, elevating challenges when appropriate.

Conclusions: This pilot demonstrates that a participatory, organization development and quality improvement approach has broad ranging effects, including improving local delivery of interventions, tailoring strategies to target specific populations, finding efficiencies in the system that could not be found using the traditional top-down approach, and improving motivation and communication between different cadres of health workers. Scale-up of this simple model can be achieved and benefits sustained over time if the process is imbedded into the programme with the training of health staff who can serve as management improvement coaches. Methods to improve operational performance that are scalable at the district level are urgently needed: this approach is a possible tactic that can significantly contribute to the achievement of global malaria eradication goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12936-020-03255-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238623PMC
May 2020

Bridging the quality gap in diagnosis and treatment of malaria.

BMJ 2020 Apr 22;369:m1176. Epub 2020 Apr 22.

HEALTHQUAL, Institute for Global Health Sciences, University of California, San Francisco, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m1176DOI Listing
April 2020

Current treatment of lichen sclerosus and stricture.

World J Urol 2020 Dec 5;38(12):3061-3067. Epub 2019 Dec 5.

Department of Urology Monterrey, Hospital San Jose TecSalud, Nuevo Leon, Mexico.

Introduction: Lichen sclerosus (LS) is a common cause of urethral stricture disease. The purpose of this article is to review the literature over the past 5 years, to describe current treatment of lichen sclerosus as it relates to urethral stricture in men.

Materials And Methods: Literature reviews were performed using PUBMED, with search terms "lichen scleros*" and "urethral stenosis", as well as "lichen scleros*" and "urethral stricture". Relevant articles published within the past 5 years were selected for review. A summary of current treatment of lichen sclerosus was prepared and synthesized.

Results: For LS affecting genital skin, topical steroids are a mainstay of therapy but in advanced cases, surgery may be required such as circumcision. When LS causes urethral stricture, urethral dilatation is unlikely to be successful long term, and surgery is often required, such as meatoplasty, single- or two-stage urethroplasty, or perineal urethrostomy. Oral mucosal grafting is the graft of choice, and usage of genital skin for flaps or grafts is best avoided due to predilection for recurrence. Biopsy and long-term surveillance of LS are recommended, due to its potential association with squamous cell carcinoma development.

Conclusion: Although debate still exists regarding the pathogenesis of LS, it is agreed that LS can pose a treatment challenge to physicians and surgeons. Treatment options for LS range from pharmacological to surgical, depending on severity and location of disease, patient factors, and response of previous treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00345-019-03030-zDOI Listing
December 2020

Ionizable lipid nanoparticles encapsulating barcoded mRNA for accelerated in vivo delivery screening.

J Control Release 2019 12 31;316:404-417. Epub 2019 Oct 31.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy, with the potential to induce protein production to treat and prevent a range of diseases. However, the widespread use of mRNA as a therapeutic requires safe and effective in vivo delivery technologies. Libraries of ionizable lipid nanoparticles (LNPs) have been designed to encapsulate mRNA, prevent its degradation, and mediate intracellular delivery. However, these LNPs are typically characterized and screened in an in vitro setting, which may not fully replicate the biological barriers that they encounter in vivo. Here, we designed and evaluated a library of engineered LNPs containing barcoded mRNA (b-mRNA) to accelerate the screening of mRNA delivery platforms in vivo. These b-mRNA are similar in structure and function to regular mRNA, and contain barcodes that enable their delivery to be quantified via deep sequencing. Using a mini-library of b-mRNA LNPs formulated via microfluidic mixing, we show that these different formulations can be pooled together, administered intravenously into mice as a single pool, and their delivery to multiple organs (liver, spleen, brain, lung, heart, kidney, pancreas, and muscle) can be quantified simultaneously using deep sequencing. In the context of liver and spleen delivery, LNPs that exhibited high b-mRNA delivery also yielded high luciferase expression, indicating that this platform can identify lead LNP candidates as well as optimal formulation parameters for in vivo mRNA delivery. Interestingly, LNPs with identical formulation parameters that encapsulated different types of nucleic acid barcodes (b-mRNA versus a DNA barcode) altered in vivo delivery, suggesting that the structure of the barcoded nucleic acid affects LNP in vivo delivery. This platform, which enables direct barcoding and subsequent quantification of a functional mRNA, can accelerate the in vivo screening and design of LNPs for mRNA therapeutic applications such as CRISPR-Cas9 gene editing, mRNA vaccination, and other mRNA-based regenerative medicine and protein replacement therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2019.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032071PMC
December 2019

Trends in urethral stricture management over two decades.

BJU Int 2019 11 22;124 Suppl 1:37-41. Epub 2019 Oct 22.

Department of Urology, Royal North Shore Hospital, University of Sydney.

Objectives: To identify trends in the management of urethral stricture disease in Australia, assess changes in the standard of care, and examine the availability of genitourinary reconstructive surgery.

Methods: Data on eight stricture management procedures were collected online via Medicare Item Reports from the Australian Government Department of Human Services, and then matched to population data from the Australian Bureau of Statistics. A survey was disseminated via the Urological Society of Australia and New Zealand (USANZ) asking whether active members performed urethroplasty and whether this was done in a rural, regional or metropolitan setting.

Results: Over a 22-year period, there were 140 540 endoscopic procedures and 5136 urethroplasties, with 27.4 endoscopic procedures per urethroplasty. From 1994 to 2016, the per capita number of passage of sounds and dilatation procedures decreased by 74% and 75%, respectively, with increases in use of optical urethrotomy of 70% and in single-stage urethroplasty of 144%. Overall, the ratio of all endoscopic procedures vs urethroplasty decreased from 58.9 to 16.8. There were as few as 16 surgeons in the USANZ performing urethroplasty, with seven providing this service in regional areas. Seven had formal fellowship training.

Conclusion: There has been a clear shift from repetitive endoscopic procedures towards urethroplasty, but the former still make up the majority of interventions. This may be explained by patients not being referred for urethroplasty earlier in the course of disease and there appears to be a gap in genitourinary reconstructive expertise in regional and rural areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.14875DOI Listing
November 2019

Is Your Career Hurting You? The Ergonomic Consequences of Surgery in 701 Urologists Worldwide.

J Endourol 2019 12 17;33(12):1037-1042. Epub 2019 Jul 17.

Department of Surgery, University of Colorado, Aurora, Colorado.

Our objective was to seek correlations between the type, volume, and duration of surgical work performed, surgeon habits and characteristics, and the prevalence of neck and back musculoskeletal complaint and intervention across career from training to retirement. An anonymous web-based multinational survey of urologists was conducted. The primary outcome measured was pain. Secondary outcomes included pain requiring intervention and surgery. Responses were subgrouped according to geography, practice patterns, and demographics. Student test, Fisher's exact test, and chi-square test were used for analysis. A total of 701 complete responses were received from this multinational survey. Gender, pain distribution, and private or academic practice did not correlate with pain, whereas exercise, lower weight, and body mass index (BMI) were protective. Dose-response of surgical type was assessed with high- and low-volume density quartiles and frequency of each pain severity; no correlation was found. Secondary analysis showed that female practitioners seek invasive therapy less than male counterparts, and practitioners of direct optical cystoscopy report no more neck trouble than others. Length of career since residency shows little relationship to pain or pain-free rates. In this, the largest surgical ergonomic study to date: surgical type, duration, volume, setting, and physician gender were unrelated to surgeon pain throughout career. Exercise was associated with lower prevalence of pain in a dose-related manner; increasing weight and BMI were positively associated with pain. Although 47% of urologists with spinal pain blame their career, we are unable to identify any dose-response relationship that supports that assumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/end.2019.0150DOI Listing
December 2019

Substitution urethroplasty for the treatment of male urethral stricture: Outcomes in an Australian center.

Low Urin Tract Symptoms 2019 Sep 7;11(4):211-216. Epub 2019 May 7.

Department of Urology, Concord Repatriation General Hospital, University of Sydney, Sydney, New South Wales, Australia.

Objective: This study evaluated the outcomes of urethroplasty performed in male patients by a single surgeon.

Methods: A retrospective review of male patients who underwent substitution urethroplasty by a single surgeon was performed. Baseline and perioperative parameters were recorded. Follow-up involved a pericatheter urethrogram at 3 weeks, a flow study at 8 weeks, and cystoscopic calibration within 6 to 12 months. Patient satisfaction was assessed using the Patient Global Impression of Improvement questionnaire. Primary outcome was functional success, as defined by no need for further intervention. Secondary outcomes were complications, patient satisfaction, and factors associated with stricture recurrence.

Results: Sixty male patients were included; two were lost to follow-up. Median patient age was 47 years (range 17-83 years). Mean stricture length was 5 cm (range 1.5-18 cm). Urethroplasty was performed using buccal mucosa graft repair in 53 patients (92%), flap repair in three patients (5%), and a combination of both techniques in two patients (3%). All complications were Clavien-Dindo Grade I to III, recorded in 20 patients (34%). At a mean follow-up of 50 months (range 12-124 months), functional success was evident in 90% of patients. Cystoscopic calibration at 6 to 18 months was performed in 28 patients (49%). Most patients (93%) reported a better quality of life after the procedure. Oral complications were low grade and uncommon (6%). Stricture recurrence was not related to age, stricture length, or etiology (all P > 0.05).

Conclusions: Substitution urethroplasty has a high success rate, durable response, and high patient satisfaction. Standardization of surveillance protocol after urethroplasty is recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/luts.12265DOI Listing
September 2019

Beyond medications: office-based procedures for benign prostatic obstruction.

World J Urol 2019 Jun 29;37(6):1023-1027. Epub 2019 Apr 29.

Department of Urology, Royal North Shore Hospital, The University of Sydney, Sydney, NSW, Australia.

Purpose: When medications fail to satisfactorily treat bothersome lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO), procedural treatments are indicated. There is much interest in minimally invasive office-based treatments which can be performed under local anesthesia, allow fast recovery and have minimal morbidity. The purpose of this article is to review recent literature regarding safety and efficacy of office-based minimally invasive therapies for BPO.

Methods: A literature search using PUBMED and Medline was performed regarding minimally invasive office-based treatments for BPO, including the prostatic urethral lift (Urolift), water vapor therapy (Rezum) and stents. Literature published within the last 5 years were reviewed.

Results: The prostatic urethral lift (Urolift) is a safe and efficacious treatment for LUTS-BPO whilst also preserving sexual function. Rezum appears to be a safe and effective treatment in Phase 2 trials. Memokath prostatic stents do not appear to be a durable treatment; Allium prostatic stents warrant further investigation prior to recommendation.

Conclusions: The prostatic urethral lift (Urolift) is a safe and effective treatment for LUTS-BPO whilst preserving sexual function. Rezum also appears to be a safe and effective treatment in small RCTs comparing performance with TURP. Memokath prostatic stents do not appear to have treatment durability. Further studies would be warranted to determine whether Allium prostatic stents are safe effective treatments for LUTS-BPO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00345-019-02720-yDOI Listing
June 2019

Intralesional Collagenase Clostridium histolyticum Causes Meaningful Improvement in Men with Peyronie's Disease: Results of a Multi-Institutional Analysis.

J Urol 2019 04;201(4):777-782

Department of Urology, University of California-Los Angeles , Los Angeles , California.

Purpose: In a multi-institutional setting we studied the efficacy and safety outcomes at multiple high volume centers where collagenase Clostridium histolyticum is used to treat Peyronie's disease.

Materials And Methods: We collected retrospective data on consecutive patients with Peyronie's disease who underwent treatment with collagenase C. histolyticum between April 2014 and March 2018 at a total of 5 institutions. Included in the study were 918 patients. Main outcomes of interest included the change in curvature after receiving collagenase C. histolyticum therapy and the frequency of serious treatment related adverse events. The 2-tailed paired Student t-test was used to compare continuous variables. Univariate and multivariate regression analyses were performed to assess predictors of the success of collagenase C. histolyticum therapy to improve curvature.

Results: In the cohort of 918 patients curvature improved from a mean of 48.2 degrees before treatment to 32.9 degrees after treatment, a 30.1% improvement from baseline (p <0.0001). Of the men 68.7% had a 20% or greater improvement in curvature. In the 502 patients who completed 4 or more cycles curvature improved from a mean of 49.7 degrees before to 32.7 degrees after treatment, a 33% improvement from baseline (p <0.0001). Of these men 74.4% experienced a 20% or greater improvement in curvature. A complication of treatment developed in 9% of patients. The number of cycles of collagenase C. histolyticum received was predictive of curvature improvement (p <0.0001).

Conclusions: This large multi-institutional analysis confirms the safety and efficacy of collagenase C. histolyticum therapy in men with Peyronie's disease. Intralesional collagenase C. histolyticum for Peyronie's disease according to the IMPRESS (Investigation of Maximal Peyronie's Reduction Efficacy and Safety Studies) trial protocol produced an improvement in penile curvature in men with Peyronie's disease with a low rate of complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000000032DOI Listing
April 2019

Liquefaction of the Brain following Stroke Shares a Similar Molecular and Morphological Profile with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism.

eNeuro 2018 Sep-Oct;5(5). Epub 2018 Nov 8.

Department of Immunobiology, University of Arizona, Tucson, AZ 85719.

Here we used mouse models of heart and brain ischemia to compare the inflammatory response to ischemia in the heart, a protein rich organ, to the inflammatory response to ischemia in the brain, a lipid rich organ. We report that ischemia-induced inflammation resolves between one and four weeks in the heart compared to between eight and 24 weeks in the brain. Importantly, we discovered that a second burst of inflammation occurs in the brain between four and eight weeks following ischemia, which coincided with the appearance of cholesterol crystals within the infarct. This second wave shares a similar cellular and molecular profile with atherosclerosis and is characterized by high levels of osteopontin (OPN) and matrix metalloproteinases (MMPs). In order to test the role of OPN in areas of liquefactive necrosis, OPN mice were subjected to brain ischemia. We found that at seven weeks following stroke, the expression of pro-inflammatory proteins and MMPs was profoundly reduced in the infarct of the OPN mice, although the number of cholesterol crystals was increased. OPN mice exhibited faster recovery of motor function and a higher number of neuronal nuclei (NeuN) positive cells in the peri-infarct area at seven weeks following stroke. Based on these findings we propose that the brain liquefies after stroke because phagocytic cells in the infarct are unable to efficiently clear cholesterol rich myelin debris, and that this leads to the perpetuation of an OPN-dependent inflammatory response characterized by high levels of degradative enzymes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0076-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223114PMC
April 2019

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes.

J Control Release 2018 11 2;290:75-87. Epub 2018 Oct 2.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allografts in mice. Further, CD:LGK974 complexes increased the bioavailability upon oral administration in mice compared to free LGK974. In a mouse lung cancer allograft model, CD:LGK974 complexes induced potent Wnt signaling inhibition with reduced intestinal toxicity compared to treatment with free drug. Collectively, the development of these complexes enables safer and repeated oral or parenteral administration of Wnt signaling inhibitors, which hold promise for the treatment of multiple types of malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2018.09.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441337PMC
November 2018

Update on minimally invasive surgery and benign prostatic hyperplasia.

Asian J Urol 2018 Jan 9;5(1):22-27. Epub 2017 Jun 9.

Sydney Adventist Hospital Clinical School, University of Sydney, Sydney, NSW, Australia.

Transurethral resection of the prostate (TURP) became the gold standard surgical treatment for benign prostatic obstruction without undergoing randomized controlled trials against the predecessor standard in open suprapubic prostatectomy. TURP has historically been associated with significant morbidity and this has fuelled the development of minimally invasive surgical treatment options. Improvements in perioperative morbidity for TURP has been creating an ever increasing standard that must be met by any new technologies that are to be compared to this gold standard. Over recent years, there has been the emergence of novel minimally invasive treatments such as the prostatic urethral lift (PUL; UroLift System), convective WAter Vapor Energy (WAVE; Rezum System), Aquablation (AQUABEAM System), Histotripsy (Vortx Rx System) and temporary implantable nitinol device (TIND). Intraprostatic injections (NX-1207, PRX-302, botulinum toxin A, ethanol) have mostly been used with limited efficacy, but may be suitable for selected patients. This review evaluates these novel minimally invasive surgical options with special reference to the literature published in the past 5 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajur.2017.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780286PMC
January 2018

Glial scars are permeable to the neurotoxic environment of chronic stroke infarcts.

Neurobiol Dis 2018 04 10;112:63-78. Epub 2018 Jan 10.

Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA; Department of Neurology, University of Arizona, Tucson, AZ 85719, USA; Arizona Center on Aging, University of Arizona, Tucson, AZ 85719, USA. Electronic address:

Following stroke, the damaged tissue undergoes liquefactive necrosis, a stage of infarct resolution that lasts for months although the exact length of time is currently unknown. One method of repair involves reactive astrocytes and microglia forming a glial scar to compartmentalize the area of liquefactive necrosis from the rest of the brain. The formation of the glial scar is a critical component of the healing response to stroke, as well as other central nervous system (CNS) injuries. The goal of this study was to evaluate the toxicity of the extracellular fluid present in areas of liquefactive necrosis and determine how effectively it is segregated from the remainder of the brain. To accomplish this goal, we used a mouse model of stroke in conjunction with an extracellular fluid toxicity assay, fluorescent and electron microscopy, immunostaining, tracer injections into the infarct, and multiplex immunoassays. We confirmed that the extracellular fluid present in areas of liquefactive necrosis following stroke is toxic to primary cortical and hippocampal neurons for at least 7 weeks following stroke, and discovered that although glial scars are robust physical and endocytic barriers, they are nevertheless permeable. We found that molecules present in the area of liquefactive necrosis can leak across the glial scar and are removed by a combination of paravascular clearance and microglial endocytosis in the adjacent tissue. Despite these mechanisms, there is delayed atrophy, cytotoxic edema, and neuron loss in regions adjacent to the infarct for weeks following stroke. These findings suggest that one mechanism of neurodegeneration following stroke is the failure of glial scars to impermeably segregate areas of liquefactive necrosis from surviving brain tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2018.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851450PMC
April 2018

AdVance male sling.

Transl Androl Urol 2017 Aug;6(4):674-681

Eastern Virginia Medical School, Norfolk, VA, USA.

The AdVance sling (American Medical Systems, Minnetonka, MN, United States of America) is a synthetic transobturator sling, which is a safe and effective minimally invasive treatment for mild to moderate stress urinary incontinence (SUI) in male patients. This article provides a step-by-step description of our technique for placement of the AdVance male sling, including details and nuances gained from surgical experience, advice for avoidance of complications and discussion on management of complications and sling failures. Patient selection is very important, including exclusion and preoperative treatment of urethral stenosis and bladder dysfunction. Previous pelvic radiation is a poor prognostic factor. In brief, the steps of sling placement are: (I) mobilization of the corpus spongiosum (CS); (II) marking and mobilization of the central tendon; (III) passage of the helical trocar needles exiting at the apex of the angle between the CS and inferior pubic ramus; (IV) fixation of the broad part of the sling body to the CS at the previous mark; (V) cystoscopy during sling tensioning; (VI) placement of a Foley urethral catheter; (VII) Subcutaneous tunnelling of the sling arms back toward the midline; (VIII) wound closure. The most common early postoperative complication is urinary retention but long-term retention is extremely rare. Management of sling failures include placement of an artificial urinary sphincter, repeat AdVance sling, urethral bulking agent or ProACT device.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tau.2017.07.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583053PMC
August 2017

Sexual congruency in the connectome and translatome of VTA dopamine neurons.

Sci Rep 2017 09 11;7(1):11120. Epub 2017 Sep 11.

Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA.

The ventral tegmental area (VTA) dopamine system is important for reward, motivation, emotion, learning, and memory. Dysfunctions in the dopamine system are linked to multiple neurological and neuropsychiatric disorders, many of which present with sex differences. Little is known about the extent of heterogeneity in the basic organization of VTA dopamine neurons with regard to sex. Here, we characterized the cell-specific connectivity of VTA dopamine neurons, their mRNA translational profile, and basic electrophysiological characteristics in a common strain of mice. We found no major differences in these metrics, except for differential expression of a Y-chromosome associated mRNA transcript, Eif2s3y, and the X-linked, X-inactivation transcript Xist. Of note, Xist transcript was significantly enriched in dopamine neurons, suggesting tight regulation of X-linked gene expression to ensure sexual congruency. These data indicate that the features that make dopamine neurons unique are highly concordant and not a principal source of sexual dimorphism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-11478-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593921PMC
September 2017

Fulfilling Patient Expectations of Urethral Stricture Surgery.

J Urol 2017 11 16;198(5):993-994. Epub 2017 Aug 16.

Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.juro.2017.08.042DOI Listing
November 2017

Incidence and Management of Lower Urinary Tract Symptoms After Urethral Stricture Repair.

Curr Urol Rep 2017 Sep;18(9):70

Eastern Virginia Medical School, Norfolk, VA, USA.

Lower urinary tract symptoms (LUTS) after urethral stricture repair are not uncommon. Urgency has been reported in 40% of men and urge incontinence in 12% of men after anterior urethroplasty. De novo urgency and urge incontinence is seen in 9 and 5% of men, respectively, after urethroplasty. Once a complication of urethroplasty (such as recurrent urethral stricture or diverticulum) has been excluded as a cause, evaluation of LUTS in such patients should focus on differentiating bladder dysfunction (overactive bladder, underactive bladder), from other outlet obstruction (such as benign prostatic obstruction), dysfunctional voiding, or medical causes (such as nocturnal polyuria). Management of overactive bladder may include behavioural modification, physical therapy, anticholinergic and/or beta-3 agonist medications, intravesical onabolulinum toxin, sacral neuromodulation or peripheral tibial nerve stimulation. Definitive treatment for underactive bladder is limited. Treatment of benign prostatic obstruction may include alpha-blocker and/or 5-alpha reductase inhibitor medication, or surgery to cavitate the prostate. Minimally invasive prostatic procedures are also an option. Although management of LUTS for patients after urethral stricture repair can usually proceed similarly as for patients without prior history of urethral reconstruction, special consideration and alterations in management need to be made when instrumenting the urethra, as the urethral lumen may be narrower in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11934-017-0716-5DOI Listing
September 2017

Analysis of Copy Number Variation in the Abp Gene Regions of Two House Mouse Subspecies Suggests Divergence during the Gene Family Expansions.

Genome Biol Evol 2017 06;9(6)

Department of Medicine, College of Medicine, University of Arizona.

The Androgen-binding protein ( Abp ) gene region of the mouse genome contains 64 genes, some encoding pheromones that influence assortative mating between mice from different subspecies. Using CNVnator and quantitative PCR, we explored copy number variation in this gene family in natural populations of Mus musculus domesticus ( Mmd ) and Mus musculus musculus ( Mmm ), two subspecies of house mice that form a narrow hybrid zone in Central Europe. We found that copy number variation in the center of the Abp gene region is very common in wild Mmd , primarily representing the presence/absence of the final duplications described for the mouse genome. Clustering of Mmd individuals based on this variation did not reflect their geographical origin, suggesting no population divergence in the Abp gene cluster. However, copy number variation patterns differ substantially between Mmd and other mouse taxa. Large blocks of Abp genes are absent in Mmm , Mus musculus castaneus and an outgroup, Mus spretus , although with differences in variation and breakpoint locations. Our analysis calls into question the reliance on a reference genome for interpreting the detailed organization of genes in taxa more distant from the Mmd reference genome. The polymorphic nature of the gene family expansion in all four taxa suggests that the number of Abp genes, especially in the central gene region, is not critical to the survival and reproduction of the mouse. However, Abp haplotypes of variable length may serve as a source of raw genetic material for new signals influencing reproductive communication and thus speciation of mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gbe/evx099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513543PMC
June 2017

Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis.

Nat Commun 2017 03 20;8:14179. Epub 2017 Mar 20.

Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts 02139, USA.

Physical forces affect tumour growth, progression and metastasis. Here, we develop polymeric mechanical amplifiers that exploit in vitro and in vivo physical forces to increase immune cytokine-mediated tumour cell apoptosis. Mechanical amplifiers, consisting of biodegradable polymeric particles tethered to the tumour cell surface via polyethylene glycol linkers, increase the apoptotic effect of an immune cytokine on tumour cells under fluid shear exposure by as much as 50% compared with treatment under static conditions. We show that targeted polymeric particles delivered to tumour cells in vivo amplify the apoptotic effect of a subsequent treatment of immune cytokine, reduce circulating tumour cells in blood and overall tumour cell burden by over 90% and reduce solid tumour growth in combination with the antioxidant resveratrol. The work introduces a potentially new application for a broad range of micro- and nanoparticles to maximize receptor-mediated signalling and function in the presence of physical forces.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms14179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364380PMC
March 2017