Publications by authors named "Michelle Yu"

64 Publications

Membrane curvature and connective fiber alignment in guinea pig round window membrane.

Acta Biomater 2021 Sep 24. Epub 2021 Sep 24.

Department of Mechanical Engineering, Columbia University, 220 Mudd Building 500 West 120th Street, New York, NY 10027, USA; Department of Otolaryngology - Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address:

The round window membrane (RWM) covers an opening between the perilymph fluid-filled inner ear space and the air-filled middle ear space. As the only non-osseous barrier between these two spaces, the RWM is an ideal candidate for aspiration of perilymph for diagnostics purposes and delivery of medication for treatment of inner ear disorders. Routine access across the RWM requires the development of new surgical tools whose design can only be optimized with a thorough understanding of the RWM's structure and properties. The RWM possesses a layer of collagen and elastic fibers so characterization of the distribution and orientation of these fibers is essential. Confocal and two-photon microscopy were conducted on intact RWMs in a guinea pig model to characterize the distribution of collagen and elastic fibers. The fibers were imaged via second-harmonic-generation, autofluorescence, and Rhodamine B staining. Quantitative analyses of both fiber orientation and geometrical properties of the RWM uncovered a significant correlation between mean fiber orientations and directions of zero curvature in some portions of the RWM, with an even more significant correlation between the mean fiber orientations and linear distance along the RWM in a direction approximately parallel to the cochlear axis. The measured mean fiber directions and dispersions can be incorporated into a generalized structure tensor for use in the development of continuum anisotropic mechanical constitutive models that in turn will enable optimization of surgical tools to access the cochlea. STATEMENT OF SIGNIFICANCE: The Round Window Membrane (RWM) is the only non-osseous barrier separating the middle and inner ear spaces, and thus is an ideal portal for medical access to the cochlea. An understanding of RWM structure and mechanical response is necessary to optimize the design of surgical tools for this purpose. The RWM geometry and the connective fiber orientation and dispersion are measured via confocal and 2-photon microscopy. A region of the RWM geometry is characterized as a hyperbolic paraboloid and another region as a tapered parabolic cylinder. Predominant fiber directions correlate well with directions of zero curvature in the hyperbolic paraboloid region. Overall fiber directions correlate well with position along a line approximately parallel to the central axis of the cochlea's spiral.
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http://dx.doi.org/10.1016/j.actbio.2021.09.036DOI Listing
September 2021

EDITORIAL COMMENT.

Urology 2021 Jul;153:235

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1016/j.urology.2020.12.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302454PMC
July 2021

A Novel 3D-Printed Head Holder for Guinea Pig Ear Surgery.

Otol Neurotol 2021 10;42(9):e1197-e1202

Department of Otolaryngology - Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons.

Background: Otologic surgery in guinea pig requires head immobilization for microscopic manipulation. Existing commercially available stereotaxic frames are expensive and impede access to the ear as they rely on ear bars or mouthpieces to secure the head.

Method: Prototype head holders were designed using the Solidworks 2019 software and 3D-printed using Formlabs Form 2 Printers with photopolymer resin. The head holder consists of a C-shaped brace with adjustable radial inserts of 1/4-20 UNC standard screws with cone point tips providing head fixation for animals of various sizes. The C-shaped brace is attached to a rod that can be secured to a commercially available micromanipulator. The head holder design was tested during in vivo guinea pig experiments where their head motion with (n = 22) and without the head holder (n = 2) was evaluated visually through a stereotaxic microscope at 24× magnification during surgery.

Results: The head holder design was easy to use and allowed for both nose cone administration of anesthesia and access to the ear for intraoperative auditory testing and manipulation. Functionally, the head holder successfully minimized head movement. Furthermore, harvested round window membranes evaluated at 72 hours following surgery showed precise perforations with the use of head holder.

Conclusion: The novel 3D-printed head holder enables simultaneous access for nose cone administration of anesthesia and surgical manipulation of the ear and brain. Moreover, it provides a modular, intuitive, and economical alternative to commercial stereotaxic devices for minimizing head motion during small animal surgery.
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http://dx.doi.org/10.1097/MAO.0000000000003255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448908PMC
October 2021

The centralization of bladder cancer care and its implications for patient travel distance.

Urol Oncol 2021 Jun 20. Epub 2021 Jun 20.

Department of Urology; Center for Research on Health Care.

Objectives: To evaluate the impact of centralized surgical and nonsurgical care (i.e., radiation and chemotherapy) on travel distances and survival outcomes for patients with advanced bladder cancer. Bladder cancer is a disease with high mortality for which treatment access is paramount and survival is superior in patients receiving surgery at high-volume centers.

Methods: Using SEER-Medicare, we identified patients 66 years or older diagnosed with bladder cancer between 2004-2013. We categorized patients as treated with either surgical (i.e., radical cystectomy) or nonsurgical (i.e., radiation or chemotherapy) care. We fit a linear probability model to generate the predicted proportion of patients treated at the top quintile of volume over time and assessed travel distance, 1-year all-cause mortality, and 1-year bladder cancer-specific mortality over time.

Results: A total of 6,756 and 10,383 patients underwent surgical and nonsurgical care, respectively. The percentage of patients treated at high-volume centers increased over the study period for both surgical care (53% to 62%) and nonsurgical care (47% to 55%), (both P< 0.001). Median travel distance increased (11.8 to 20.3 miles) for surgical care and (6.5 to 8.3 miles) for nonsurgical care, (both P < 0.001). The 1-year adjusted all-cause mortality and 1-year adjusted bladder-cancer specific mortality decreased significantly for both surgical and nonsurgical care (both P < 0.05).

Conclusions: Over time, centralization of surgical and nonsurgical care for bladder cancer patients increased, which was associated with increasing patient travel distance and decreased all-cause and bladder-cancer specific mortality.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.030DOI Listing
June 2021

Health Disparities in Communities of Color During the COVID-19 Pandemic.

Health Equity 2020 30;4(1):571-578. Epub 2020 Dec 30.

Medical Director, Advocate Health, Chicago, Illinois, USA.

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http://dx.doi.org/10.1089/heq.2020.29003.rtlDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176433PMC
December 2020

Clinical Characteristics and Transmission of COVID-19 in Children and Youths During 3 Waves of Outbreaks in Hong Kong.

JAMA Netw Open 2021 05 3;4(5):e218824. Epub 2021 May 3.

Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.

Importance: Schools were closed intermittently across Hong Kong to control the COVID-19 outbreak, which led to significant physical and psychosocial problems among children and youths.

Objective: To compare the clinical characteristics and sources of infection among children and youths with COVID-19 during the 3 waves of outbreaks in Hong Kong in 2020.

Design, Setting, And Participants: This cross-sectional study involved children and youths aged 18 years or younger with COVID-19 in the 3 waves of outbreaks from January 23 through December 2, 2020. Data were analyzed from December 2020 through January 2021.

Main Outcomes And Measures: Demographic characteristics, travel and contact histories, lengths of hospital stay, and symptoms were captured through the central electronic database. Individuals who were infected without recent international travel were defined as having domestic infections.

Results: Among 397 children and youths confirmed with COVID-19 infections, the mean (SD) age was 9.95 (5.34) years, 220 individuals (55.4%) were male, and 154 individuals (38.8%) were asymptomatic. There were significantly more individuals who were infected without symptoms in the second wave (59 of 118 individuals [50.0%]) and third wave (94 of 265 individuals [35.5%]) than in the first wave (1 of 14 individuals [7.1%]) (P = .001). Significantly fewer individuals who were infected in the second and third waves, compared with the first wave, had fever (first wave: 10 individuals [71.4%]; second wave: 22 individuals [18.5%]; third wave: 98 individuals [37.0%]; P < .001) or cough (first wave: 6 individuals [42.9%]; second wave: 15 individuals [12.7%]; third wave: 52 individuals [19.6%]; P = .02). Among all individuals, 394 individuals (99.2%) had mild illness. One patient developed chilblains (ie, COVID toes), 1 patient developed multisystem inflammatory syndrome in children, and 1 patient developed post-COVID-19 autoimmune hemolytic anemia. In all 3 waves, 204 patients with COVID-19 (51.4%) had domestic infections. Among these individuals, 186 (91.2%) reported having a contact history with another individual with COVID-19, of which most (183 individuals [90.0%]) were family members. In the third wave, 18 individuals with domestic infections had unknown contact histories. Three schoolmates were confirmed with COVID-19 on the same day and were reported to be close contacts.

Conclusions And Relevance: This cross-sectional study found that nearly all children and youths with COVID-19 in Hong Kong had mild illness. These findings suggest that household transmission was the main source of infection for children and youths with domestic infections and that the risk of being infected at school was small.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.8824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094012PMC
May 2021

Drugs to Be Used With a Filter for Preparation and/or Administration-2019.

Hosp Pharm 2021 Apr 11;56(2):81-87. Epub 2019 Aug 11.

The University of Illinois at Chicago, USA.

This chart is an update to the 2012 article published in Hospital Pharmacy on injectable drugs to be used with a filter. To update the chart, drugs approved from December 2011 to April 2019 were reviewed to determine if they require filtration and drugs included in the 2012 table were reviewed for accuracy. Readers are urged to review national standards of practice for information about clinical situations that warrant the use of a filter for medication preparation or administration, independent of the drug being given, and the reader should consult the Food and Drug Administration (FDA)-approved prescribing information for the most up-to-date information.
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http://dx.doi.org/10.1177/0018578719867660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958362PMC
April 2021

A random forest-based framework for genotyping and accuracy assessment of copy number variations.

NAR Genom Bioinform 2020 Sep 22;2(3):lqaa071. Epub 2020 Sep 22.

Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Detection of copy number variations (CNVs) is essential for uncovering genetic factors underlying human diseases. However, CNV detection by current methods is prone to error, and precisely identifying CNVs from paired-end whole genome sequencing (WGS) data is still challenging. Here, we present a framework, CNV-JACG, for udging the ccuracy of NVs and enotyping using paired-end WGS data. CNV-JACG is based on a random forest model trained on 21 distinctive features characterizing the CNV region and its breakpoints. Using the data from the 1000 Genomes Project, Genome in a Bottle Consortium, the Human Genome Structural Variation Consortium and in-house technical replicates, we show that CNV-JACG has superior sensitivity over the latest genotyping method, SV, particularly for the small CNVs (≤1 kb). We also demonstrate that CNV-JACG outperforms SV in terms of Mendelian inconsistency in trios and concordance between technical replicates. Our study suggests that CNV-JACG would be a useful tool in assessing the accuracy of CNVs to meet the ever-growing needs for uncovering the missing heritability linked to CNVs.
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http://dx.doi.org/10.1093/nargab/lqaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671382PMC
September 2020

Comparison of thoracoscopy vs. thoracotomy on musculoskeletal outcomes of children with congenital pulmonary airway malformation (CPAM).

J Pediatr Surg 2021 Oct 27;56(10):1732-1736. Epub 2021 Jan 27.

Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong. Electronic address:

Background: It has been postulated that video-assisted thoracoscopic surgery (VATS) is superior than conventional thoracotomy for resection of congenital pulmonary airway malformation (CPAM) in terms of shorter hospital length of stay, reduced post-operative complication and better long-term pulmonary outcome. However, there is limited available data concerning the effect of VATS and conventional thoracotomy on musculoskeletal aspects in patients with CPAM. This study aims to compare the long-term effects of both surgical techniques on musculoskeletal outcomes in this group of patients.

Methods: Thirty-five patients with mean age of 11.38 years old who underwent VATS or conventional thoracotomy for CPAM resection were recruited in this study. The mean follow-up time was 10.42 years (5.48 to 17.71 years). Musculoskeletal examination included screening of musculoskeletal deformities (elevation of shoulder, asymmetry of nipple level, breast/ pectoral muscle maldevelopment, winging of scapula, scoliosis), measurement of bilateral chest wall in relation to anatomical parameter, and testing of shoulder range of motion and power.

Results: The prevalence of winged scapula was significantly lower in patients who underwent VATS than thoracotomy (13% vs 58%, p = 0.008). There is also a smaller reduction in operated-side chest wall vertical distance in VATS patients (0.982 vs 0.956, p = 0.058). There were no significant difference in prevalence of other musculoskeletal deformities, other chest wall measurements, shoulder range of motion and power between two groups.

Conclusion: Thoracoscopy decreases the incidence of scapular winging but has no effect on effect on other musculoskeletal deformities.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.01.028DOI Listing
October 2021

Referral pattern for urologic malignancies before and during the COVID-19 pandemic.

Urol Oncol 2021 05 8;39(5):268-276. Epub 2020 Dec 8.

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Introduction: The COVID-19 pandemic has required significant restructuring of healthcare with conservation of resources and maintaining social distancing standards. With these new initiatives, it is conceivable that the diagnosis of cancer care may be delayed. We aimed to evaluate differences in patient populations being evaluated for cancer before and during the COVID-19 pandemic.

Methods And Materials: We performed a retrospective review of our electronic medical record and examined patient characteristics of those presenting for a possible new cancer diagnosis to our urologic oncology clinic. Data was analyzed using logistic and linear regression models.

Results: During the 3-month period before the COVID-19 pandemic began, 585 new patients were seen in one urologic oncology practice. The following 3-month period, during the COVID-19 pandemic, 362 patients were seen, corresponding to a 38% decline. Visits per week increased to pre-COVID-19 levels for kidney and bladder cancer as the county entered the green phase. Prostate cancer visits per week remained below pre-COVID-19 levels in the green phase. When the 2 populations pre-COVID-19 and COVID-19 were compared, there were no notable differences on regression analysis.

Conclusion: The COVID-19 pandemic decreased the total volume of new patient referrals for possible genitourinary cancer diagnoses. The impact this will have on cancer survival remains to be determined.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722486PMC
May 2021

Novel 3D-printed hollow microneedles facilitate safe, reliable, and informative sampling of perilymph from guinea pigs.

Hear Res 2021 02 2;400:108141. Epub 2020 Dec 2.

Department of Otolaryngology - Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, 180 Fort Washington Avenue, Harkness Pavilion, 8th Floor, New York, NY 10032, United States; Department of Mechanical Engineering, Columbia University, New York, NY, United States. Electronic address:

Background: Inner ear diagnostics is limited by the inability to atraumatically obtain samples of inner ear fluid. The round window membrane (RWM) is an attractive portal for accessing perilymph samples as it has been shown to heal within one week after the introduction of microperforations. A 1 µL volume of perilymph is adequate for proteome analysis, yet the total volume of perilymph within the scala tympani of the guinea pig is limited to less than 5 µL. This study investigates the safety and reliability of a novel hollow microneedle device to aspirate perilymph samples adequate for proteomic analysis.

Methods: The guinea pig RWM was accessed via a postauricular surgical approach. 3D-printed hollow microneedles with an outer diameter of 100 µm and an inner diameter of 35 µm were used to perforate the RWM and aspirate 1 µL of perilymph. Two perilymph samples were analyzed by liquid chromatography-mass spectrometry-based quantitative proteomics as part of a preliminary study. Hearing was assessed before and after aspiration using compound action potential (CAP) and distortion product otoacoustic emissions (DPOAE). RWMs were harvested 72 h after aspiration and evaluated for healing using confocal microscopy.

Results: There was no permanent damage to hearing at 72 h after perforation as assessed by CAP (n = 7) and DPOAE (n = 8), and all perforations healed completely within 72 h (n = 8). In the two samples of perilymph analyzed, 620 proteins were detected, including the inner ear protein cochlin, widely recognized as a perilymph marker.

Conclusion: Hollow microneedles can facilitate aspiration of perilymph across the RWM at a quality and volume adequate for proteomic analysis without causing permanent anatomic or physiologic dysfunction. Microneedles can mediate safe and effective intracochlear sampling and show great promise for inner ear diagnostics.
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http://dx.doi.org/10.1016/j.heares.2020.108141DOI Listing
February 2021

EDITORIAL COMMENT.

Urology 2020 Dec;146:195

University of Pittsburgh Medical Center, Department of Urology, Pittsburgh, PA.

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http://dx.doi.org/10.1016/j.urology.2020.06.118DOI Listing
December 2020

Human Fetal Tissue Regulation. Impact on Pediatric and Adult Respiratory-related Research.

Ann Am Thorac Soc 2021 02;18(2):204-208

Medicine/Pulmonary and Critical Care Division, University of California San Francisco, San Francisco, California.

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http://dx.doi.org/10.1513/AnnalsATS.202005-460PSDOI Listing
February 2021

SARS-CoV-2 detection by nasal strips: A superior tool for surveillance of paediatric population.

J Infect 2021 04 12;82(4):84-123. Epub 2020 Nov 12.

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong.; CUHK-UMCU Joint Research Laboratory of Respiratory Virus & Immunobiology, Faculty of Medicine, The Chinese University of Hong Kong. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658621PMC
April 2021

Childhood bronchiolitis obliterans in Hong Kong-case series over a 20-year period.

Pediatr Pulmonol 2021 01 24;56(1):153-161. Epub 2020 Nov 24.

Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong.

Background And Objective: Bronchiolitis obliterans (BO) is a rare but serious condition. The natural history and outcomes remain poorly understood. In this clinical review, we aimed to describe the clinical characteristics and outcomes of children diagnosed with BO in Hong Kong (HK).

Methods: This was a retrospective study of pediatric patients with BO under the care of six respiratory units in HK from January 1996 to December 2015. Information was retrieved from medical records.

Results: Fifty-six patients were included with a male predominance (67.9%). The median age at diagnosis was 1.98 years (interquartile range [IQR]: 0.84-4.99 years). Postinfectious BO (PIBO) was the commonest cause (64.3%) followed by posthematopoietic stem-cell transplant (21.4%). Adenovirus (63.2%) was the commonest causative pathogen among PIBO. The median follow-up duration was 9.7 years (IQR: 2.9-14.3 years). Twenty-five patients (44.6%) could achieve symptom-free recovery at the time of follow-up. Five (8.9%) and three (5.4%) were oxygen or ventilator dependent, respectively. There were two deaths, both had posttransplant BO. Patients who developed BO after transplant had significantly worse lung function than those with PIBO. There were no risk factors significantly associated with worse clinical outcomes (oxygen/ventilator dependence or death) by logistic regression. Among patients with PIBO, coinfection at presentation was significantly associated with persistent symptoms at follow-up (p = .028).

Conclusions: The most common cause of childhood BO in HK is postinfectious and coinfection at presentation was associated with persistent symptoms at follow-up. Further studies are needed to better elucidate disease progression, treatment options and long term outcomes.
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http://dx.doi.org/10.1002/ppul.25166DOI Listing
January 2021

Large reduction in opioid prescribing by a multipronged behavioral intervention after major urologic surgery.

Cancer 2021 01 1;127(2):257-265. Epub 2020 Oct 1.

Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Surgeons play a pivotal role in combating the opioid crisis that currently grips the United States. Changing surgeon behavior is difficult, and the degree to which behavioral science can steer surgeons toward decreased opioid prescribing is unclear.

Methods: This was a single-institution, single-arm, pre- and postintervention study examining the prescribing of opioids by urologists for adult patients undergoing prostatectomy or nephrectomy. The primary outcome was the quantity of opioids prescribed in oral morphine equivalents (OMEs) after hospital discharge. The primary exposure was a multipronged behavioral intervention designed to decrease opioid prescribing. The intervention had 3 components: 1) formal education, 2) individual audit feedback, and 3) peer comparison performance feedback. There were 3 phases to the study: a pre-intervention phase, an intervention phase, and a washout phase.

Results: Three hundred eighty-two patients underwent prostatectomy, and 306 patients underwent nephrectomy. The median OMEs decreased from 195 to 19 in the prostatectomy patients and from 200 to 0 in the nephrectomy patients (P < .05 for both). The median OMEs prescribed did not increase during the washout phase. Prostatectomy patients discharged with opioids had higher levels of anxiety than patients discharged without opioids (P < .05). Otherwise, prostatectomy and nephrectomy patients discharged with and without opioids did not differ in their perception of postoperative pain management, activity levels, psychiatric symptoms, or somatic symptoms (P > .05 for all).

Conclusions: Implementing a multipronged behavioral intervention significantly reduced opioid prescribing for patients undergoing prostatectomy or nephrectomy without compromising patient-reported outcomes.
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http://dx.doi.org/10.1002/cncr.33200DOI Listing
January 2021

Sex Hormone Therapy and Tenofovir Diphosphate Concentration in Dried Blood Spots: Primary Results of the Interactions Between Antiretrovirals And Transgender Hormones Study.

Clin Infect Dis 2021 Oct;73(7):e2117-e2123

Department of Medicine, University of California-San Francisco, San Francisco, California, USA.

Background: Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood.

Methods: TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657).

Results: From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, -6%; 95% confidence interval [CI], -21% to 12%; P = .47), comparable between TGW and CGM (mean difference, -12%; 95% CI, -27% to 7%; P = .21) and were lower among TGM compared with CGW (mean difference, -23%; 95% CI, -36% to -7%; P = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus.

Conclusions: CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use.

Clinical Trials Registration: NCT04050371.
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http://dx.doi.org/10.1093/cid/ciaa1160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492111PMC
October 2021

Antibiotic adverse reactions in adult cystic fibrosis patients.

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3631-3633.e1. Epub 2020 Jul 14.

Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, Calif.

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http://dx.doi.org/10.1016/j.jaip.2020.06.060DOI Listing
May 2021

Beta-amyloid deposition around hepatic bile ducts is a novel pathobiological and diagnostic feature of biliary atresia.

J Hepatol 2020 12 16;73(6):1391-1403. Epub 2020 Jun 16.

Dr. Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, The University of Hong Kong, Hong Kong; Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Department of Surgery, University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. Electronic address:

Background And Aims: Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA.

Methods: We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA.

Results: Liver organoids derived from patients with BA and a rhesus rotavirus A-infected mouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids.

Conclusion: The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential.

Lay Summary: Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.
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http://dx.doi.org/10.1016/j.jhep.2020.06.012DOI Listing
December 2020

Inner ear delivery: Challenges and opportunities.

Laryngoscope Investig Otolaryngol 2020 Feb 11;5(1):122-131. Epub 2019 Dec 11.

Department of Otolaryngology-Head and Neck Surgery Columbia University Vagelos College of Physicians and Surgeons New York New York.

Objectives: The treatment of inner ear disorders remains challenging due to anatomic barriers intrinsic to the bony labyrinth. The purpose of this review is to highlight recent advances and strategies for overcoming these barriers and to discuss promising future avenues for investigation.

Data Sources: The databases used were PubMed, EMBASE, and Web of Science.

Results: Although some studies aimed to improve systemic delivery using nanoparticle systems, the majority enhanced local delivery using hydrogels, nanoparticles, and microneedles. Developments in direct intracochlear delivery include intracochlear injection and intracochlear implants.

Conclusions: In the absence of a systemic drug that targets only the inner ear, the best alternative is local delivery that harnesses a combination of new strategies to overcome anatomic barriers. The combination of microneedle technology with hydrogel and nanoparticle delivery is a promising area for future investigation.

Level Of Evidence: NA.
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http://dx.doi.org/10.1002/lio2.336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042639PMC
February 2020

Sensing Living Bacteria Using d-Alanine-Derived C Radiotracers.

ACS Cent Sci 2020 Feb 4;6(2):155-165. Epub 2020 Feb 4.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California 94158, United States.

Incorporation of d-amino acids into peptidoglycan is a unique metabolic feature of bacteria. Since d-amino acids are not metabolic substrates in most mammalian tissues, this difference can be exploited to detect living bacteria . Given the prevalence of d-alanine in peptidoglycan muropeptides, as well as its role in several antibiotic mechanisms, we targeted this amino acid for positron emission tomography (PET) radiotracer development. d-[3-C]Alanine and the dipeptide d-[3-C]alanyl-d-alanine were synthesized via asymmetric alkylation of glycine-derived Schiff-base precursors with [C]methyl iodide in the presence of a cinchonidinium phase-transfer catalyst. In cell experiments, both tracers showed accumulation by a wide variety of both Gram-positive and Gram-negative pathogens including and . In a mouse model of acute bacterial myositis, d-[3-C]alanine was accumulated by living microorganisms but was not taken up in areas of sterile inflammation. When compared to existing clinical nuclear imaging tools, specifically 2-deoxy-2-[F]fluoro-d-glucose and a gallium citrate radiotracer, d-alanine showed more bacteria-specific uptake. Decreased d-[3-C]alanine uptake was also observed in antibiotic-sensitive microbes after antimicrobial therapy, when compared to that in resistant organisms. Finally, prominent uptake of d-[3-C]alanine uptake was seen in rodent models of discitis-osteomyelitis and pneumonia. These data provide strong justification for clinical translation of d-[3-C]alanine to address a number of important human infections.
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http://dx.doi.org/10.1021/acscentsci.9b00743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047270PMC
February 2020

Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.

J Clin Invest 2020 04;130(4):2041-2053

Department of Medicine, UCSF, San Francisco, California, USA.

Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets and TRPC6 are what we believe to be novel therapeutic targets in the treatment of CF lung disease.
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http://dx.doi.org/10.1172/JCI129635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108932PMC
April 2020

Anatomical and Functional Consequences of Microneedle Perforation of Round Window Membrane.

Otol Neurotol 2020 02;41(2):e280-e287

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons.

Hypothesis: Microneedles can create microperforations in the round window membrane (RWM) without causing anatomic or physiologic damage.

Background: Reliable delivery of agents into the inner ear for therapeutic and diagnostic purposes remains a challenge. Our novel approach employs microneedles to facilitate intracochlear access via the RWM. This study investigates the anatomical and functional consequences of microneedle perforations in guinea pig RWMs in vivo.

Methods: Single three-dimensional-printed, 100 μm diameter microneedles were used to perforate the guinea pig RWM via the postauricular sulcus. Hearing was assessed both before and after microneedle perforation using compound action potential and distortion product otoacoustic emissions. Confocal microscopy was used ex vivo to examine harvested RWMs, measuring the size, shape, and location of perforations and documenting healing at 0 hours (n = 7), 24 hours (n = 6), 48 hours (n = 6), and 1 week (n = 6).

Results: Microneedles create precise and accurate perforations measuring 93.1 ± 29.0 μm by 34.5 ± 16.8 μm and produce a high-frequency threshold shift that disappears after 24 hours. Examination of perforations over time demonstrates healing progression over 24 to 48 hours and complete perforation closure by 1 week.

Conclusion: Microneedles can create a temporary microperforation in the RWM without causing significant anatomic or physiologic dysfunction. Microneedles have the potential to mediate safe and effective intracochlear access for diagnosis and treatment of inner ear disease.
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http://dx.doi.org/10.1097/MAO.0000000000002491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462276PMC
February 2020

3D-Printed Microneedles Create Precise Perforations in Human Round Window Membrane in Situ.

Otol Neurotol 2020 02;41(2):277-284

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons.

Hypothesis: Three-dimensional (3D)-printed microneedles can create precise holes on the scale of micrometers in the human round window membrane (HRWM).

Background: An intact round window membrane is a barrier to delivery of therapeutic and diagnostic agents into the inner ear. Microperforation of the guinea pig round window membrane has been shown to overcome this barrier by enhancing diffusion 35-fold. In humans, the challenge is to design a microneedle that can precisely perforate the thicker HRWM without damage.

Methods: Based on the thickness and mechanical properties of the HRWM, two microneedle designs were 3D-printed to perforate the HRWM from fresh frozen temporal bones in situ (n = 18 total perforations), simultaneously measuring force and displacement. Perforations were analyzed using confocal microscopy; microneedles were examined for deformity using scanning electron microscopy.

Results: HRWM thickness was determined to be 60.1 ± 14.6 (SD) μm. Microneedles separated the collagen fibers and created slit-shaped perforations with the major axis equal to the microneedle shaft diameter. Microneedles needed to be displaced only minimally after making initial contact with the RWM to create a complete perforation, thus avoiding damage to intracochlear structures. The microneedles were durable and intact after use.

Conclusion: 3D-printed microneedles can create precise perforations in the HRWM without damaging intracochlear structures. As such, they have many potential applications ranging from aspiration of cochlear fluids using a lumenized needle for diagnosis and creating portals for therapeutic delivery into the inner ear.
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http://dx.doi.org/10.1097/MAO.0000000000002480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189659PMC
February 2020

Opium Wars to the Opioid Epidemic: The Same Narcotics Cause Addiction and Kill.

Eur Urol 2020 01 8;77(1):76-77. Epub 2019 Nov 8.

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1016/j.eururo.2019.10.006DOI Listing
January 2020

Editorial Comment.

J Urol 2020 01 3;203(1):150. Epub 2019 Oct 3.

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1097/01.JU.0000602704.44846.e4DOI Listing
January 2020

Modulating Pathogenesis with Mobile-CRISPRi.

J Bacteriol 2019 11 21;201(22). Epub 2019 Oct 21.

Chan Zuckerberg Biohub, San Francisco, California, USA

Conditionally essential (CE) genes are required by pathogenic bacteria to establish and maintain infections. CE genes encode virulence factors, such as secretion systems and effector proteins, as well as biosynthetic enzymes that produce metabolites not found in the host environment. Due to their outsized importance in pathogenesis, CE gene products are attractive targets for the next generation of antimicrobials. However, the precise manipulation of CE gene expression in the context of infection is technically challenging, limiting our ability to understand the roles of CE genes in pathogenesis and accordingly design effective inhibitors. We previously developed a suite of CRISPR interference-based gene knockdown tools that are transferred by conjugation and stably integrate into bacterial genomes that we call Mobile-CRISPRi. Here, we show the efficacy of Mobile-CRISPRi in controlling CE gene expression in an animal infection model. We optimize Mobile-CRISPRi in for use in a murine model of pneumonia by tuning the expression of CRISPRi components to avoid nonspecific toxicity. As a proof of principle, we demonstrate that knock down of a CE gene encoding the type III secretion system (T3SS) activator ExsA blocks effector protein secretion in culture and attenuates virulence in mice. We anticipate that Mobile-CRISPRi will be a valuable tool to probe the function of CE genes across many bacterial species and pathogenesis models. Antibiotic resistance is a growing threat to global health. To optimize the use of our existing antibiotics and identify new targets for future inhibitors, understanding the fundamental drivers of bacterial growth in the context of the host immune response is paramount. Historically, these genetic drivers have been difficult to manipulate precisely, as they are requisite for pathogen survival. Here, we provide the first application of Mobile-CRISPRi to study conditionally essential virulence genes in mouse models of lung infection through partial gene perturbation. We envision the use of Mobile-CRISPRi in future pathogenesis models and antibiotic target discovery efforts.
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http://dx.doi.org/10.1128/JB.00304-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805112PMC
November 2019

Modeling Female Social Aggression: Predictors from Multiple Developmental Contexts.

J Genet Psychol 2019 Jul-Aug;180(4-5):185-204. Epub 2019 Jul 31.

Department of Psychology, California State University, East Bay , Hayward CA , USA.

A diverse array of proposed antecedents of social aggression (SA) were examined in two studies. This work is informed by ecological systems theory and examined predictors from the micro- and mesosystems. In Study 1, women ( = 284). completed measures of aggression, digit ratio, emotional intelligence (EI), agreeableness, parenting styles, attachment insecurity with parents and peers, and television (TV) consumption. Aggression correlated with EI, agreeableness, parental authoritarianism, attachment insecurity with fathers and peers, and TV consumption; these variables accounted for 22% of the variance in SA. Father attachment insecurity moderated the TV-SA association, suggesting that positive experiences with parents can buffer negative effects of TV consumption. Study 2 aimed to increase the predictive power of the model. Females ( = 115) completed measures of aggression, digit ratio, EI, agreeableness, parental authoritarianism, interparental conflict, dominance goals, popularity goals, physical appearance comparison, and TV consumption. Aggression correlated with EI, agreeableness, interparental conflict, dominance goals, popularity goals, and appearance comparison. Together, these variables accounted for 40% of the variance in SA; agreeableness, dominance goals, and popularity goals were significant predictors. Interparental conflict moderated the TV-SA association, again suggesting that positive experiences with parents can cushion effects of TV consumption. Implications for development of SA are discussed.
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http://dx.doi.org/10.1080/00221325.2019.1632254DOI Listing
January 2020

Recurrent fetal hydrops with maternal M alloimmunisation: not a benign condition.

BMJ Case Rep 2019 Jul 21;12(7). Epub 2019 Jul 21.

Westmead Institute for Maternal and Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.

Haemolytic disease of the fetus and newborn (HDFN) is associated with red cell antibodies. Anti-M usually results in a mild haemolysis and is rarely clinically significant. There is no established consensus on management of pregnancies with anti-M. A case of recurrent HDFN with maternal M alloimmunisation was identified at a tertiary hospital in Australia. We collected the patient and neonate's clinical and pathological data and interpreted the case with available literature. This is the first case in literature of recurrent fetal hydrops in the setting of M alloimmunisation. Neonate was delivered in a poor condition, intubated and admitted to the neonatal intensive care unit for ionotropic support, red cell transfusion and plasma transfusion for coagulopathy. Direct Coombs test was positive, confirming HDFN. Although anti-M rarely causes HDFN, accurate history, fetal surveillance and monitoring is essential for identification of fetal anaemia. Concurrent placental disease may increase fetal risk from anti-M antibodies.
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http://dx.doi.org/10.1136/bcr-2019-230552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664319PMC
July 2019

3 Steps to a Strong Pricing Strategy.

Authors:
Michelle Yu

Manag Care 2019 Jun;28(6):49

The need for a strong pricing strategy is a foregone conclusion. Hospitals and health systems have a window of opportunity now to craft a thoughtful approach to pricing that avoids common pitfalls and ultimately creates a competitive advantage in the market.
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http://dx.doi.org/DOI Listing
June 2019
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