Publications by authors named "Jessica Wang"

109 Publications

Interdisciplinary treatment with implant-supported two-unit cantilever prosthesis for a patient with hypodontia: A clinical report.

J Prosthet Dent 2021 Sep 3. Epub 2021 Sep 3.

Attending Physician, Division of Periodontics, Department of Stomatology, National Cheng Kung University Hospital, Tainan, Taiwan, ROC.

A 21-year-old woman with multiple congenitally missing maxillary anterior teeth received interdisciplinary treatment to restore function and esthetics. The treatment was initiated with orthodontic treatment, followed by implant placement, bone and soft-tissue augmentation, and prosthetic treatment including a screw-retained implant-supported 2-unit cantilever fixed dental prosthesis.
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http://dx.doi.org/10.1016/j.prosdent.2021.07.023DOI Listing
September 2021

Breakfast Consumption Habits at Age 6 and Cognitive Ability at Age 12: A Longitudinal Cohort Study.

Nutrients 2021 Jun 17;13(6). Epub 2021 Jun 17.

Human Nutrition Department, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar.

This study aimed to assess the relationship between breakfast composition and long-term regular breakfast consumption and cognitive function. Participants included 835 children from the China Jintan Cohort Study for the cross-sectional study and 511 children for the longitudinal study. Breakfast consumption was assessed at ages 6 and 12 through parental and self-administered questionnaires. Cognitive ability was measured as a composition of IQ at age 6 and 12 and academic achievement at age 12, which were assessed by the Chinese versions of the Wechsler Intelligence Scales and standardized school reports, respectively. Multivariable general linear and mixed models were used to evaluate the relationships between breakfast consumption, breakfast composition and cognitive performance. In the longitudinal analyses, 94.7% of participants consumed breakfast ≥ 4 days per week. Controlling for nine covariates, multivariate mixed models reported that compared to infrequent breakfast consumption, regular breakfast intake was associated with an increase of 5.54 points for verbal and 4.35 points for full IQ scores ( < 0.05). In our cross-sectional analyses at age 12, consuming grain/rice or meat/egg 6-7 days per week was significantly associated with higher verbal, performance, and full-scale IQs, by 3.56, 3.69, and 4.56 points, respectively ( < 0.05), compared with consuming grain/rice 0-2 days per week. Regular meat/egg consumption appeared to facilitate academic achievement (mean difference = 0.232, = 0.043). No association was found between fruit/vegetable and dairy consumption and cognitive ability. In this 6-year longitudinal study, regular breakfast habits are associated with higher IQ. Frequent grain/rice and meat/egg consumption during breakfast may be linked with improved cognitive function in youth.
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http://dx.doi.org/10.3390/nu13062080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234310PMC
June 2021

Low dose venetoclax in combination with bortezomib, daratumumab, and dexamethasone for the treatment of relapsed/refractory multiple myeloma patients-a single-center retrospective study.

Ann Hematol 2021 Aug 14;100(8):2061-2070. Epub 2021 May 14.

James R. Berenson, MD, Inc, West Hollywood, CA, 90069, USA.

Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.
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http://dx.doi.org/10.1007/s00277-021-04555-3DOI Listing
August 2021

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Circulation 2021 Jul 5;144(1):7-19. Epub 2021 May 5.

Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.

Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.

Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (, , , , , , , , , , ) or strong () evidence. Seven genes (14%; , , , , , , ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.

Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247549PMC
July 2021

Sex differences in inflammatory markers in patients hospitalized with COVID-19 infection: Insights from the MGH COVID-19 patient registry.

PLoS One 2021 28;16(4):e0250774. Epub 2021 Apr 28.

From the Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States of America.

Background: Men are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known.

Study Design And Methods: We examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression.

Results: Initial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04-2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29-19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52-5.18, p = 0.009 in women, Pinteraction = 0.02).

Conclusions: In a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250774PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081177PMC
May 2021

Hospital Care for Opioid use in Illinois, 2016-2019.

J Behav Health Serv Res 2021 Jan 27. Epub 2021 Jan 27.

Northwestern University Feinberg School of Medicine, 211 E. Ontario Suite, Chicago, IL, 200 312 694-7000, USA.

This study analyzes trends in hospital emergency room visits and admissions for patients with opioid diagnoses seen at 214 hospitals in Illinois over 42 months. Visits were coded hierarchically for opioid overdose, dependence, abuse, or use. Visit rates per 100,000 were stratified by zip code level of poverty. Regression estimates of the likelihood of inpatient admission and death are presented. There were 239,069 visits accounting for almost $5 billion in total charges and over 710,000 inpatient hospital days with less than a 1% death rate. The Illinois opioid epidemic is concentrated in the poorest areas of the Chicago metropolitan area. There was a sharp gradient in visits rates and deaths rates by poverty level area and more than a fivefold difference in hospital deaths. Effective state policy responses should expand to include decriminalization and proven harm reduction strategies such as medically assisted treatment, access to safe syringes, take home naloxone, and supervised safe consumption facilities.
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http://dx.doi.org/10.1007/s11414-020-09748-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839292PMC
January 2021

Changes to care delivery at nine international pediatric diabetes clinics in response to the COVID-19 global pandemic.

Pediatr Diabetes 2021 05 16;22(3):463-468. Epub 2021 Feb 16.

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Pediatric diabetes clinics around the world rapidly adapted care in response to COVID-19. We explored provider perceptions of care delivery adaptations and challenges for providers and patients across nine international pediatric diabetes clinics.

Methods: Providers in a quality improvement collaborative completed a questionnaire about clinic adaptations, including roles, care delivery methods, and provider and patient concerns and challenges. We employed a rapid analysis to identify main themes.

Results: Providers described adaptations within multiple domains of care delivery, including provider roles and workload, clinical encounter and team meeting format, care delivery platforms, self-management technology education, and patient-provider data sharing. Providers reported concerns about potential negative impacts on patients from COVID-19 and the clinical adaptations it required, including fears related to telemedicine efficacy, blood glucose and insulin pump/pen data sharing, and delayed care-seeking. Particular concern was expressed about already vulnerable patients. Simultaneously, providers reported 'silver linings' of adaptations that they perceived as having potential to inform care and self-management recommendations going forward, including time-saving clinic processes, telemedicine, lifestyle changes compelled by COVID-19, and improvements to family and clinic staff literacy around data sharing.

Conclusions: Providers across diverse clinical settings reported care delivery adaptations in response to COVID-19-particularly telemedicine processes-created challenges and opportunities to improve care quality and patient health. To develop quality care during COVID-19, providers emphasized the importance of generating evidence about which in-person or telemedicine processes were most beneficial for specific care scenarios, and incorporating the unique care needs of the most vulnerable patients.
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http://dx.doi.org/10.1111/pedi.13180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013674PMC
May 2021

The role of obesity in inflammatory markers in COVID-19 patients.

Obes Res Clin Pract 2021 Jan-Feb;15(1):96-99. Epub 2020 Dec 23.

The Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States; Division of Cardiology, Massachusetts General Hospital, Boston, MA, United States. Electronic address:

Obesity has emerged as a significant risk factor for severe COVID-19 worldwide. Given both COVID-19 infection and obesity have been associated with increased systemic inflammation, we evaluated inflammatory markers in obese and non-obese individuals hospitalized for COVID-19 at Massachusetts General Hospital. We hypothesized that obese patients would have a more exuberant inflammatory response as evidenced by higher initial and peak inflammatory markers along with worse clinical outcomes. Of the 781 patients, 349 were obese (45%). Obese individuals had higher initial and peak levels of CRP and ESR as well as higher peak d-dimer (P < 0.01 for all) in comparison to non-obese individuals, while. IL-6 and ferritin were similar. In addition, obese individuals had a higher odds of requiring vasopressor use (OR 1.54, 95% CI 1.00-2.38, P = 0.05), developing hypoxemic respiratory failure (OR 1.58, 95% CI 1.04-2.40, P = 0.03) and death (OR 2.20, 95% CI 1.31-3.70, P = 0.003) within 28 days of presentation to care. Finally, higher baseline levels of CRP and D-dimer were associated with worse clinical outcomes even after adjustment for BMI. Our findings suggest greater disease severity in obese individuals is characterized by more exuberant inflammation.
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http://dx.doi.org/10.1016/j.orcp.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833898PMC
February 2021

Cancer-secreted miRNAs regulate amino-acid-induced mTORC1 signaling and fibroblast protein synthesis.

EMBO Rep 2021 02 20;22(2):e51239. Epub 2020 Dec 20.

Department of Pathology, University of California, San Diego, La Jolla, CA, USA.

Metabolic reprogramming of non-cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer-derived metabolic and non-metabolic factors, is an emerging aspect of cancer-host interaction. We show that in normal and cancer-associated fibroblasts, breast cancer-secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation. This is through delivery of cancer-derived miR-105 and miR-204, which target RAGC, a component of Rag GTPases that regulate mTORC1 signaling. Following amino acid starvation and subsequent re-feeding, C-arginine labeling of de novo synthesized proteins shows selective translation of proteins that cluster to specific cellular functional pathways. The repertoire of these newly synthesized proteins is altered in fibroblasts treated with cancer-derived extracellular vesicles, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR-105 in the stroma. Our results suggest that through educating fibroblasts to reduce and re-prioritize mRNA translation, cancer cells rewire the metabolic fluxes of amino acid pool and dynamically regulate stroma-produced proteins during periodic nutrient fluctuations.
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http://dx.doi.org/10.15252/embr.202051239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857427PMC
February 2021

Why are listeners sometimes (but not always) egocentric? Making inferences about using others' perspective in referential communication.

PLoS One 2020 26;15(10):e0240521. Epub 2020 Oct 26.

School of Psychology, University of Birmingham, Edgbaston, United Kingdom.

Theory of Mind (ToM) is the ability to understand others' mental states, and that these mental states can differ from our own. Although healthy adults have little trouble passing conceptual tests of ToM (e.g., the false belief task [1]), they do not always succeed in using ToM [2,3]. In order to be successful in referential communication, listeners need to correctly infer the way in which a speaker's perspective constrains reference and inhibit their own perspective accordingly. However, listeners may require prompts to take these effortful inferential steps. The current study investigated the possibility of embedding prompts in the instructions for listeners to make inference about using a speaker's perspective. Experiment 1 showed that provision of a clear introductory example of the full chain of inferences resulted in large improvement in performance. Residual egocentric errors suggested that the improvement was not simply due to superior comprehension of the instructions. Experiment 2 further dissociated the effect by placing selective emphasis on making inference about inhibiting listeners' own perspective versus using the speaker's perspective. Results showed that only the latter had a significant effect on successful performance. The current findings clearly demonstrated that listeners do not readily make inferences about using speakers' perspectives, but can do so when prompted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240521PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588066PMC
December 2020

CP49 and filensin intermediate filaments are essential for formation of cold cataract.

Mol Vis 2020 23;26:603-612. Epub 2020 Aug 23.

Vision Science and Optometry, University of California, Berkeley, Berkeley, CA.

Purpose: To investigate the molecular and cellular mechanisms of cataract induced by cold temperatures in young lenses of wild-type C57BL/6J (B6), wild-type 129SvJae (129), and filensin knockout (KO) mice. To determine how lens intermediate filament proteins, filensin (BFSP1) and CP49 (BFSP2), are involved in the formation of cold cataract.

Methods: The formation of cold cataract was examined in enucleated lenses at different temperatures and was imaged under a dissecting microscope. Lens vibratome sections were prepared, immunostained with different antibodies and fluorescent probes, and then imaged with a laser confocal microscope to evaluate the protein distribution and the membrane and cytoskeleton structures in the lens fibers.

Results: Postnatal day 14 (P14) wild-type B6 lenses showed cataracts dependent on cold temperatures in interior fibers about 420-875 µm (zone III) and 245-875 µm (zone II and zone III) from the lens surface, under 25 °C and 4 °C, respectively. In contrast, wild-type 129 (with gene deletion) and filensin KO (on the B6 background) lenses did not have cold cataracts at 25 °C but displayed a reduced cold cataract, especially in zone III, at 4 °C. Immunofluorescent staining data revealed that CP49 and filensin proteins were uniformly distributed in fiber cell cytosols without cold cataracts but accumulated or aggregated in the cell boundaries of the fibers where cold cataracts appeared.

Conclusions: CP49 and filensin are important components for the formation of cold cataract in young B6 mouse lenses. Accumulated or aggregated CP49 and filensin beaded intermediate filaments in fiber cell boundaries might directly or indirectly contribute to the light scattering of cold cataract. Cold cataract in zone II is independent of beaded intermediate filaments. CP49 and filensin intermediate filaments and other lens proteins probably form distinct high molecular organizations to regulate lens transparency in interior fibers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479064PMC
July 2021

Digital Gangrene as a Sign of Catastrophic Coronavirus Disease 2019-related Microangiopathy.

Plast Reconstr Surg Glob Open 2020 Jul 16;8(7):e3025. Epub 2020 Jun 16.

Department of Plastic Surgery, Center for Wound Healing, MedStar Georgetown University Hospital, Washington, D.C.

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http://dx.doi.org/10.1097/GOX.0000000000003025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413788PMC
July 2020

Conceptual Framework for a Plastic Surgery Residency Leadership Curriculum.

Plast Reconstr Surg Glob Open 2020 Jul 14;8(7):e2852. Epub 2020 Jul 14.

Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, Washington, D.C.

Leadership development remains an overlooked component in the plastic surgery residency curriculum. Through a mixed-methods assessment of physician perceptions, this study aims to establish the value and structure of a formal leadership course for trainees.

Methods: Qualitative interviews were conducted with plastic surgery residents to identify common themes concerning the current state of leadership training and goals for improvement. These themes then guided the design of a quantitative assessment, which surveyed faculty and residents regarding their perceived need for a curriculum, the domains that should be included, and the format of delivery.

Results: Six residents underwent interviews, which yielded the following themes: (1) surgical residents require a distinct set of leadership skills that warrants more intensive training and (2) leadership training should assume a more structured format. The survey achieved a 76% (29/38) response rate, with residents comprising 55% of respondents. Participants were neutral to slightly satisfied with current resident leadership and "learning on the job" (4.62 and 4.03 on a 7-point Likert scale, respectively). Respondents reported a moderate need for formal leadership training (2.97 on a 5-point scale). Availability was ranked as the greatest barrier to curriculum implementation. Topics considered most important included effective communication, self-awareness/emotional intelligence, and strategic thinking. Formats considered most effective included in-person lectures, small group exercises, and case studies.

Conclusion: This study presents a conceptual framework for the implementation of a leadership curriculum for plastic surgery residents that may empower the development of stronger physician leaders.
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http://dx.doi.org/10.1097/GOX.0000000000002852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413817PMC
July 2020

A bimodular PKS platform that expands the biological design space.

Metab Eng 2020 09 6;61:389-396. Epub 2020 Aug 6.

Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, United States; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; QB3 Institute, University of California-Berkeley, 5885 Hollis Street, 4th Floor, Emeryville, CA, 94608, United States; Department of Chemical & Biomolecular Engineering, University of California, Berkeley, CA, 94720, United States; Department of Bioengineering, University of California, Berkeley, CA, 94720, United States; Novo Nordisk Foundation Center for Biosustainability, Technical University Denmark, DK2970, Horsholm, Denmark; Synthetic Biochemistry Center, Institute for Synthetic Biology, Shenzhen Institutes for Advanced Technologies, Shenzhen, China. Electronic address:

Traditionally engineered to produce novel bioactive molecules, Type I modular polyketide synthases (PKSs) could be engineered as a new biosynthetic platform for the production of de novo fuels, commodity chemicals, and specialty chemicals. Previously, our investigations manipulated the first module of the lipomycin PKS to produce short chain ketones, 3-hydroxy acids, and saturated, branched carboxylic acids. Building upon this work, we have expanded to multi-modular systems by engineering the first two modules of lipomycin to generate unnatural polyketides as potential biofuels and specialty chemicals in Streptomyces albus. First, we produce 20.6 mg/L of the ethyl ketone, 4,6 dimethylheptanone through a reductive loop exchange in LipPKS1 and a ketoreductase knockouts in LipPKS2. We then show that an AT swap in LipPKS1 and a reductive loop exchange in LipPKS2 can produce the potential fragrance 3-isopropyl-6-methyltetrahydropyranone. Highlighting the challenge of maintaining product fidelity, in both bimodular systems we observed side products from premature hydrolysis in the engineered first module and stalled dehydration in reductive loop exchanges. Collectively, our work expands the biological design space and moves the field closer to the production of "designer" biomolecules.
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http://dx.doi.org/10.1016/j.ymben.2020.07.001DOI Listing
September 2020

Characterization of youth goal setting in the self-management of type 1 diabetes and associations with HbA1c: The Flexible Lifestyle Empowering Change trial.

Pediatr Diabetes 2020 11 1;21(7):1343-1352. Epub 2020 Sep 1.

Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

Introduction: Youth with type 1 diabetes (T1D) commonly do not meet HbA1c targets. Youth-directed goal setting as a strategy to improve HbA1c has not been well characterized and associations between specific goal focus areas and glycemic control remain unexplored.

Objective: To inform future trials, this analysis characterized intended focus areas of youth self-directed goals and examined associations with change in HbA1c over a 18 months.

Methods: We inductively coded counseling session data from youth in the Flexible Lifestyle Empowering Change Intervention (n = 122, 13-16 years, T1D duration >1 year, HbA1c 8-13%) to categorize intended goal focus areas and examine associations between frequency of goal focus areas selected by youth and change in HbA1c between first and last study visit.

Results: We identified 13 focus areas that categorized youth goal intentions. Each session where youth goal setting concurrently incorporated blood glucose monitoring (BGM), continuous glucose monitoring (CGM), and insulin dosing was associated with a 0.4% (95% CI: -0.77, -0.01; P = .03) lower HbA1c at the end of intervention participation. No association was observed between HbA1c and frequency of sessions where goal intentions focused on BG only (without addressing insulin or CGM) (β: 0.07; 95% CI: -0.07, 0.21; P = .33) nor insulin dosing only (without addressing BGM or CGM) (β: 0.00; 95% CI: -0.11, 0.10; P = .95).

Conclusions: Findings exemplify how guiding youth goal development and combining multiple behaviors proximally related to glycemic control into goal setting may benefit HbA1c among youth with T1D. More research characterizing optimal goal setting practices in youth with T1D is needed.
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http://dx.doi.org/10.1111/pedi.13099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855488PMC
November 2020

Acquired Long QT Syndrome after Acute Myocardial Infarction: A Rare but Potentially Fatal Entity.

Tex Heart Inst J 2020 04;47(2):163-164

Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90025.

Acquired long QT syndrome is typically caused by medications, electrolyte disturbances, bradycardia, or catastrophic central nervous system events. We report a case of myocardial infarction-related acquired long QT syndrome in a 58-year-old woman that had no clear cause and progressed to torsades de pointes requiring treatment with isoproterenol and magnesium. Despite negative results of DNA testing against a known panel of genetic mutations and polymorphisms associated with long QT syndrome, the patient's family history of fatal cardiac disease suggests a predisposing genetic component. This report serves to remind clinicians of this potentially fatal ventricular arrhythmia after myocardial infarction.
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http://dx.doi.org/10.14503/THIJ-18-6872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328093PMC
April 2020

The GTPase-activating protein p120RasGAP has an evolutionarily conserved "FLVR-unique" SH2 domain.

J Biol Chem 2020 07 15;295(31):10511-10521. Epub 2020 Jun 15.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA

The Src homology 2 (SH2) domain has a highly conserved architecture that recognizes linear phosphotyrosine motifs and is present in a wide range of signaling pathways across different evolutionary taxa. A hallmark of SH2 domains is the arginine residue in the conserved FLVR motif that forms a direct salt bridge with bound phosphotyrosine. Here, we solve the X-ray crystal structures of the C-terminal SH2 domain of p120RasGAP () in its apo and peptide-bound form. We find that the arginine residue in the FLVR motif does not directly contact pTyr of a bound phosphopeptide derived from p190RhoGAP; rather, it makes an intramolecular salt bridge to an aspartic acid. Unexpectedly, coordination of phosphotyrosine is achieved by a modified binding pocket that appears early in evolution. Using isothermal titration calorimetry, we find that substitution of the FLVR arginine R377A does not cause a significant loss of phosphopeptide binding, but rather a tandem substitution of R398A (SH2 position βD4) and K400A (SH2 position βD6) is required to disrupt the binding. These results indicate a hitherto unrecognized diversity in SH2 domain interactions with phosphotyrosine and classify the C-terminal SH2 domain of p120RasGAP as "FLVR-unique."
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http://dx.doi.org/10.1074/jbc.RA120.013976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397115PMC
July 2020

Chemoinformatic-Guided Engineering of Polyketide Synthases.

J Am Chem Soc 2020 06 18;142(22):9896-9901. Epub 2020 May 18.

Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, California 94608, United States.

Polyketide synthase (PKS) engineering is an attractive method to generate new molecules such as commodity, fine and specialty chemicals. A significant challenge is re-engineering a partially reductive PKS module to produce a saturated β-carbon through a reductive loop (RL) exchange. In this work, we sought to establish that chemoinformatics, a field traditionally used in drug discovery, offers a viable strategy for RL exchanges. We first introduced a set of donor RLs of diverse genetic origin and chemical substrates  into the first extension module of the lipomycin PKS (LipPKS1). Product titers of these engineered unimodular PKSs correlated with chemical structure similarity between the substrate of the donor RLs and recipient LipPKS1, reaching a titer of 165 mg/L of short-chain fatty acids produced by the host  J1074. Expanding this method to larger intermediates that require bimodular communication, we introduced RLs of divergent chemosimilarity into LipPKS2 and determined triketide lactone production. Collectively, we observed a statistically significant correlation between atom pair chemosimilarity and production, establishing a new chemoinformatic method that may aid in the engineering of PKSs to produce desired, unnatural products.
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http://dx.doi.org/10.1021/jacs.0c02549DOI Listing
June 2020

Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line.

Nat Commun 2020 05 11;11(1):2345. Epub 2020 May 11.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA.

The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAF mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.
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http://dx.doi.org/10.1038/s41467-020-15956-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214418PMC
May 2020

Comparison of Ultrasound-Derived Muscle Thickness With Computed Tomography Muscle Cross-Sectional Area on Admission to the Intensive Care Unit: A Pilot Cross-Sectional Study.

JPEN J Parenter Enteral Nutr 2021 01 15;45(1):136-145. Epub 2020 Apr 15.

Nutrition Department, Alfred Health, Melbourne, Australia.

Introduction: The development of bedside methods to assess muscularity is an essential critical care nutrition research priority. We aimed to compare ultrasound-derived muscle thickness at 5 landmarks with computed tomography (CT) muscle area at intensive care unit (ICU) admission. Secondary aims were to (1) combine muscle thicknesses and baseline covariates to evaluate correlation with CT muscle area and (2) assess the ability of the best-performing ultrasound model to identify patients with low CT muscle area.

Methods: Adult patients who underwent CT scanning at the third lumbar area <72 hours after ICU admission were prospectively recruited. Muscle thickness was measured at mid-upper arm, forearm, abdomen, and thighs. Low CT muscle area was determined using published cutoffs. Pearson correlation compared ultrasound-derived muscle thickness and CT muscle area. Linear regression was used to develop ultrasound prediction models. Bland-Altman analyses compared ultrasound-predicted and CT-measured muscle area.

Results: Fifty ICU patients were enrolled, aged 52 ± 20 years. Ultrasound-derived muscle thickness at each landmark correlated with CT muscle area (P < .001). The sum of muscle thickness at mid-upper arm and bilateral thighs, including age, sex, and the Charlson Comorbidity Index, improved the correlation with CT muscle area (r = 0.85; P < .001). Mean difference between ultrasound-predicted and CT-measured muscle area was -2 cm (95% limits of agreement, -40 cm to +36 cm ). The best-performing ultrasound model demonstrated good ability to identify 14 patients with low CT muscle area (area under curve = 0.79).

Conclusion: Ultrasound shows potential for assessing muscularity at ICU admission (Clinicaltrials.gov NCT03019913).
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http://dx.doi.org/10.1002/jpen.1822DOI Listing
January 2021

Comparison between carbon monoxide poisoning from hookah smoking versus other sources.

Clin Toxicol (Phila) 2020 12 7;58(12):1320-1325. Epub 2020 Apr 7.

Ronald O Perelman Department of Emergency Medicine, New York University School of Medicine, New York, NY, USA.

Carbon monoxide exposure is a relatively unknown risk of smoking hookah. Dozens of cases of hookah-associated carbon monoxide toxicity have been described over the past decades, but smoking hookah is generally perceived as safe. Only recently have larger series of hookah-associated carbon monoxide toxicity been published. This study evaluates the incidence of hookah-associated carbon monoxide toxicity over 4 years, and compares the exposures from hookah against other carbon monoxide sources. This is a retrospective cohort study of all patients with carbon monoxide toxicity referred for hyperbaric oxygen therapy at an urban hyperbaric oxygen referral center from January 2015 through December 2018. Cases of hookah-associated carbon monoxide toxicity were compared to patients exposed to other carbon monoxide sources, with an analysis of patient comorbidities, symptomatology, and laboratory evaluation. Over a 48-month period, 376 patients underwent hyperbaric oxygen therapy for carbon monoxide exposure. After exclusions, 265 patients with carbon monoxide toxicity from various sources were analyzed. There were 58 patients with hookah-associated carbon monoxide toxicity (22%). The proportion of hookah-associated carbon monoxide cases increased markedly in the latter years: 2015: 9.5%, 2016: 8.6%, 2017: 24.1%, 2018 41.6%. In the final 2 years analyzed, hookah smoking was the most frequent source of carbon monoxide toxicity referred for therapy. Hookah-associated carbon monoxide patients were younger(28.1 vs. 45.0 years, mean difference 16.8 years, 95% confidence interval: 11.5, 22.1 years,  < 0.001) and more likely to be female (60% vs. 46.6%,  = 0.06) than patients exposed to other carbon monoxide sources. The mean difference in carboxyhemoglobin concentration between hookah associated and those exposed to other carbon monoxide sources was 4.6% (mean 20.1% vs. 24.6%, 95%CI: 1.7, 7.5,  = 0.002). A substantial portion of patients with severe carbon monoxide toxicity was exposed through smoking hookah. The incidence of hookah-related carbon monoxide toxicity appears to be increasing.
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http://dx.doi.org/10.1080/15563650.2020.1745225DOI Listing
December 2020

Connexin 50-R205G Mutation Perturbs Lens Epithelial Cell Proliferation and Differentiation.

Invest Ophthalmol Vis Sci 2020 03;61(3):25

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Purpose: To investigate the underlying mechanisms for how the mouse Cx50-R205G point mutation, a homologue of the human Cx50-R198W mutation that is linked to cataract-microcornea syndrome, affects proper lens growth and fiber cell differentiation to lead to severe lens phenotypes.

Methods: EdU labeling, immunostaining, confocal imaging analysis, and primary lens epithelial cell culture were performed to characterize the lens epithelial cell (LEC) proliferation and fiber cell differentiation in wild-type and Cx50-R205G mutant lenses in vivo and in vitro.

Results: The Cx50-R205G mutation severely disrupts the lens size and transparency. Heterozygous and homozygous Cx50-R205G mutant and Cx50 knockout lenses all show decreased central epithelium proliferation while only the homozygous Cx50-R205G mutant lenses display obviously decreased proliferating LECs in the germinative zone of neonatal lenses. Cultured Cx50-R205G lens epithelial cells reveal predominantly reduced Cx50 gap junction staining but no change of the endoplasmic reticulum stress marker BiP. The heterozygous Cx50-R205G lens fibers show moderately disrupted Cx50 and Cx46 gap junctions while the homozygous Cx50-R205G lens fibers have drastically reduced Cx50 and Cx46 gap junctions with severely altered fiber cell shape in vivo.

Conclusions: The Cx50-R205G mutation inhibits both central and equatorial lens epithelial cell proliferation to cause small lenses. This mutation also disrupts the assembly and functions of both Cx50 and Cx46 gap junctions in lens fibers to alter fiber cell differentiation and shape to lead to severe lens phenotypes.
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http://dx.doi.org/10.1167/iovs.61.3.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401428PMC
March 2020

Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy.

Chronic Dis Transl Med 2019 Dec 8;5(4):258-266. Epub 2020 Jan 8.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.

Despite tremendous efforts to fight cancer, it remains a major public health problem and a leading cause of death worldwide. With increased knowledge of cancer pathways and improved technological platforms, precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes. Nevertheless, a primary cause of unsuccessful cancer therapy remains cancer drug resistance. In this review, we summarize the broad classes of resistance to cancer therapy, particularly pharmacokinetics, the tumor microenvironment, and drug resistance mechanisms. Furthermore, we describe how bacterial-mediated cancer therapy, a bygone mode of treatment, has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies. Through genetic engineering, we discuss how bacteria can be potent anticancer agents given their tumor targeting potential, anti-tumor activity, safety, and coordinated delivery of anti-cancer drugs.
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http://dx.doi.org/10.1016/j.cdtm.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004931PMC
December 2019

Perspective-taking across cultures: shared biases in Taiwanese and British adults.

R Soc Open Sci 2019 Nov 20;6(11):190540. Epub 2019 Nov 20.

School of Psychology, University of Birmingham, Birmingham B15 2TT, UK.

The influential hypothesis by Markus & Kitayama (Markus, Kitayama 1991. , 224) postulates that individuals from interdependent cultures place others above self in interpersonal contexts. This led to the prediction and finding that individuals from interdependent cultures are less egocentric than those from independent cultures (Wu, Barr, Gann, Keysar 2013. , 1-7; Wu, Keysar. 2007 , 600-606). However, variation in egocentrism can only provide indirect evidence for the Markus and Kitayama hypothesis. The current study sought direct evidence by giving British (independent) and Taiwanese (interdependent) participants two perspective-taking tasks on which an other-focused 'altercentric' processing bias might be observed. One task assessed the calculation of simple perspectives; the other assessed the use of others' perspectives in communication. Sixty-two Taiwanese and British adults were tested in their native languages at their home institutions of study. Results revealed similar degrees of both altercentric and egocentric interference between the two cultural groups. This is the first evidence that listeners account for a speaker's limited perspective at the cost of their own performance. Furthermore, the shared biases point towards similarities rather than differences in perspective-taking across cultures.
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http://dx.doi.org/10.1098/rsos.190540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894566PMC
November 2019

Mutations in the Neuraminidase-Like Protein of Bat Influenza H18N11 Virus Enhance Virus Replication in Mammalian Cells, Mice, and Ferrets.

J Virol 2020 02 14;94(5). Epub 2020 Feb 14.

Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA

To characterize bat influenza H18N11 virus, we propagated a reverse genetics-generated H18N11 virus in Madin-Darby canine kidney subclone II cells and detected two mammal-adapting mutations in the neuraminidase (NA)-like protein (NA-F144C and NA-T342A, N2 numbering) that increased the virus titers in three mammalian cell lines (i.e., Madin-Darby canine kidney, Madin-Darby canine kidney subclone II, and human lung adenocarcinoma [Calu-3] cells). In mice, wild-type H18N11 virus replicated only in the lungs of the infected animals, whereas the NA-T342A and NA-F144C/T342A mutant viruses were detected in the nasal turbinates, in addition to the lungs. Bat influenza viruses have not been tested for their virulence or organ tropism in ferrets. We detected wild-type and single mutant viruses each possessing NA-F144C or NA-T342A in the nasal turbinates of one or several infected ferrets, respectively. A mutant virus possessing both the NA-F144C and NA-T342A mutations was isolated from both the lung and the trachea, suggesting that it has a broader organ tropism than the wild-type virus. However, none of the H18N11 viruses caused symptoms in mice or ferrets. The NA-F144C/T342A double mutation did not substantially affect virion morphology or the release of virions from cells. Collectively, our data demonstrate that the propagation of bat influenza H18N11 virus in mammalian cells can result in mammal-adapting mutations that may increase the replicative ability and/or organ tropism of the virus; overall, however, these viruses did not replicate to high titers throughout the respiratory tract of mice and ferrets. Bats are reservoirs for several severe zoonotic pathogens. The genomes of influenza A viruses of the H17N10 and H18N11 subtypes have been identified in bats, but no live virus has been isolated. The characterization of artificially generated bat influenza H18N11 virus in mammalian cell lines and animal models revealed that this virus can acquire mammal-adapting mutations that may increase its zoonotic potential; however, the wild-type and mutant viruses did not replicate to high titers in all infected animals.
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http://dx.doi.org/10.1128/JVI.01416-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022354PMC
February 2020

Proximally Based Split Abductor Hallucis Turnover Flap for Medial Hindfoot Reconstruction: A Case Report.

J Foot Ankle Surg 2019 Nov;58(6):1072-1076

Surgeon, Department of Plastic Surgery, Center for Wound Healing, MedStar Georgetown University Hospital, Washington, DC.

Limited reconstructive options exist for soft tissue defects of the foot and ankle because of a lack of surrounding tissue. Although microsurgical free flaps have become a popular treatment modality for this anatomic region, pedicled muscle flaps can provide robust coverage of small foot wounds with significantly less donor site comorbidity. One such muscle is the abductor hallucis, which can be used as a proximally based turnover flap to cover medial hindfoot defects. However, complete distal disinsertion of the muscle may lead to loss of support over the medial arch and first metatarsophalangeal joint, leading to pes planus and hallux valgus. In this case report, we describe a modified technique of a split abductor hallucis turnover flap for a young patient with a chronic, traumatic medial heel wound complicated by calcaneal osteomyelitis. By preserving part of the muscle's distal tendinous attachment, this technique allows for adequate soft tissue coverage while maintaining long-term biomechanical function.
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http://dx.doi.org/10.1053/j.jfas.2019.06.004DOI Listing
November 2019

Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice.

J Vis Exp 2019 10 3(152). Epub 2019 Oct 3.

Department of Medicine, University of California;

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics stress-induced cardiomyopathy, the chronic model, administered through an osmotic pump, mimics advanced heart failure in humans. The purpose of the described protocol is to create the chronic ISO-induced heart failure model in mice using an implanted mini-pump. This protocol has been used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation are described in detail and may be relevant to anyone interested in creating a heart failure model in mice. In addition, the weekly cardiac remodeling changes based on echocardiographic parameters for each strain and expected time to model development are presented. In summary, the method is simple and reproducible. Continuous ISO administered via the implanted mini-pump over 3 to 4 weeks is sufficient to induce cardiac remodeling. Finally, the success for ISO model creation may be assessed in vivo by serial echocardiography demonstrating hypertrophy, ventricular dilation, and dysfunction.
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http://dx.doi.org/10.3791/59646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374011PMC
October 2019

Kidney and Ureteral Stones.

Emerg Med Clin North Am 2019 Nov 19;37(4):637-648. Epub 2019 Aug 19.

Department of Emergency Medicine, Jacobi Medical Center, Building 6, Room 1B25, 1400 Pelham Parkway South, Bronx, NY 10461, USA.

Renal colic is a common complaint that presents to the emergency department. It is estimated that 13% of men and 7% of women will develop a renal stone. There is a high probability of recurrence, with 50% within 5 years. Computed tomographic scan of the abdomen and pelvis without contrast and the ultrasound of the kidneys, ureters, and bladder are the common diagnostic imaging modalities used for diagnosis. Initial treatment includes analgesics and medical expulsive therapy. Most of the patients will pass their stone spontaneously within 3 days. The remaining 20% will require urologic intervention.
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http://dx.doi.org/10.1016/j.emc.2019.07.004DOI Listing
November 2019

Utility of a modified components separation for abdominal wall reconstruction in the liver and kidney transplant population.

Arch Plast Surg 2019 Sep 15;46(5):462-469. Epub 2019 Sep 15.

Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital, Washington, DC, USA.

Background: Incisional hernia is a common complication following visceral organ transplantation. Transplant patients are at increased risk of primary and recurrent hernias due to chronic immune suppression and large incisions. We conducted a retrospective review of patients with a history of liver or kidney transplantation who underwent hernia repair to analyze outcomes and hernia recurrence.

Methods: This is a single center, retrospective review of 19 patients who received kidney and/or liver transplantation prior to presenting with an incisional hernia from 2011 to 2017. All hernias were repaired with open component separation technique (CST) with biologic mesh underlay.

Results: The mean age of patients was 61.0±8.3 years old, with a mean body mass index of 28.4±4.8 kg/m2, 15 males (78.9%), and four females (21.1%). There were seven kidney, 11 liver, and one combined liver and kidney transplant patients. The most common comorbidities were hypertension (16 patients, 84.2%), diabetes (9 patients, 47.4%), and tobacco use (8 patients, 42.1%). Complications occurred in six patients (31.6%) including hematoma (1/19), abscess (1/19), seroma (2/19), and hernia recurrence (3/19) at mean follow-up of 28.7±22.8 months. With the exception of two patients with incomplete follow-up, all patients healed at a median time of 27 days.

Conclusions: This small, retrospective series of complex open CST in transplant patients shows acceptable rates of long-term hernia recurrence and healing. By using a multidisciplinary approach for abdominal wall reconstruction, we believe that modified open CST with biologic mesh is a safe and effective technique in the transplant population with complex abdominal hernias.
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http://dx.doi.org/10.5999/aps.2018.01361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759439PMC
September 2019
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