Publications by authors named "Christine Liu"

58 Publications

Cerebrospinal fluid (CSF) augments metabolism and virulence expression factors in Acinetobacter baumannii.

Sci Rep 2021 Feb 26;11(1):4737. Epub 2021 Feb 26.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, 800 N State College Blvd, Fullerton, CA, 92831, USA.

In a recent report by the Centers for Disease Control and Prevention (CDC), multidrug resistant (MDR) Acinetobacter baumannii is a pathogen described as an "urgent threat." Infection with this bacterium manifests as different diseases such as community and nosocomial pneumonia, bloodstream infections, endocarditis, infections of the urinary tract, wound infections, burn infections, skin and soft tissue infections, and meningitis. In particular, nosocomial meningitis, an unwelcome complication of neurosurgery caused by extensively-drug resistant (XDR) A. baumannii, is extremely challenging to manage. Therefore, understanding how A. baumannii adapts to different host environments, such as cerebrospinal fluid (CSF) that may trigger changes in expression of virulence factors that are associated with the successful establishment and progress of this infection is necessary. The present in-vitro work describes, the genetic changes that occur during A. baumannii infiltration into CSF and displays A. baumannii's expansive versatility to persist in a nutrient limited environment while enhancing several virulence factors to survive and persist. While a hypervirulent A. baumannii strain did not show changes in its transcriptome when incubated in the presence of CSF, a low-virulence isolate showed significant differences in gene expression and phenotypic traits. Exposure to 4% CSF caused increased expression of virulence factors such as fimbriae, pilins, and iron chelators, and other virulence determinants that was confirmed in various model systems. Furthermore, although CSF's presence did not enhance bacterial growth, an increase of expression of genes encoding transcription, translation, and the ATP synthesis machinery was observed. This work also explores A. baumannii's response to an essential component, human serum albumin (HSA), within CSF to trigger the differential expression of genes associated with its pathoadaptibility in this environment.
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http://dx.doi.org/10.1038/s41598-021-81714-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910304PMC
February 2021

Perceptions of Physical Activity in African American Older Adults on Hemodialysis: Themes From Key Informant Interviews.

Arch Rehabil Res Clin Transl 2020 Sep 15;2(3):100056. Epub 2020 May 15.

Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.

Objective: To determine key themes underlying the perceptions of older (≥65y) adults on hemodialysis regarding physical activity using qualitative methodology.

Design: Semistructured key informant interviews.

Setting: Academic medical center.

Participants: Convenience sample of older adults on hemodialysis (N=10).

Interventions: None.

Main Outcome Measures: Interview transcripts were coded and analyzed using the framework method to extract themes and subthemes. Participants also answered Likert statements regarding their perceptions of physical activity, and the responses were tallied.

Results: Ten older adults on hemodialysis participated (mean age 73±5y; 60% women); all were African American. All participants stated physical activity would make them feel better. The major themes that emerged were barriers and facilitators. Facilitators included internal motivators, family and friend support, and feasibility of incorporating physical activity into routine activities. Barriers were lack of motivation, health issues, and environmental restrictions.

Conclusions: Physical activity potentially could prevent the physical decline commonly seen in older adults on hemodialysis. Yet information regarding the perceptions of this population toward physical activity is sparse. Although the study is limited by selection bias, our study presents qualitative evidence that black older adults on hemodialysis desire physical activity for their health. Future interventions to increase physical activity in this population should consider leveraging existing facilitators, such as the support of family and friends, and use strategies to address barriers like minimal motivation.
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http://dx.doi.org/10.1016/j.arrct.2020.100056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853361PMC
September 2020

Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults: A Randomized Clinical Trial.

JAMA Netw Open 2021 01 4;4(1):e2031266. Epub 2021 Jan 4.

Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, Georgia.

Importance: Trivalent adjuvanted inactivated influenza vaccine (aIIV3) and trivalent high-dose inactivated influenza vaccine (HD-IIV3) are US-licensed for adults aged 65 years and older. Data are needed on the comparative safety, reactogenicity, and health-related quality of life (HRQOL) effects of these vaccines.

Objective: To compare safety, reactogenicity, and changes in HRQOL scores after aIIV3 vs HD-IIV3.

Design, Setting, And Participants: This randomized blinded clinical trial was a multicenter US study conducted during the 2017 to 2018 and 2018 to 2019 influenza seasons. Among 778 community-dwelling adults aged at least 65 years and assessed for eligibility, 13 were ineligible and 8 withdrew before randomization. Statistical analysis was performed from August 2019 to August 2020.

Interventions: Intramuscular administration of aIIV3 or HD-IIV3 after age-stratification (65-79 years; ≥80 years) and randomization.

Main Outcomes And Measures: Proportions of participants with moderate-to-severe injection-site pain and 14 other solicited reactions during days 1 to 8, using a noninferiority test (5% noninferiority margin), and serious adverse events (SAE) and adverse events of clinical interest (AECI), including new-onset immune-mediated conditions, during days 1 to 43. Changes in HRQOL scores before and after vaccination (days 1, 3) were also compared between study groups.

Results: A total of 757 adults were randomized, 378 to receive aIIV3 and 379 to receive HD-IIV3. Of these participants, there were 420 women (55%) and 589 White individuals (78%) with a median (range) age of 72 (65-97) years. The proportion reporting moderate-to-severe injection-site pain, limiting or preventing activity, after aIIV3 (12 participants [3.2%]) (primary outcome) was noninferior compared with HD-IIV3 (22 participants [5.8%]) (difference -2.7%; 95% CI, -5.8 to 0.4). Ten reactions met noninferiority criteria for aIIV3; 4 (moderate-to-severe injection-site tenderness, arthralgia, fatigue, malaise) did not. It was inconclusive whether these 4 reactions occurred in higher proportions of participants after aIIV3. No participant sought medical care for a vaccine reaction. No AECI was observed. Nine participants had at least SAE after aIIV3 (2.4%; 95% CI,1.1% to 4.5%); 3 had at least 1 SAE after HD-IIV3 (0.8%; 95% CI, 0.2% to 2.2%). No SAE was associated with vaccination. Changes in prevaccination and postvaccination HRQOL scores were not clinically meaningful and not different between the groups.

Conclusions And Relevance: Overall safety and HRQOL findings were similar after aIIV3 and HD-IIV3, and consistent with prelicensure data. From a safety standpoint, this study's results support using either vaccine to prevent influenza in older adults.

Trial Registration: ClinicalTrials.gov Identifier: NCT03183908.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.31266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809592PMC
January 2021

COVID-19 Infection Risk Among Hemodialysis Patients in Long-term Care Facilities.

Kidney Med 2020 Nov-Dec;2(6):810-811. Epub 2020 Sep 25.

William B. Schwartz Division of Nephrology, Tufts Medical Center, Boston, MA.

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http://dx.doi.org/10.1016/j.xkme.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518199PMC
September 2020

Reply to: APP gene copy number changes reflect exogenous contamination.

Nature 2020 08 19;584(7821):E29-E33. Epub 2020 Aug 19.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

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http://dx.doi.org/10.1038/s41586-020-2523-2DOI Listing
August 2020

Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group.

Value Health 2020 05 1;23(5):529-539. Epub 2020 Apr 1.

The University of Manchester, Manchester, England, UK.

Precision medicine is a dynamic area embracing a diverse and increasing type of approaches that allow the targeting of new medicines, screening programs or preventive healthcare strategies, which include the use of biologic markers or complex tests driven by algorithms also potentially taking account of patient preferences. The International Society for Pharmacoeconomics and Outcome Research expanded its current work around precision medicine to (1) describe the evolving paradigm of precision medicine with examples of current and evolving applications, (2) describe key stakeholders perspectives on the value of precision medicine in their respective domains, and (3) define the core factors that should be considered in a value assessment framework for precision medicine. With the ultimate goal of improving health of well-defined patient groups, precision medicine will affect all stakeholders in the healthcare system at multiple levels spanning the individual perspective to the societal perspective. For an efficient, timely and practical precision medicine value assessment framework, it will be important to address these multiple perspectives through building consensus among the stakeholders for robust procedures and measures of value aspects, including performance of precision mechanism; aligned reimbursement processes of precision mechanism and subsequent treatment; transparent expectations for evidence requirements and study designs adequately matched to the intended use of the precision mechanism and to the smaller target patient populations; recognizing the potential range of value-generation such as ruling-in and ruling-out decisions.
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http://dx.doi.org/10.1016/j.jval.2019.11.010DOI Listing
May 2020

Distinct Mechanisms of Dissemination of NDM-1 Metallo-β-Lactamase in Species in Argentina.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA

A 4-year surveillance of carbapenem-resistant spp. isolates in Argentina identified 40 strains carrying Genome sequencing revealed that most were , whereas seven represented other spp. The genomes were closely related, suggesting recent spread. was located in the chromosome of strains and on a plasmid in non- strains. A resistance gene island carrying and other resistance determinants was found on a plasmid in some strains.
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http://dx.doi.org/10.1128/AAC.00324-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179578PMC
April 2020

JAK Inhibition Differentially Affects NK Cell and ILC1 Homeostasis.

Front Immunol 2019 19;10:2972. Epub 2019 Dec 19.

Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States.

Janus kinase (JAK) inhibitors are widely used in the treatment of multiple autoimmune and inflammatory diseases. Immunologic and transcriptomic profiling have revealed major alterations on natural killer (NK) cell homeostasis associated with JAK inhibitions, while information on other innate lymphoid cells (ILCs) is still lacking. Herein, we observed that, in mice, the homeostatic pool of liver ILC1 was less affected by JAK inhibitors compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance.
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http://dx.doi.org/10.3389/fimmu.2019.02972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930870PMC
November 2020

Human pleural fluid triggers global changes in the transcriptional landscape of Acinetobacter baumannii as an adaptive response to stress.

Sci Rep 2019 11 21;9(1):17251. Epub 2019 Nov 21.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA.

Acinetobacter baumannii is a feared, drug-resistant pathogen, characterized by its ability to resist extreme environmental and nutrient-deprived conditions. Previously, we showed that human serum albumin (HSA) can increase foreign DNA acquisition specifically and alter the expression of genes associated with pathogenicity. Moreover, in a recent genome-wide transcriptomic study, we observed that pleural fluid (PF), an HSA-containing fluid, increases DNA acquisition, can modulate cytotoxicity, and control immune responses by eliciting changes in the A. baumannii metabolic profile. In the present work, using more stringent criteria and focusing on the analysis of genes related to pathogenicity and response to stress, we analyzed our previous RNA-seq data and performed phenotypic assays to further explore the impact of PF on A. baumannii's microbial behavior and the strategies used to overcome environmental stress. We observed that PF triggered differential expression of genes associated with motility, efflux pumps, antimicrobial resistance, biofilm formation, two-component systems (TCSs), capsule synthesis, osmotic stress, and DNA-damage response, among other categories. Phenotypic assays of A. baumannii A118 and two other clinical A. baumannii strains, revealed differences in their responses to PF in motility, biofilm formation, antibiotic susceptibility, osmotic stress, and outer membrane vesicle (OMV) production, suggesting that these changes are strain specific. We conclude that A. baumannii's pathoadaptive responses is induced by HSA-containing fluids and must be part of this bacterium armamentarium to persist in hostile environments.
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http://dx.doi.org/10.1038/s41598-019-53847-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872806PMC
November 2019

High throughput pSTAT signaling profiling by fluorescent cell barcoding and computational analysis.

J Immunol Methods 2020 02 11;477:112667. Epub 2019 Nov 11.

Translational Immunology Section, Office of Science Technology (OST), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Fluorescent cell barcoding (FCB) is a multiplexing technique for high-throughput flow cytometry (FCM). Although powerful in minimizing staining variability, it remains a subjective FCM technique because of inter-operator variability and differences in data analysis. FCB was implemented by combining two-dye barcoding (DyLight 350 plus Pacific Orange) with five-color surface marker antibody and intracellular staining for phosphoprotein signaling analysis. We proposed a robust method to measure intra- and inter-assay variability of FCB in T/B cells and monocytes by combining range and ratio of variability to standard statistical analyses. Data analysis was carried out by conventional and semi-automated workflows and built with R software. Results obtained from both analyses were compared to assess feasibility and reproducibility of FCB data analysis by machine-learning methods. Our results showed efficient FCB using DyLight 350 and Pacific Orange at concentrations of 0, 15 or 30, and 250 μg/mL, and a high reproducibility of FCB in combination with surface marker and intracellular antibodies. Inter-operator variability was minimized by adding an internal control bridged across matrices used as rejection criterion if significant differences were present between runs. Computational workflows showed comparable results to conventional gating strategies. FCB can be used to study phosphoprotein signaling in T/B cells and monocytes with high reproducibility across operators, and the addition of bridge internal controls can further minimize inter-operator variability. This FCB protocol, which has high throughput analysis and low intra- and inter-assay variability, can be a powerful tool for clinical trial studies. Moreover, FCB data can be reliably analyzed using computational software.
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http://dx.doi.org/10.1016/j.jim.2019.112667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981073PMC
February 2020

Characterization of transgenic mouse models targeting neuromodulatory systems reveals organizational principles of the dorsal raphe.

Nat Commun 2019 10 11;10(1):4633. Epub 2019 Oct 11.

Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, 94720, USA.

The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate neurons. Consequently, investigations of DR circuitry require Cre-driver lines that restrict transgene expression to precisely defined cell populations. Here, we present a systematic evaluation of mouse lines targeting neuromodulatory cells in the DR. We find substantial differences in specificity between lines targeting DA neurons, and in penetrance between lines targeting 5HT neurons. Using these tools to map DR circuits, we show that populations of neurochemically distinct DR neurons are arranged in a stereotyped topographical pattern, send divergent projections to amygdala subnuclei, and differ in their presynaptic inputs. Importantly, targeting DR DA neurons using different mouse lines yielded both structural and functional differences in the neural circuits accessed. These results provide a refined model of DR organization and support a comparative, case-by-case evaluation of the suitability of transgenic tools for any experimental application.
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http://dx.doi.org/10.1038/s41467-019-12392-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789139PMC
October 2019

Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults.

Exp Gerontol 2019 11 4;127:110722. Epub 2019 Sep 4.

Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Tufts University, Boston, MA, USA. Electronic address:

Evidence in support of a gut-muscle axis has been reported in rodents, but studies in older adult humans are limited. Accordingly, the primary goals of the present study were to compare gut microbiome composition in older adults that differed in terms of the percentage of whole body lean mass and physical functioning (high-functioning, HF, n = 18; low-functioning, LF, n = 11), and to evaluate the causative role of the gut microbiome on these variables by transferring fecal samples from older adults into germ-free mice. Family-level Prevotellaceae, genus-level Prevotella and Barnesiella, and the bacterial species Barnesiella intestinihominis were higher in HF older adults at the initial study visit, at a 1-month follow-up visit, in HF human fecal donors, and in HF-colonized mice, when compared with their LF counterparts. Grip strength was significantly increased by 6.4% in HF-, when compared with LF-colonized mice. In contrast, despite significant differences for the percentage of whole body lean mass and physical functioning when comparing the human fecal donors, the percentage of whole body lean mass and treadmill endurance capacity were not different when comparing human microbiome-containing mice. In sum, these data suggest a role for gut bacteria on the maintenance of muscle strength, but argue against a role for gut bacteria on the maintenance of the percentage of whole body lean mass or endurance capacity, findings that collectively add to elucidation of the gut-muscle axis in older adults.
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http://dx.doi.org/10.1016/j.exger.2019.110722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823114PMC
November 2019

Vibrational Therapies for Vocal Fatigue.

J Voice 2021 Jan 2;35(1):29-39. Epub 2019 Aug 2.

Department of Otolaryngology, West China Hospital, Sichuan University, Chengdu, China.

Background: Vibration is commonly used to relax tension in the limb and truck muscle. Vibration used directly on the muscle concerned and vertical vibration used on the whole-body through a foot platform have been reported in the literature to be useful to release muscle tension.

Aim: The present study investigated the effect of indirect whole-body vibration (WBV) and direct localized perilaryngeal vibration (LPV) on the phonatory functions of nondysphonic individuals with vocal fatigue.

Methods: Forty-four subjects (mean age = 21.67 years) with normal voice, were randomly assigned to either the WBV group, the LPV group, or the Control (sham hand-held vibratory device) group. They performed karaoke singing for at least 95 minutes. They then received either WBV through a Turbosonic vibratory machine, LPV with a Novofan vibrator, or a sham vibrator for 10 minutes. The highest pitch produced, and self-reported vocal fatigue score were taken before singing, after singing, and after the intervention. Data were analyzed separately for the gender subgroups.

Results: All subject groups showed significant reduction of vocal function (highest pitch production, and vocal fatigue score) after singing. Following the vibrational interventions, both the WBV and LPV groups showed significantly recovery in the highest pitch production and the perception of vocal fatigue (P < 0.002) than the Control groups.

Conclusion: Vibrational therapy, whether it is localized vibration on the peri-laryngeal muscles, or whole-body vibration, is more effective than voice rest per se in relieving vocal fatigue. Vibrational methods are recommended for treating vocal fatigue.
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http://dx.doi.org/10.1016/j.jvoice.2019.07.009DOI Listing
January 2021

Human Pleural Fluid Elicits Pyruvate and Phenylalanine Metabolism in to Enhance Cytotoxicity and Immune Evasion.

Front Microbiol 2019 17;10:1581. Epub 2019 Jul 17.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University, Fullerton, Fullerton, CA, United States.

() is one of the most treacherous pathogens among those causing hospital-acquired pneumonia (HAP). possesses an adaptable physiology, seen not only in its antibiotic resistance and virulence phenotypes but also in its metabolic versatility. In this study, we observed that undergoes global transcriptional changes in response to human pleural fluid (PF), a key host-derived environmental signal. Differential gene expression analyses combined with experimental approaches revealed changes in metabolism, affecting cytotoxicity, persistence, bacterial killing, and chemotaxis. Over 1,220 genes representing 55% of the differentially expressed transcriptomic data corresponded to metabolic processes, including the upregulation of glutamate, short chain fatty acid, and styrene metabolism. We observed an upregulation by 1.83- and 2.61-fold of the pyruvate dehydrogenase complex subunits E3 and E2, respectively. We also found that pyruvate (PYR), in conjunction with PF, triggers an pathogenic behavior that adversely impacts human epithelial cell viability. Interestingly, PF also amplified cytotoxicity against murine macrophages, suggesting an immune evasion strategy implemented by . Moreover, we uncovered opposing metabolic strategies dependent on the degree of pathogenicity of the strains, where less pathogenic strains demonstrated greater utilization of PYR to promote persister formation in the presence of PF. Additionally, our transcriptomic analysis and growth studies of suggest the existence of an alternative phenylalanine (PA) catabolic route independent of the phenylacetic acid pathway, which converts PA to phenylpyruvate (PP) and shuttles intermediates into styrene metabolism. This alternative route promoted a neutrophil-evasive state, as PF-induced degradation of PP significantly reduced overall human neutrophil chemotaxis in chemotactic assays. Taken together, these data highlight pathoadaptabililty in response to host signals and provide further insight into the role of bacterial metabolism in virulence traits, antibiotic persistence strategies, and host innate immune evasion.
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http://dx.doi.org/10.3389/fmicb.2019.01581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650585PMC
July 2019

Risk Factors for Misuse of Prescribed Opioids: A Systematic Review and Meta-Analysis.

Ann Emerg Med 2019 11 20;74(5):634-646. Epub 2019 Jun 20.

Department of Emergency Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Vancouver General Hospital, Vancouver, British Columbia, Canada. Electronic address:

Study Objective: Increasing opioid prescribing has been linked to an epidemic of opioid misuse. Our objective is to synthesize the available evidence about patient-, prescriber-, medication-, and system-level risk factors for developing misuse among patients prescribed opioids for noncancer pain.

Methods: We performed a systematic search of the scientific and gray literature for studies reporting on risk factors for prescription opioid misuse. Two reviewers independently reviewed titles, abstracts, and full texts; extracted data; and assessed study quality. We excluded studies with greater than 50% cancer patients, palliative patients, and illicit opioid initiation. When possible, we synthesized the effect sizes of dichotomous risk factors and their associations with opioid misuse, using inverse-variance random-effects meta-analysis. We calculated the mean difference between opioid misusers and nonmisusers for continuous risk factors. When studies lacked homogeneity, we synthesized their results qualitatively.

Results: Of 9,629 studies, 65 met our inclusion criteria. Among patients with outpatient opioid prescriptions, the following factors were associated with the development of misuse: any current or previous substance use (odds ratio [OR] 3.55; 95% confidence interval [CI] 2.62 to 4.82), any mental health diagnosis (OR 2.45; 95% CI 1.91 to 3.15), younger age (OR 2.19; 95% CI 1.81 to 2.64), and male sex (OR 1.23; 95% CI 1.10 to 1.36).

Conclusion: Although clinicians should endeavor to offer alternative pain management strategies to all patients, those who are younger, are male patients, and report a history of or current substance use or mental health diagnoses were associated with a greater risk of developing opioid misuse. Clinicians should consider prioritizing alternative pain management strategies for these higher-risk patients.
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http://dx.doi.org/10.1016/j.annemergmed.2019.04.019DOI Listing
November 2019

Increasing the Technicity Index to 92% in a Community Hospital: A 5-Year Retrospective Review.

J Obstet Gynaecol Can 2019 Dec 1;41(12):1709-1716. Epub 2019 Apr 1.

Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, BC; Department of Obstetrics and Gynecology, Langley Memorial Hospital, Fraser Health Authority, Langley, BC. Electronic address:

Objective: This study describes the observed trends in hysterectomy routes at Langley Memorial Hospital (LMH) in Langley, British Columbia, over 5 consecutive years. Associations between patient characteristics and surgical approach were explored, and approach-based surgical outcomes were evaluated using the institutional technicity index (TI), defined as the ratio of hysterectomies performed by minimally invasive surgery to all hysterectomies.

Methods: A retrospective descriptive study involving 706 women who underwent hysterectomy at LMH between January 1, 2012 and December 31, 2016 by six full-time surgeons was performed. From the patient characteristics and surgical outcomes associated with the route of hysterectomy, the annual institutional and overall rates of hysterectomy by type were calculated according to the Canadian Task Force Classification II-2.

Results: The TI increased from 67% to 92% from 2012 to 2016. Specifically, the proportion of hysterectomies completed by a total laparoscopic approach increased from 37% to 78%, whereas hysterectomies performed by the abdominal or laparoscopic-assisted vaginal approach decreased from 32% to 8% and from 17% to 1%, respectively. Vaginal hysterectomy rates remained constant across the study period. Minimally invasive surgery was associated with significantly reduced surgical blood loss and decreased length of hospital stay, with no difference in surgical time compared with an open approach.

Conclusions: As far as the study investigators are aware, the TI at LMH is among the highest reported to date in Canada. Potential contributing factors include well-trained and experienced gynaecologic surgeons, readily available peer-to-peer mentorship, certified gynaecologic assistance, dedicated surgical staff, and consistency in the operating room set-up. Hence, achieving a high TI in a community setting is feasible without increasing the risk of surgical complications or length of surgery.
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http://dx.doi.org/10.1016/j.jogc.2019.02.003DOI Listing
December 2019

Low Oleic/Stearic Desaturation Index in Great Blue Herons () with Steatitis in Southern California, USA.

J Wildl Dis 2019 Oct 11;55(4):995-999. Epub 2019 Mar 11.

Department of Medicine, Division of Endocrinology, 1501 N Campbell Avenue, Room 6408, University of Arizona, Tucson, Arizona 85724, USA.

We explored differences between the adipose tissue fatty acid profiles of Great Blue Herons () with and without steatitis. Adipose tissue from birds with steatitis exhibited inflammatory cell infiltration, low abundance of oleic acid, and a lower oleic/stearic desaturation index compared with tissue from birds without steatitis.
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October 2019

Publisher Correction: Somatic APP gene recombination in Alzheimer's disease and normal neurons.

Nature 2019 02;566(7743):E6

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

In this Article, the top label in Fig. 5d should read 'DISH 3/16' instead of 'DISH 3/17'. This error has been corrected online.
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http://dx.doi.org/10.1038/s41586-019-0905-0DOI Listing
February 2019

Effect of Losartan and Fish Oil on Plasma IL-6 and Mobility in Older Persons. The ENRGISE Pilot Randomized Clinical Trial.

J Gerontol A Biol Sci Med Sci 2019 09;74(10):1612-1619

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Low-grade chronic inflammation, characterized by elevations in plasma Interleukin-6 (IL-6), is an independent risk factor of impaired mobility in older persons. Angiotensin receptor blockers and omega-3 polyunsaturated fatty acids (ω-3) may reduce IL-6 and may potentially improve physical function. To assess the main effects of the angiotensin receptor blocker losartan and ω-3 as fish oil on IL-6 and 400 m walking speed, we conducted the ENRGISE Pilot multicenter randomized clinical trial.

Methods: The ENRGISE Pilot enrolled participants between April 2016 and June 2017, who participated for 12 months. Participants were aged ≥70 years with mobility impairment, had IL-6 between 2.5 and 30 pg/mL, and were able to walk 400 m at baseline. Participants were randomized in three strata 2 × 2 factorial to: (i) losartan 50-100 mg/d or placebo (n = 43), (ii) fish oil 1,400-2,800 mg/d or placebo (n = 180), and (iii) with both (n = 66).

Results: Two hundred eighty-nine participants were randomized (mean age 78.3 years, 47.4% women, 17.0% black). There was no effect of losartan (difference of means = -0.065 ± 0.116 [SE], 95% confidence interval [CI]: -0.293-0.163, p = .58) or fish oil (-0.020 ± 0.077, 95% CI: -0.171-0.132, p = .80) on the log of IL-6. Similarly, there was no effect of losartan (-0.025 ± 0.026, 95% CI: -0.076-0.026, p = .34) or fish oil (0.010 ± 0.017, 95% CI: -0.025-0.044, p = .58) on walking speed (m/s).

Conclusions: These results do not support the use of these interventions to prevent mobility loss in older adults at risk of disability with low-grade chronic inflammation.

Registration: Clinicaltrials.gov NCT02676466.
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http://dx.doi.org/10.1093/gerona/gly277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748815PMC
September 2019

A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System.

Neuron 2019 01 29;101(1):133-151.e7. Epub 2018 Nov 29.

Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and negative motivational stimuli is incompletely understood. Using in vivo fiber photometry, we simultaneously recorded activity in DA terminals in different nucleus accumbens (NAc) subnuclei during an aversive and reward conditioning task. We find that DA terminals in the ventral NAc medial shell (vNAcMed) are excited by unexpected aversive outcomes and to cues that predict them, whereas DA terminals in other NAc subregions are persistently depressed. Excitation to reward-predictive cues dominated in the NAc lateral shell and was largely absent in the vNAcMed. Moreover, we demonstrate that glutamatergic (VGLUT2-expressing) neurons in the lateral hypothalamus represent a key afferent input for providing information about aversive outcomes to vNAcMed-projecting DA neurons. Collectively, we reveal the distinct functional contributions of separate mesolimbic DA subsystems and their afferent pathways underlying motivated behaviors. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317997PMC
January 2019

Somatic APP gene recombination in Alzheimer's disease and normal neurons.

Nature 2018 11 21;563(7733):639-645. Epub 2018 Nov 21.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here we describe recombination of the Alzheimer's disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant 'genomic cDNAs' (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non-neuronal cells. Mechanistic studies supported neuronal 'retro-insertion' of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer's disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer's disease that were absent from healthy neurons. Neuronal gene recombination may allow 'recording' of neural activity for selective 'playback' of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.
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http://dx.doi.org/10.1038/s41586-018-0718-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391999PMC
November 2018

Human fluids alter DNA-acquisition in Acinetobacter baumannii.

Diagn Microbiol Infect Dis 2019 Mar 23;93(3):183-187. Epub 2018 Oct 23.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA. Electronic address:

Transformation is one of the mechanisms of acquisition of foreign genetic material leading to the emergence of multidrug resistant (MDR) bacteria. Recently, human serum albumin (HSA) was shown to specifically increase transformation frequency in the nosocomial pathogen Acinetobacter baumannii. To further assess the relevance of HSA as a possible modulator of A. baumannii transformation in host-pathogen interactions, in this work we examined the effect of different human fluids. We observed a significant increase in transformation frequencies in the presence of pleural fluid, whole blood cells and liquid ascites, and to a lesser extent with urine. The observed effects correlate with both HSA and bacterial content found in the assayed patient fluids. Taken together, these results are in agreement with our previous findings that highlight HSA as a possible host signal with the ability to trigger natural transformation in A. baumannii.
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http://dx.doi.org/10.1016/j.diagmicrobio.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372348PMC
March 2019

Effect of 24-month physical activity on cognitive frailty and the role of inflammation: the LIFE randomized clinical trial.

BMC Med 2018 10 24;16(1):185. Epub 2018 Oct 24.

Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Background: Whether physical activity can reduce cognitive frailty-a relatively new "compound" phenotype proposed in 2013-and whether the effect of physical activity differs based on levels of inflammation are unknown. Therefore, this study aimed to evaluate the effect of physical activity on cognitive frailty and whether baseline interleukin-6 (IL-6) levels modified this effect.

Methods: We used data from the Lifestyle Interventions and Independence for Elders (LIFE) Study, a multicenter, single-blinded randomized trial conducted at eight US field centers between February 2010 and December 2013. The main outcome was cognitive frailty at 24 months, expressed as an ordinal variable based on the six combinations of its two components: frailty (non-frail, pre-frail, and frail) and mild cognitive impairment (yes, no). Frailty and cognition were assessed by the Study of Osteoporotic Fractures (SOF) index and the Modified Mini-Mental State Examination (3MSE) scale, respectively. Plasma IL-6 was measured at baseline. Of the 1635 original randomized sedentary participants (70-89 years), this study included 1298 participants with data on both cognitive frailty and IL-6 assessments at baseline.

Results: After adjusting for field center, sex, and baseline levels of cognitive frailty, the ordinal logistic regression model revealed that participants in the physical activity group had 21% lower odds (odds ratio, 0.79; 95% confidence interval, 0.64-0.98) of worsening cognitive frailty over 24 months than those in the health education group. The effect of physical activity on cognitive frailty did not differ according to baseline IL-6 levels (P for interaction = 0.919). The results did not change after additional adjustment for IL-6 subgroups and the inverse probability of remaining in the study. Comparable results were observed according to age, sex, ethnicity/race, and short physical performance battery score (P for interaction = 0.835, 0.536, 0.934, and 0.458, respectively).

Conclusions: A 24-month structured, moderate-intensity physical activity program reduced cognitive frailty compared with a health education program in sedentary older persons, and this beneficial effect did not differ according to baseline levels of inflammatory biomarker IL-6. These findings suggest that the new cognitive frailty construct is modifiable and highlight the potential of targeting cognitive frailty for promoting healthy aging.

Trial Registration: Clinicaltrials.gov, NCT01072500.
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http://dx.doi.org/10.1186/s12916-018-1174-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199791PMC
October 2018

Submegabase copy number variations arise during cerebral cortical neurogenesis as revealed by single-cell whole-genome sequencing.

Proc Natl Acad Sci U S A 2018 10 27;115(42):10804-10809. Epub 2018 Sep 27.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;

Somatic copy number variations (CNVs) exist in the brain, but their genesis, prevalence, forms, and biological impact remain unclear, even within experimentally tractable animal models. We combined a transposase-based amplification (TbA) methodology for single-cell whole-genome sequencing with a bioinformatic approach for filtering unreliable CNVs (FUnC), developed from machine learning trained on lymphocyte V(D)J recombination. TbA-FUnC offered superior genomic coverage and removed >90% of false-positive CNV calls, allowing extensive examination of submegabase CNVs from over 500 cells throughout the neurogenic period of cerebral cortical development in Thousands of previously undocumented CNVs were identified. Half were less than 1 Mb in size, with deletions 4× more common than amplification events, and were randomly distributed throughout the genome. However, CNV prevalence during embryonic cortical development was nonrandom, peaking at midneurogenesis with levels triple those found at younger ages before falling to intermediate quantities. These data identify pervasive small and large CNVs as early contributors to neural genomic mosaicism, producing genomically diverse cellular building blocks that form the highly organized, mature brain.
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http://dx.doi.org/10.1073/pnas.1812702115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196524PMC
October 2018

Progressive Resistance Training Improves Torque Capacity and Strength in Mobility-Limited Older Adults.

J Gerontol A Biol Sci Med Sci 2019 07;74(8):1316-1321

Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.

Background: Progressive resistance training (PRT) is consistently shown to improve muscle strength in older adults. The efficacy of PRT to improve muscle fatigue in older adults with demonstrated mobility limitations remains unclear.

Methods: Mobility-limited (Short Physical Performance Battery [SPPB] ≤ 9) older adults (age 70-92 years) were recruited for this study and randomized to either PRT or home-based flexibility (FLEX) 3 d/wk for 12 weeks. Muscle fatigue and strength outcomes were assessed at baseline and 12 weeks. The primary outcome was torque capacity, a composite measure of strength and fatigue, defined as the sum of peak torques from an isokinetic fatigue test.

Results: Seventy participants were randomized (mean [SD] age 78.9 [5.4] years; 60% female; mean [SD] SPPB 7.5 [1.6]). At follow-up, the PRT group improved significantly in torque capacity, mean between-group difference (95% confidence interval) 466.19 (138.4, 793.97) Nm (p = .006), and maximal strength 127.3 (60.96, 193.61) Nm (p = .0003), when compared with FLEX group. Neither group demonstrated significant changes in muscle fatigue or torque variability.

Conclusion: Twelve weeks of PRT improved torque capacity, as well as strength in mobility-limited older adults. These results demonstrate PRT improves multiple age-related muscular impairments.
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http://dx.doi.org/10.1093/gerona/gly199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625591PMC
July 2019

Genomic mosaicism in the developing and adult brain.

Dev Neurobiol 2018 11 1;78(11):1026-1048. Epub 2018 Aug 1.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.

Since the discovery of DNA, the normal developing and functioning brain has been assumed to be composed of cells with identical genomes, which remains the dominant view even today. However, this pervasive assumption is incorrect, as proven by increasing numbers of reports within the last 20 years that have identified multiple forms of somatically produced genomic mosaicism (GM), wherein brain cells-especially neurons-from a single individual show diverse alterations in DNA, distinct from the germline. Critically, these changes alter the actual DNA nucleotide sequences-in contrast to epigenetic mechanisms-and almost certainly contribute to the remarkably diverse phenotypes of single brain cells, including single-cell transcriptomic profiles. Here, we review the history of GM within the normal brain, including its major forms, initiating mechanisms, and possible functions. GM forms include aneuploidies and aneusomies, smaller copy number variations (CNVs), long interspersed nuclear element type 1 (LINE1) repeat elements, and single nucleotide variations (SNVs), as well as DNA content variation (DCV) that reflects all forms of GM with greatest coverage of large, brain cell populations. In addition, technical considerations are examined, along with relationships among GM forms and multiple brain diseases. GM affecting genes and loci within the brain contrast with current neural discovery approaches that rely on sequencing nonbrain DNA (e.g., genome-wide association studies (GWAS)). Increasing knowledge of neural GM has implications for mechanisms of development, diversity, and function, as well as understanding diseases, particularly considering the overwhelming prevalence of sporadic brain diseases that are unlinked to germline mutations. © 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol, 2018.
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http://dx.doi.org/10.1002/dneu.22626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214721PMC
November 2018

Translating the Lifestyle Interventions and Independence for Elders Clinical Trial to Older Adults in a Real-World Community-Based Setting.

J Gerontol A Biol Sci Med Sci 2019 05;74(6):924-928

Nutrition, Exercise Physiology and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.

Background: The Lifestyle Interventions and Independence for Elders (LIFE) clinical trial demonstrated that a structured program of physical activity (PA) reduced mobility-disability in older adults by up to 28%. It remains unknown whether the benefits of LIFE PA can be translated to older adults at risk for mobility-disability in real-world community-based settings. To address this knowledge gap, we conducted the ENhancing independence using Group-based community interventions for healthy AGing in Elders (ENGAGE) pilot study and examined the safety, feasibility, and preliminary effectiveness of translating LIFE PA to a community-based senior center.

Methods: Forty older adults with severe lower extremity functional limitations (age: 76.9 ± 7.3 years; body mass index: 32.7 ± 8 kg/m2; 85% female; short physical performance battery score: 6.3 ± 2.2) were randomized to 24 weeks of PA or a health education control intervention.

Results: Community-based PA was safe (serious adverse events: PA vs health education, 0:2; nonserious adverse events: PA vs health education, 3:1) and participants successfully adhered to the PA intervention (65.2%). Compared to health education, PA participants who attended ≥25% of scheduled visits had meaningful and sustained short physical performance battery improvements at follow-up (between group short physical performance battery score differences: ~0.7 units).

Conclusions: ENGAGE has demonstrated the preliminary safety, feasibility, and effectiveness of LIFE PA in a real-world community-based setting. Larger-scale translational studies are needed to further disseminate the benefits of LIFE PA to vulnerable older adults in a variety of community-based settings.
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http://dx.doi.org/10.1093/gerona/gly152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521918PMC
May 2019

Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system.

Nat Chem Biol 2018 07 4;14(7):655-663. Epub 2018 Jun 4.

Department of Chemistry, University of California, Berkeley, CA, USA.

The unusually high demand for metals in the brain, along with insufficient understanding of how their dysregulation contributes to neurological diseases, motivates the study of how inorganic chemistry influences neural circuitry. We now report that the transition metal copper is essential for regulating rest-activity cycles and arousal. Copper imaging and gene expression analysis in zebrafish identifies the locus coeruleus-norepinephrine (LC-NE) system, a vertebrate-specific neuromodulatory circuit critical for regulating sleep, arousal, attention, memory and emotion, as a copper-enriched unit with high levels of copper transporters CTR1 and ATP7A and the copper enzyme dopamine β-hydroxylase (DBH) that produces NE. Copper deficiency induced by genetic disruption of ATP7A, which loads copper into DBH, lowers NE levels and hinders LC function as manifested by disruption in rest-activity modulation. Moreover, LC dysfunction caused by copper deficiency from ATP7A disruption can be rescued by restoring synaptic levels of NE, establishing a molecular CTR1-ATP7A-DBH-NE axis for copper-dependent LC function.
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http://dx.doi.org/10.1038/s41589-018-0062-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008210PMC
July 2018

Social media for social change in science.

Science 2018 04 12;360(6385):162-163. Epub 2018 Apr 12.

Department of Chemistry and Biology, Ryerson University, Toronto, ON M5B 2K3, Canada.

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http://dx.doi.org/10.1126/science.aat7303DOI Listing
April 2018

Chronic neutrophilic leukemia.

Am J Hematol 2018 Jun 14;93(6):841-842. Epub 2018 Mar 14.

Centre for Haematology, St Mary's Hospital Campus of Imperial College London, St Mary's Hospital, London, W2 1NY, United Kingdom.

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http://dx.doi.org/10.1002/ajh.25073DOI Listing
June 2018