Publications by authors named "Aimee Zhang"

18 Publications

  • Page 1 of 1

Endothelial Transient Receptor Potential V4 Channels Mediate Lung Ischemia-Reperfusion Injury.

Ann Thorac Surg 2021 May 4. Epub 2021 May 4.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA. Electronic address:

Background: Lung ischemia-reperfusion injury (IRI), involving severe inflammation and edema, is a major cause of primary graft dysfunction following transplant. Activation of transient receptor potential vanilloid 4 (TRPV4) channels modulates vascular permeability. Thus, this study tests the hypothesis that endothelial TRPV4 channels mediate lung IRI.

Methods: C57BL/6 wild-type (WT), TRPV4, tamoxifen-inducible endothelial TRPV4 knockout (TRPV4), and tamoxifen-treated control (TRPV4) mice underwent lung IR using a left lung hilar-ligation model (n≥6 mice/group). WT mice were also treated with a TRPV4-specific inhibitor (GSK2193874; 1mg/kg) (WT+GSK219). Partial pressure of oxygen (PaO), edema (wet-to-dry weight ratio), compliance, neutrophil infiltration, and cytokine concentrations in bronchioalveolar lavage fluid were assessed. Pulmonary microvascular endothelial cells (PMVECs) were characterized in vitro following exposure to hypoxia-reoxygenation.

Results: Compared to WT, PaO following IR was significantly improved in TRPV4 mice (133.1±43.9 vs 427.8±83.1 mmHg, p<0.001) and WT+GSK219 mice (133.1±43.9 vs 447.0±67.6 mmHg, p<0.001). Pulmonary edema and neutrophil infiltration were also significantly reduced after IR in TRPV4 and WT+GSK219 mice versus WT. TRPV4 mice following IR demonstrated significantly improved oxygenation versus control (109.2±21.6 vs 405.3±41.4 mmHg, p<0.001) as well as significantly improved compliance, and significantly less edema, neutrophil infiltration and proinflammatory cytokine production (TNF-α, CXCL1, IL-17, IFN-γ). Hypoxia-reoxygenation-induced permeability and CXCL1 expression by PMVECs was significantly attenuated by TRPV4 inhibitors.

Conclusions: Endothelial TRPV4 plays a key role in vascular permeability and lung inflammation following IR. TRPV4 channels may be a promising therapeutic target to mitigate lung IRI and decrease the incidence of primary graft dysfunction following transplant. (Word Count: 249/250).
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.052DOI Listing
May 2021

Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908;

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.
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http://dx.doi.org/10.1073/pnas.2023130118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092599PMC
April 2021

Secondary Burn Progression Mitigated by an Adenosine 2A Receptor Agonist.

J Burn Care Res 2021 Mar 26. Epub 2021 Mar 26.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.

Background: Current burn therapy is largely supportive with limited therapies to curb secondary burn progression. Adenosine 2A receptor (A2AR) agonists have anti-inflammatory effects with decreased inflammatory cell infiltrate and release of pro-inflammatory mediators. Using a porcine comb burn model, we examined whether A2AR agonists could mitigate burn progression.

Study Design: Eight full-thickness comb burns (4 prongs with 3 spaces per comb) per pig were generated with the following specifications: temperature 115° C, 3 kg force, and 30 second application time. In a randomized fashion, animals (4 per group) were then treated with A2AR agonist (ATL-1223, 3 ng/kg/min, intravenous infusion over 6 hours) or vehicle control. Necrotic interspace development was the primary outcome and additional histologic assessments were conducted.

Results: Analysis of unburned interspaces (72 per group) revealed that ATL-1223 treatment decreased the rate of necrotic interspace development over the first 4 days following injury (p<0.05). Treatment significantly decreased dermal neutrophil infiltration at 48 hours following burn (14.63±4.30 vs 29.71±10.76 neutrophils/high-power field, p=0.029). Additionally, ATL-1223 treatment was associated with fewer interspaces with evidence of microvascular thrombi through post-burn day 4 (18.8% vs 56.3%, p=0.002). Two weeks following insult, the depth of injury at distinct burn sites (adjacent to interspaces) was significantly reduced by ATL-1223 treatment (2.91±0.47 vs 3.28±0.58 mm, p=0.038).

Conclusion: This work demonstrates the ability of an A2AR agonist to mitigate burn progression through dampening local inflammatory processes. Extended dosing strategies may yield additional benefit and improve cosmetic outcome in those with severe injury.
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http://dx.doi.org/10.1093/jbcr/irab053DOI Listing
March 2021

Two Hours of In Vivo Lung Perfusion Improves Lung Function in Sepsis-Induced Acute Respiratory Distress Syndrome.

Semin Thorac Cardiovasc Surg 2021 Mar 11. Epub 2021 Mar 11.

Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Sepsis is the leading cause of acute respiratory distress syndrome (ARDS) in adults and carries a high mortality. Utilizing a previously validated porcine model of sepsis-induced ARDS, we sought to refine our novel therapeutic technique of in vivo lung perfusion (IVLP). We hypothesized that 2 hours of IVLP would provide non-inferior lung rehabilitation compared to 4 hours of treatment. Adult swine (n = 8) received lipopolysaccharide to develop ARDS and were placed on central venoarterial extracorporeal membrane oxygenation. Animals were randomized to 2 vs 4 hours of IVLP. The left pulmonary vessels were cannulated to IVLP using antegrade Steen solution. After IVLP treatment, the left lung was decannulated and reperfused for 4 hours. Total lung compliance and pulmonary venous gases from the right lung (control) and left lung (treatment) were sampled hourly. Biochemical analysis of tissue and bronchioalveolar lavage was performed along with tissue histologic assessment. Throughout IVLP and reperfusion, treated left lung PaO/FiO ratio was significantly higher than the right lung control in the 2-hour group (332.2 ± 58.9 vs 264.4 ± 46.5, P = 0.01). In the 4-hour group, there was no difference between treatment and control lung PaO/FiO ratio (258.5 ± 72.4 vs 253.2 ± 90.3, P = 0.58). Wet-to-dry weight ratios demonstrated reduced edema in the treated left lungs of the 2-hour group (6.23 ± 0.73 vs 7.28 ± 0.61, P = 0.03). Total lung compliance was also significantly improved in the 2-hour group. Two hours of IVLP demonstrated superior lung function in this preclinical model of sepsis-induced ARDS. Clinical translation of IVLP may shorten duration of mechanical support and improve outcomes.
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http://dx.doi.org/10.1053/j.semtcvs.2021.02.034DOI Listing
March 2021

Pulsed Ultrasound of the Spleen Prolongs Survival of Rats With Severe Intra-abdominal Sepsis.

J Surg Res 2021 03 3;259:97-105. Epub 2020 Dec 3.

Department of Surgery, University of Virginia Health System, Charlottesville, Virginia. Electronic address:

Background: The spleen is an important contributor to the uncontrolled, excessive release of proinflammatory signals during sepsis that leads to the development of tissue injury and diffuse end-organ dysfunction. Therapeutic pulsed ultrasound (pUS) has been shown to inhibit splenic leukocyte release and reduce cytokine production in other inflammatory disease processes. We hypothesized that pUS treatment inhibits spleen-derived inflammatory responses and increases survival duration in rats with severe intra-abdominal sepsis leading to septic shock.

Materials And Methods: Rats with intra-abdominal sepsis, induced by cecal ligation and incision, underwent abdominal washout, intra-peritoneal administration of cefazolin, and then either no further treatment (control), splenectomy, or pUS of the spleen. Animals were observed for the primary endpoint of survival duration.

Results: Survival curves were significantly different for all groups (P < 0.01). Median survival increased from 9.5 h in control rats to 19.8 h in pUS rats and 35.0 h in splenectomy rats (P < 0.01). At 4 h after cecal ligation and incision, the pUS group had decreased splenic contraction and leukocyte count (P = 0.03) compared with control, indicating reduced exodus of splenic leukocytes. In addition, elevation in plasma TNF-α and MCP-1 was significantly attenuated in the pUS group (P < 0.05 versus control). Splenic β adrenergic receptor levels and phosphorylated Akt were significantly more elevated in the pUS group (P < 0.01 versus control).

Conclusions: pUS significantly prolonged the survival duration of rats with severe intra-abdominal sepsis. This treatment may be an effective, noninvasive therapy that dampens detrimental immune responses during septic shock by activating β adrenergic receptor-Akt phosphorylation in the cholinergic anti-inflammatory pathway.
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http://dx.doi.org/10.1016/j.jss.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897287PMC
March 2021

Isolated Lung Perfusion in the Management of Acute Respiratory Distress Syndrome.

Int J Mol Sci 2020 Sep 17;21(18). Epub 2020 Sep 17.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22902, USA.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. While our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. There is a dramatic need for the development and breakthrough of new methods for the treatment of ARDS. Isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. Initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ARDS. This review presents current tenants of ARDS management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (EVLP) has paved the way for current investigations utilizing in vivo lung perfusion (IVLP) in the treatment of severe ARDS.
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http://dx.doi.org/10.3390/ijms21186820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555278PMC
September 2020

Enhanced Recovery After Thoracic Surgery.

Thorac Surg Clin 2020 Aug 17;30(3):259-267. Epub 2020 Apr 17.

Division of Thoracic & Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA 22908-0679, USA; Thoracic Surgery, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA 22908-0679, USA. Electronic address:

Enhanced recovery pathways (ERPs), used across multiple surgical subspecialties, is a multidisciplinary delivery of perioperative care designed to lessen the psychological stress of patients undergoing surgery. Thoracic ERP has been implemented but is not widespread, and variations exist between programs. Evidence of the benefit of thoracic ERP is emerging. This article presents common components of a thoracic surgery ERP and reviews contemporary outcomes.
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http://dx.doi.org/10.1016/j.thorsurg.2020.04.005DOI Listing
August 2020

Gastrointestinal Complications After Cardiac Surgery: Highly Morbid but Improving Over Time.

J Surg Res 2020 10 5;254:306-313. Epub 2020 Jun 5.

Division of Thoracic & Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Background: Gastrointestinal complications after cardiac surgery are associated with high morbidity and mortality. We sought to determine the granular impact of individual gastrointestinal complications after cardiac surgery and assess contemporary outcomes.

Materials And Methods: Patients undergoing cardiac surgery from 2010 to 2017 (6070 patients) were identified from an institutional Society of Thoracic Surgeons database. Records were paired with institutional data assessing gastrointestinal complications and cost. Patients were stratified by early (2010-2013) and current (2014-2017) eras.

Results: A total of 280 (4.6%) patients experienced gastrointestinal complications including Clostridiumdifficile infection (94, 33.6%), gastrointestinal bleed (86, 30.7%), hepatic failure (66, 23.6%), prolonged ileus (59, 21.1%), mesenteric ischemia (47, 16.8%), acute cholecystitis (17, 6.0%), and pancreatitis (14, 5.0%). Gastrointestinal complications were associated with higher rates of early postoperative major morbidity [206 (73.6%) versus 773 (13.4%), P < 0.0001], mortality [78 (27.9%) versus 161 (2.8%), P < 0.0001], length of stay (23 versus 6 d, P < 0.0001), and discharge to a facility [115 (41.1%) versus 1395 (24.1%), P < 0.0001]. Patients suffering gastrointestinal complications had worse risk-adjusted long-term survival (hazard ratio: 3.0, P < 0.0001) and higher adjusted cost ($9,173, P = 0.05). Between eras, there was no difference in incidence of gastrointestinal complications [139 (4.4%) versus 141 (4.8%), P = 0.51] or rate of specific complications (all P > 0.05). However, long-term survival increased in modern era (P < 0.0001).

Conclusions: Although incidence of gastrointestinal complications after cardiac surgery has not changed over time, long-term survival has improved. Gastrointestinal complications remain associated with high resource utilization and major morbidity, but patients are now more likely to recover, highlighting the benefit of quality improvement efforts.
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http://dx.doi.org/10.1016/j.jss.2020.02.019DOI Listing
October 2020

Emergent life events in the delivery of a caregiver-mediated evidence-based intervention for children with autism spectrum disorder in publicly funded mental health services.

Autism 2020 07 31;24(5):1286-1299. Epub 2020 Jan 31.

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

Lay Abstract: Mental health clinicians often report significant challenges when delivering evidence-based interventions (EBI) in community settings, particularly when unexpected client stressors (or emergent life events; ELEs) interfere with the therapy process. The current study sought to extend the study of ELEs to children with Autism Spectrum Disorder (ASD) by examining the occurrence and impact of ELEs in the context of a collaborative, caregiver-mediated intervention for reducing challenging behaviors in children with ASD. This intervention was n ndividualized ental ealth ntervention for children with ASD (referred to as AIM HI). Participants included 38 clinicians and child clients who were enrolled in a community effectiveness trial of AIM HI. Video recordings of 100 therapy sessions were coded for caregiver-reported ELEs and also how well clinicians adhered to the AIM HI protocol. Results indicated that mild to severe ELEs were reported in 36% of therapy sessions, and were reported for 58% of children at some point during the intervention. Children who had a greater number of diagnoses (in addition to the autism diagnosis) tended to have more ELEs. In addition, clinicians with less years of experience tended to have sessions with more ELEs. There was no significant link between ELEs and how well clinicians adhered to the AIM HI protocol. Findings offer implications for the implementation of EBI, particularly the importance of incorporating clinician training in addressing complex presentations and crises in the context of EBIs.
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http://dx.doi.org/10.1177/1362361319881084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115197PMC
July 2020

Preoperative bleeding requiring transfusion: An under-reported indication for hemorrhoidectomy.

Am J Surg 2020 08 6;220(2):428-431. Epub 2019 Dec 6.

Department of Surgery, The University of Virginia Health System, Charlottesville, Virginia, USA.

Background: Though hemorrhoids commonly cause minor gastrointestinal bleeding, major hemorrhage requiring blood transfusion is believed to be rare. We sought to identify the prevalence and risk factors for preoperative transfusion in surgical hemorrhoidectomy patients.

Methods: Patients undergoing surgical hemorrhoidectomy at a single institution (2012-2017) were evaluated for preoperative bleeding requiring transfusion. Bivariate analysis compared patients requiring transfusion to those who did not, and multivariable analysis evaluated for independent risk factors for transfusion.

Results: Out of 520 patients, 7.3% experienced hemorrhoidal bleeding requiring transfusion, and 80.6% reported bleeding. On multivariable analysis, the use of either an anticoagulant or non-aspirin antiplatelet agent was associated with transfusion (OR 3.08, p = 0.03). Patients requiring transfusion had extensive preoperative workups, including colonoscopy (94.7%), flexible sigmoidoscopy (7.89%), upper endoscopy (50%) and capsule endoscopy (26.3%).

Conclusions: Bleeding requiring transfusion is an under-reported complication of hemorrhoids. Increased recognition could lead to expeditious surgical treatment and less costly diagnostic workup.
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http://dx.doi.org/10.1016/j.amjsurg.2019.12.009DOI Listing
August 2020

Pulsed ultrasound attenuates the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury.

J Thorac Cardiovasc Surg 2021 04 2;161(4):e297-e306. Epub 2019 Nov 2.

Department of Surgery, University of Virginia, Charlottesville, Va. Electronic address:

Objective: Acute hyperglycemia during myocardial infarction worsens outcomes in part by inflammatory mechanisms. Pulsed ultrasound has anti-inflammatory potential in bone healing and neuromodulation. We hypothesized that pulsed ultrasound would attenuate the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury via the cholinergic anti-inflammatory pathway.

Methods: Acute hyperglycemia was induced in wild-type C57BL6 or acetylcholine-receptor knockout (α7nAChR) mice by intraperitoneal injection of glucose. Pulsed ultrasound (frequency 7 MHz, bursting mechanical index 1.2, duration 1 second, repeated every 6 seconds for 2 minutes, 20-second total exposure) was performed at the spleen or neck after glucose injection. Separate mice underwent vagotomy before treatment. The left coronary artery was occluded for 20 minutes, followed by 60 minutes of reperfusion. The primary end point was infarct size in explanted hearts.

Results: Splenic pulsed ultrasound significantly decreased infarct size in wild-type C57BL6 mice exposed to acute hyperglycemia and myocardial ischemia-reperfusion injury (5.2% ± 4.4% vs 16.9% ± 12.5% of risk region, P = .013). Knockout of α7nAChR abrogated the beneficial effect of splenic pulsed ultrasound (22.2% ± 12.1%, P = .79 vs control). Neck pulsed ultrasound attenuated the hyperglycemic exacerbation of myocardial infarct size (3.5% ± 4.8%, P = .004 vs control); however, the cardioprotective effect disappeared in mice that underwent vagotomy. Plasma acetylcholine, β2 adrenergic receptor, and phosphorylated Akt levels were increased after splenic pulsed ultrasound treatment.

Conclusions: Pulsed ultrasound treatment of the spleen or neck attenuated the hyperglycemic exacerbation of myocardial ischemia-reperfusion injury leading to a 3-fold decrease in infarct size. Pulsed ultrasound may provide cardioprotection via the cholinergic anti-inflammatory pathway and could be a promising new nonpharmacologic, noninvasive therapy to reduce infarct size during acute myocardial infarction and improve patient outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2019.10.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195241PMC
April 2021

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death.

J Heart Lung Transplant 2020 01 18;39(1):74-82. Epub 2019 Sep 18.

Departments of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Background: Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs.

Methods: A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion.

Results: After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm HO vs. 10.2 ± 3.5 ml/cm HO, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1β expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group.

Conclusions: EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.
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http://dx.doi.org/10.1016/j.healun.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001159PMC
January 2020

In-Session Caregiver Behaviors during Evidence-Based Intervention Delivery for Children with ASD in Community Mental Health Services.

Evid Based Pract Child Adolesc Ment Health 2019 7;4(1):55-71. Epub 2019 Feb 7.

Department of Psychiatry, University of California, San Diego.

An Individualized Mental Health Intervention for ASD, ("AIM HI"), is a collaborative, caregiver-mediated and child-directed intervention for reducing challenging behaviors in children with autism spectrum disorder developed for delivery in community mental health programs. Using observational data from AIM HI sessions, the present study characterized the occurrence of two types of in-session caregiver behaviors: expressed concerns (i.e., ) and participation engagement (i.e., ). Further analyses examined cultural differences in caregiver behaviors and associations between caregiver behaviors and clinician adherence. Participants included 39 caregiver-clinician dyads enrolled in a community effectiveness trial of AIM HI. Video recordings from 107 sessions during the first two months of treatment were coded for in-session caregiver behaviors and clinician adherence. Results indicated that expressed concerns were observed in 47% of sessions. When controlling for household income, Latinx caregivers were rated lower for and demonstrated lower participation engagement behaviors in session compared with non-Latinx White caregivers, suggesting that cultural factors may impact verbal engagement in sessions. Finally, , , and participation engagement were positively associated with clinician adherence. Findings suggest that some expressed concerns and participation engagement behaviors may be indicators of positive caregiver engagement in the context of a collaborative intervention, and lower levels of such caregiver engagement may actually impede clinicians' delivery of intensive evidence-based intervention in routine care.
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http://dx.doi.org/10.1080/23794925.2019.1565500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602542PMC
February 2019

High-Resolution Mapping of Homologous Recombination Events in rad3 Hyper-Recombination Mutants in Yeast.

PLoS Genet 2016 Mar 11;12(3):e1005938. Epub 2016 Mar 11.

Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, United States of America.

The Saccharomyces cerevisae RAD3 gene is the homolog of human XPD, an essential gene encoding a DNA helicase of the TFIIH complex involved in both nucleotide excision repair (NER) and transcription. Some mutant alleles of RAD3 (rad3-101 and rad3-102) have partial defects in DNA repair and a strong hyper-recombination (hyper-Rec) phenotype. Previous studies showed that the hyper-Rec phenotype associated with rad3-101 and rad3-102 can be explained as a consequence of persistent single-stranded DNA gaps that are converted to recombinogenic double-strand breaks (DSBs) by replication. The systems previously used to characterize the hyper-Rec phenotype of rad3 strains do not detect the reciprocal products of mitotic recombination. We have further characterized these events using a system in which the reciprocal products of mitotic recombination are recovered. Both rad3-101 and rad3-102 elevate the frequency of reciprocal crossovers about 100-fold. Mapping of these events shows that three-quarters of these crossovers reflect DSBs formed at the same positions in both sister chromatids (double sister-chromatid breaks, DSCBs). The remainder reflects DSBs formed in single chromatids (single chromatid breaks, SCBs). The ratio of DSCBs to SCBs is similar to that observed for spontaneous recombination events in wild-type cells. We mapped 216 unselected genomic alterations throughout the genome including crossovers, gene conversions, deletions, and duplications. We found a significant association between the location of these recombination events and regions with elevated gamma-H2AX. In addition, there was a hotspot for deletions and duplications at the IMA2 and HXT11 genes near the left end of chromosome XV. A comparison of these data with our previous analysis of spontaneous mitotic recombination events suggests that a sub-set of spontaneous events in wild-type cells may be initiated by incomplete NER reactions, and that DSCBs, which cannot be repaired by sister-chromatid recombination, are a major source of mitotic recombination between homologous chromosomes.
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http://dx.doi.org/10.1371/journal.pgen.1005938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788294PMC
March 2016

The self-rating of the effects of alcohol questionnaire predicts heavy episodic drinking in a high-risk eating disorder population.

Int J Eat Disord 2015 Apr 31;48(3):333-6. Epub 2014 Oct 31.

Department of Psychiatry, Stanford University Medical Center, Stanford, California.

Objective: Heavy episodic drinking (HED) is a serious problem among college women at high-risk for developing eating disorders (EDs). The main objectives of this study are to determine the relationship of the self-rating of the effects of alcohol (SRE) questionnaire and HED over time, and to determine the effects of relationship breakups on HED among college-aged women at high-risk for EDs.

Method: Data collected from 163 participants in a randomized controlled trial evaluating the effectiveness of an ED prevention program were used in the analyses. Measures included the SRE, obtained at baseline, and self-reports of the number of HED episodes and relationship breakups each month for the past 12 months.

Results: Generalized linear mixed-effect regression models with Poisson distribution were conducted to test the effects of several variables on reported HED episodes over 12 months. Analyses demonstrated that SRE scores and the presence of a breakup predicted increased HED over time.

Discussion: The SRE may be useful in identifying individuals at risk of or with EDs who are at increased risk of HED. Furthermore, relationship breakups predict HED. Findings from the current study could be used to inform clinical interventions for this population.
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http://dx.doi.org/10.1002/eat.22365DOI Listing
April 2015

Validation of a six-item male body image concerns scale (MBICS).

Eat Disord 2014 25;22(5):420-34. Epub 2014 Jun 25.

a Department of Psychiatry & Behavioral Sciences , Stanford University School of Medicine , Stanford , California , USA.

Elevated body image concerns may be a risk factor for eating disorders among males and contribute to a range of other mental health problems. This study tested a 6-item measure of general male body image concerns in two studies with adolescent males ages 14-18 (total N = 122). The measure showed strong convergent validity, scale score reliability, and test-retest reliability, and was significantly correlated with the number of episodes of binge eating in the past month. A short scale will relieve participant burden and provide a useful research tool for studies with males at risk for or with eating disorders.
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http://dx.doi.org/10.1080/10640266.2014.925768DOI Listing
May 2015

Effectiveness of acceptance and commitment therapy for depression: comparison among older and younger veterans.

Aging Ment Health 2013 22;17(5):555-63. Epub 2013 Apr 22.

Mental Health Services, U.S. Department of Veterans Affairs Central Office, Washington, DC, United States.

Objectives: Limited data exist on outcomes of older adults receiving psychotherapy for depression in real-world settings. Acceptance and Commitment Therapy for depression (ACT-D) offers potential utility for older individuals who may experience issues of loss, reduced control, and other life changes. The present article examines and compares outcomes of older and younger Veterans receiving ACT-D nationally in the U.S. Department of Veterans Affairs health care system.

Method: Patient outcomes were assessed using the Beck Depression Inventory-Second Edition and the World Health Organization Quality of Life-BREF. Therapeutic alliance was assessed using the Working Alliance Inventory-Short Revised.

Results: Six hundred fifty-five Veterans aged 18-64 and 76 Veterans aged 65+ received ACT-D. Seventy-eight percent of older and 67% of younger patients completed all sessions or finished early. Mean depression scores declined from 28.4 (SD = 11.4) to 17.5 (SD = 12.0) in the older group and 30.3 (SD = 10.6) to 19.1 (SD = 14.3) in the younger group. Within-group effect sizes were d = .95 and d = 1.06 for the two age groups, respectively. Quality of life and therapeutic alliance also increased during treatment.

Conclusion: The findings suggest that ACT-D is an effective and acceptable treatment for older Veterans treated in routine clinical settings, including those with high levels of depression.
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http://dx.doi.org/10.1080/13607863.2013.789002DOI Listing
October 2013

Intra-genotypic variation of predominant genotype II strains of dengue type-3 virus isolated during different epidemics in Thailand from 1973 to 2001.

Virus Genes 2013 Apr 13;46(2):203-18. Epub 2012 Mar 13.

Science and Engineering Apprentice Program at the Walter Reed Army Institute of Research, Silver Spring, MD, USA.

The prevalence of all four dengue virus (DENV) serotypes has increased dramatically in recent years in many tropical and sub-tropical countries accompanied by an increase in genetic diversity within each serotype. This expansion in genetic diversity is expected to give rise to viruses with altered antigenicity, virulence, and transmissibility. We previously demonstrated the co-circulation of multiple DENV genotypes in Thailand and identified a predominant genotype for each serotype. In this study, we performed a comparative analysis of the complete genomic sequences of 28 DENV-3 predominant genotype II strains previously collected during different DENV-3 epidemics in Thailand from 1973 to 2001 with the goal to define mutations that might correlate with virulence, transmission frequency, and epidemiological impact. The results revealed (1) 37 amino acid and six nucleotide substitutions adopted and fixed in the virus genome after their initial substitutions over nearly 30-year-sampling period, (2) the presence of more amino acid and nucleotide substitutions in recent virus isolates compared with earlier isolates, (3) six amino acid substitutions in capsid (C), pre-membrane (prM), envelope (E), and nonstructural (NS) proteins NS4B and NS5, which appeared to be associated with periods of high DENV-3 epidemic activity, (4) the highest degree of conservation in C, NS2B and the 5'-untranslated region (UTR), and (5) the highest percentage of amino acid substitutions in NS2A protein.
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http://dx.doi.org/10.1007/s11262-012-0720-2DOI Listing
April 2013