Publications by authors named "Jennifer Y Chen"

29 Publications

  • Page 1 of 1

Stress testing reveals gaps in clinic readiness of image-based diagnostic artificial intelligence models.

NPJ Digit Med 2021 Jan 21;4(1):10. Epub 2021 Jan 21.

Dermatology Service, San Francisco VA Health Care System, San Francisco, CA, USA.

Artificial intelligence models match or exceed dermatologists in melanoma image classification. Less is known about their robustness against real-world variations, and clinicians may incorrectly assume that a model with an acceptable area under the receiver operating characteristic curve or related performance metric is ready for clinical use. Here, we systematically assessed the performance of dermatologist-level convolutional neural networks (CNNs) on real-world non-curated images by applying computational "stress tests". Our goal was to create a proxy environment in which to comprehensively test the generalizability of off-the-shelf CNNs developed without training or evaluation protocols specific to individual clinics. We found inconsistent predictions on images captured repeatedly in the same setting or subjected to simple transformations (e.g., rotation). Such transformations resulted in false positive or negative predictions for 6.5-22% of skin lesions across test datasets. Our findings indicate that models meeting conventionally reported metrics need further validation with computational stress tests to assess clinic readiness.
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http://dx.doi.org/10.1038/s41746-020-00380-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820258PMC
January 2021

Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.

Sci Transl Med 2020 08;12(557)

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.

Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.
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http://dx.doi.org/10.1126/scitranslmed.aay8798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976849PMC
August 2020

Brief Report: High Rates of Adverse Birth Outcomes in HIV and Syphilis Coinfected Women in Botswana.

J Acquir Immune Defic Syndr 2019 08;81(5):e135-e140

Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

Background: Little is known about the combined impact of HIV/syphilis coinfection on birth outcomes.

Methods: Antenatal HIV and syphilis test results, obstetric history, and infant birth outcomes were collected from obstetric records in maternity wards in Botswana between 2008 and 2011 (5 sites) and 2014 and 2016 (8 sites). We used logistic regression to compare adverse birth outcomes by HIV and syphilis status. Outcomes included stillbirth, preterm delivery, low birth weight, and in-hospital neonatal death.

Results: Of 76,466 women, 75,770 (99.1%) had HIV test results, and 20,520 (27.1%) were HIV positive. Syphilis test results were available for 67,290 (88.0%), and 697 (1.0%) had reactive rapid plasma reagin. Among 692 women with syphilis and an HIV test result, 261 (37.7%) were coinfected. HIV-infected women were more likely to be infected with syphilis than HIV-uninfected women [odds ratio (OR) = 1.68; 95% confidence interval (CI): 1.44 to 1.96]. From 2008-2011 to 2014-2016, the proportion of women with syphilis remained constant (1.1% vs. 1.0%, P = 0.41), but HIV/syphilis coinfection declined from 45% to 27% (P < 0.0001). Stillbirth occurred in 5.8% of coinfected women, compared with 1.9% with no HIV/syphilis (OR = 3.09; 95% CI: 1.83 to 5.23); 3.4% with HIV alone (OR = 1.75; 95% CI: 1.03 to 2.97), or 3.7% with syphilis alone (OR = 1.58; 95% CI: 0.77 to 3.25). Low birth weight occurred in 24.1% of coinfected women, compared with 12.1% with no HIV/syphilis (OR 2.31; 95% CI: 1.74 to 3.08; 20% with HIV alone (OR = 1.27; 95% CI: 0.96 to 1.69); or 14.6% with syphilis alone (OR = 1.85; 95% CI: 1.26 to 2.74).

Conclusions: Although HIV/syphilis coinfection in pregnancy has declined in the past decade, coinfection was associated with adverse birth outcomes.
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http://dx.doi.org/10.1097/QAI.0000000000002082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636337PMC
August 2019

Examining the feasibility of a "top-down" approach to enhancing the keratinocyte-implant adhesion.

Exp Cell Res 2019 03 14;376(2):105-113. Epub 2019 Feb 14.

Department of Chemistry, Drexel University, Philadelphia, PA 19104, United States. Electronic address:

The adhesion of human epidermal keratinocytes to the implant surface is one of the most critical steps during the patient's recovery from implantation of transcutaneous prosthesis. To improve the success rate of transcutaneous prosthetic implants, we explored a new "top-down" approach to promoting this dynamic adhering process through modulation of upstream cell signaling pathways. To examine the feasibility of this novel approach, we first established an in vitro platform that is capable of providing a non-invasive, real-time, quantitative characterization of the keratinocyte-implant interaction. This platform is based on the dissipation monitoring function of the quartz crystal microbalance with dissipation monitoring (QCM-D) in conjunction with the open-module setup of the QCM-D. We then employed this platform to assess the effects of various pathways-specific modulators on the adhering process of keratinocytes. We demonstrated that this "top-down" approach is as effective in enhancing the adhesion of keratinocytes as the conventional "bottom-up" approach that relies on modifying the substrate surface with the adhesion protein such as fibronectin. We envision that this new "top-down" approach combined with the QCM-D-based in vitro platform will help facilitate the future development of new therapies for enhancing osseointegration and promoting wound healing.
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http://dx.doi.org/10.1016/j.yexcr.2019.01.024DOI Listing
March 2019

On the Measurement of Energy Dissipation of Adhered Cells with the Quartz Microbalance with Dissipation Monitoring.

Anal Chem 2018 09 22;90(17):10340-10349. Epub 2018 Aug 22.

Department of Mechanical and Materials Engineering , University of Nebraska-Lincoln , Lincoln , Nebraska 68588 , United States.

We previously reported the finding of a linear correlation between the change of energy dissipation (Δ D) of adhered cells measured with the quartz crystal microbalance with dissipation monitoring (QCM-D) and the level of focal adhesions of the cells. To account for this correlation, we have developed a theoretical framework for assessing the Δ D-response of adhered cells. We rationalized that the mechanical energy of an oscillating QCM-D sensor coupled with a cell monolayer is dissipated through three main processes: the interfacial friction through the dynamic restructuring (formation and rupture) of cell-extracellular matrix (ECM) bonds, the interfacial viscous damping by the liquid trapped between the QCM-D sensor and the basal membrane of the cell layer, and the intracellular viscous damping through the viscous slip between the cytoplasm and stress fibers as well as among stress fibers themselves. Our modeling study shows that the interfacial viscous damping by the trapped liquid is the primary process for energy dissipation during the early stage of the cell adhesion, whereas the dynamic restructuring of cell-ECM bonds becomes more prevalent during the later stage of the cell adhesion. Our modeling study also establishes a positive linear correlation between the Δ D-response and the level of cell adhesion quantified with the number of cell-ECM bonds, which corroborates our previous experimental finding. This correlation with a wide well-defined linear dynamic range provides a much needed theoretical validation of the dissipation monitoring function of the QCM-D as a powerful quantitative analytical tool for cell study.
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http://dx.doi.org/10.1021/acs.analchem.8b02153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669898PMC
September 2018

Emulating a target trial of antiretroviral therapy regimens started before conception and risk of adverse birth outcomes.

AIDS 2018 Jan;32(1):113-120

Division of Infectious Disease, Beth Israel Deaconess Medical Center.

Objective: To compare the effect of preconception initiation of zidovudine, lamivudine, nevirapine (ZDV/3TC/NVP) versus tenofovir, emtricitabine, efavirenz (TDF/FTC/EFV) on adverse birth outcomes.

Design: Emulation of a hypothetical (target) trial using a birth surveillance study in Botswana during an era of CD4-based antiretroviral therapy (ART) initiation.

Methods: In women who initiated ART less than 3 years from HIV diagnosis, conceived 0.5-5 years after ART initiation, and delivered at least 24-week gestation, we estimated risk ratios for stillbirth, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), small-for-gestational-age (SGA) (<10 percentile), very SGA (<3 percentile), and any adverse or severe birth outcome for first-line ZDV/3TC/NVP versus TDF/FTC/EFV. We conducted a historical comparison in women who initiated TDF/FTC/EFV in 2012-2015 and ZDV/3TC/NVP in 2004-2011, and a contemporaneous comparison in an era of overlapping use from 2009 to 2013.

Results: In the historical comparison, 1108 women initiated TDF/FTC/EFV and 637 initiated ZDV/3TC/NVP. In the contemporaneous comparison, 1052 initiated TDF/FTC/EFV and 298 initiated ZDV/3TC/NVP. TDF/FTC/EFV initiators were younger and more likely to be nulliparous than ZDV/3TC/NVP initiators in both comparisons. In the historical comparison, the adjusted risk ratios (95% confidence interval) comparing ZDV/3TC/NVP with TDF/FTC/EFV were 2.95 (1.76, 4.96) for stillbirth, 1.40 (1.17, 1.67) for preterm delivery, 2.58 (1.70, 3.91) for very preterm delivery, 1.96 (1.64, 2.34) for SGA, 2.32 (1.73, 3.09) for very SGA, 1.54 (1.38, 1.72) for any adverse birth outcome, and 2.20 (1.76, 2.75) for any severe birth outcome, and were similar in the contemporaneous comparison.

Conclusion: Preconception initiation of ZDV/3TC/NVP compared with TDF/FTC/EFV may increase the risk of adverse birth outcomes.
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http://dx.doi.org/10.1097/QAD.0000000000001673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718935PMC
January 2018

Cardiovascular pressor effects of orexins in the dorsomedial hypothalamus.

Eur J Pharmacol 2018 Jan 2;818:343-350. Epub 2017 Nov 2.

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei 110, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei 110, Taiwan. Electronic address:

Orexins are important regulators of cardiovascular functions in various physiological and pathological conditions. The dorsomedial hypothalamus (DMH), an essential mediator of cardiovascular responses to stress, contains dense orexinergic innervations and receptors. We examined whether orexins can regulate cardiovascular functions through their actions in the DMH in anesthetized rats. An intra-DMH injection of orexin A (30pmol) produced elevation of arterial pressure and heart rate. Orexin A-sensitive sites were located within or immediately adjacent to the DMH and larger responses were induced at the compact part of the dorsomedial hypothalamic nucleus. Orexin A-induced responses were attenuated by intra-DMH pretreatment with an orexin receptor 1 (OX1R) antagonist, SB-334867 (15nmol) (17.7 ± 2.8 vs. 5.2 ± 1.0mmHg; 54.6 ± 10.0 vs. 22.8 ± 7.4 beats/min). Intra-DMH applied [Ala,D-Leu]-orexin B (300 pmol), an orexin receptor 2 (OX2R) agonist, elicited cardiovascular responses mimicking the responses of orexin A, except for a smaller pressor response (7.4 ± 1.7 vs. 16.4 ± 1.8mmHg). In a series of experiment, effects of orexin B (100pmol) and then orexin A (30pmol), were examined at a same site. Two patterns of responses were observed in 12 intra-DMH sites: (1) both orexin A and B (9 sites), and (2) only orexin A (3 sites) induced cardiovascular responses, respectively suggesting OX1R/OX2R-mediated and OX1R-predominant mechanisms. In conclusion, orexins regulated cardiovascular functions through OX1R/OX2R- or OX1R-mediated mechanisms at different locations in the DMH.
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http://dx.doi.org/10.1016/j.ejphar.2017.11.004DOI Listing
January 2018

Quartz crystal microbalance: Sensing cell-substrate adhesion and beyond.

Biosens Bioelectron 2018 Jan 15;99:593-602. Epub 2017 Aug 15.

Department of Chemistry, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, United States. Electronic address:

Cell adhesion is an essential aspect of cellular behavior. Finding innovative methods to probe the adhesion of cells in their native state can greatly advance the understanding of control and regulation of cellular behavior and their impact on human health. The quartz crystal microbalance (QCM) is a label-free, biosensing system that has, in the past fifty years, evolved from a simple acoustic based mass sensor to a powerful bioanalytical tool. Its unique capability of monitoring the cell-substrate interaction non-invasively in real time has led to the emergence of its applications in areas that are relevant to fundamental cell biology and medical research. This review is intended to provide readers an overview of the use of the QCM for examination of cell-substrate adhesion. It also describes how this innovative approach can be extended to the study of other aspects of cellular behavior, such as cell morphology, cell mechanics, cell motility, cell signaling, all of which can potentially be applied to medical diagnosis and/or pharmaceutical development. In this review a major emphasis is placed on informing readers about some of the most important practical aspects of the QCM-based cell study including data acquisition and analysis, the substrate surface manipulation, and cell manipulation.
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http://dx.doi.org/10.1016/j.bios.2017.08.032DOI Listing
January 2018

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.

Sci Rep 2017 03 21;7:44867. Epub 2017 Mar 21.

Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.

Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.
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http://dx.doi.org/10.1038/srep44867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359599PMC
March 2017

Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins.

Genome Med 2016 Mar 23;8(1):31. Epub 2016 Mar 23.

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Background: Hepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis.

Methods: We performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-β) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types.

Results: We identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-β, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-β signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease.

Conclusions: lncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease.
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http://dx.doi.org/10.1186/s13073-016-0285-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804564PMC
March 2016

Expression of the M3 Muscarinic Receptor on Orexin Neurons that Project to the Rostral Ventrolateral Medulla.

Anat Rec (Hoboken) 2016 May 9;299(5):660-8. Epub 2016 Mar 9.

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Activation of central cholinergic receptors causes a pressor response in rats, and the hypothalamus is important for this response. Projections from hypothalamic orexin neurons to the rostral ventrolateral medulla (RVLM) are involved in sympatho-excitation of the cardiovascular system. A small population of orexin neurons is regulated by cholinergic inputs through M3 muscarinic acetylcholine receptor (M3 R). To elucidate whether the M3 R on orexin neurons is involved in cardiosympathetic regulation through the RVLM, we examined the presence of the M3 R on retrograde-labeled RVLM-projecting orexin neurons. The retrograde tracer was unilaterally injected into the RVLM. Within the hypothalamus, retrograde-labeled neurons were located predominantly ipsilateral to the injection side. In the anterior hypothalamus (-1.5 to -2.3 mm to the bregma), retrograde-labeled neurons were densely distributed in the paraventricular nuclei and scattered in the retrochiasmatic area. At -2.3 to -3.5 mm from the bregma, labeled neurons were located in the regions where orexin neurons were situated, that is, the tuberal lateral hypothalamic area, perifornical area, and dorsomedial nuclei. Very few retrograde-labeled neurons were observed in the hypothalamus at -3.5 to -4.5 mm from the bregma. About 19.5% ± 1.6% of RVLM-projecting neurons in the tuberal hypothalamus were orexinergic. The M3 R was present on 18.7% ± 3.0% of RVLM-projecting orexin neurons. Injection of a muscarinic agonist, oxotremorine, in the perifornical area resulted in a pressor response, which was attenuated by a pretreatment of atropine. We conclude that cholinergic inputs to orexin neurons may be involved in cardiosympathetic regulation through the M3 R on the orexin neurons that directly project to the RVLM.
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http://dx.doi.org/10.1002/ar.23329DOI Listing
May 2016

Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana.

J Acquir Immune Defic Syndr 2016 Apr;71(4):428-36

*Beth Israel Deaconess Medical Center, Boston, MA; †Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana; ‡Harvard School of Public Health, Boston, MA; §Faculty of Health Sciences, University of Botswana, Gaborone, Botswana; ‖Massachusetts General Hospital, Boston, MA; and ¶Brigham and Women's Hospital, Boston, MA.

Background: Before introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana.

Methods: We extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009-2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 ≥350 and ART for CD4 <350, and again in 2013-2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB).

Results: Among 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7).

Conclusions: Adverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception.
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http://dx.doi.org/10.1097/QAI.0000000000000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767604PMC
April 2016

Initial programmatic implementation of WHO option B in Botswana associated with increased projected MTCT.

J Acquir Immune Defic Syndr 2015 Mar;68(3):245-9

*Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA; †Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana; ‡Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA; §Department of Medicine, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA; ‖Department of Biostatistics, Harvard School of Public Health, Boston, MA; ¶Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA; #Department of Pathology, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana; and **Department of HIV/AIDS Prevention and Care, Ministry of Health, Gaborone, Botswana.

: Botswana was one of the first African countries to transition from WHO Option A to Option B for prevention of mother-to-child HIV transmission (MTCT). We evaluated the impact of this transition on projected MTCT risk through review of 10,681 obstetric records of HIV-infected women delivering at 6 maternity wards. Compared with Option A, women receiving antenatal care under Option B were more likely to receive combination antiretroviral therapy (ART), adjusted odds ratio (aOR): 2.59 (95% confidence interval: 2.25 to 2.98), but they were also more likely to receive no antenatal antiretrovirals, aOR: 2.10 (95% confidence interval: 1.74 to 2.53). Consequently, initial implementation of Option B was associated with increased projected MTCT at 6 months of age, 3.79% under Option A and 4.69% under Option B (P < 0.001). Successful implementation of Option B or B+ may require that ART can be initiated within antenatal clinics, and novel strategies to remove barriers to rapid ART initiation.
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http://dx.doi.org/10.1097/QAI.0000000000000482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326565PMC
March 2015

Noncommunicable diseases in HIV infection in low- and middle-income countries: gastrointestinal, hepatic, and nutritional aspects.

J Acquir Immune Defic Syndr 2014 Sep;67 Suppl 1:S79-86

*Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom; †Department of Medicine, University of Zambia School of Medicine, Lusaka, Zambia; ‡Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa; and §Massachusetts General Hospital, Boston, MA.

The purpose of this review was to outline the interaction between HIV and noncommunicable diseases affecting the gastrointestinal (GI) tract, liver, and nutritional disorders in low- and middle-income countries (LMICs), and to identify research priorities. Noncommunicable GI tract disorders are only moderately influenced by HIV, and peptic ulceration is actually less common. However, the impact of HIV on GI cancers needs further investigation. HIV interacts strongly with environmental enteropathy, exacerbating malabsorption of nutrients and drugs. HIV has 2 major effects on noncommunicable liver disease: drug-induced liver injury and nonalcoholic fatty liver disease (particularly in persons of African genetic descent). The effect of HIV on nutrition was one of the first markers of the epidemic in the 1980s, and HIV continues to have major nutritional consequences. Childhood malnutrition and HIV frequently coexist in some regions, for example, southern Africa, resulting in powerful negative interactions with poorer responses to standard nutritional rehabilitation. HIV and nutritional care need to be better integrated, but many questions on how best to do this remain unanswered. Across the spectrum of GI, hepatic, and nutritional disorders in HIV infection, there is increasing evidence that the microbiome may play an important role in disease pathogenesis, but work in this area, especially in low- and middle-income countries, is in its infancy.
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http://dx.doi.org/10.1097/QAI.0000000000000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159720PMC
September 2014

HCV and HIV co-infection: mechanisms and management.

Nat Rev Gastroenterol Hepatol 2014 Jun 18;11(6):362-71. Epub 2014 Feb 18.

Liver Center and Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.

HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading cause of non-AIDS-related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared with HCV-monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.
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http://dx.doi.org/10.1038/nrgastro.2014.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330991PMC
June 2014

Effects of the expression level of epidermal growth factor receptor on the ligand-induced restructuring of focal adhesions: a QCM-D study.

Anal Bioanal Chem 2013 Feb 22;405(4):1153-8. Epub 2012 Nov 22.

Chemistry Department, Drexel University, Philadelphia, PA 19104, USA.

Epidermal growth factor receptor (EGFR) plays a major role in cell migration and invasion and is considered to be the primary source of activation of various malignant tumors. To gain insight into how elevated levels of EGFR influence cellular function, particularly cell motility, we used a quartz crystal microbalance with dissipation monitoring (QCM-D) to examine restructuring of focal adhesions in MCF-10A cells induced by epidermal growth factor. Engineered cells that overexpress epidermal growth factor receptor (EGFR) exhibited a very different kinetic profile from wildtype MCF-10A cells that have a lower level of EGFR with a higher rate for the initial disassembly of focal adhesion and a much lower rate for the later reassembly of focal adhesions. It is conceivable that these effects exhibited by EGFR-overexpressing cells may promote the initiation and maintenance of a more favorable adhesion state for cell migration. This study has demonstrated the capability of the dissipation monitoring function of the QCM-D to quantitatively assess kinetic aspects of cellular processes with a high temporal resolution and sensitivity.
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http://dx.doi.org/10.1007/s00216-012-6558-6DOI Listing
February 2013

Future classes of hepatitis C virus therapeutic agents.

Infect Dis Clin North Am 2012 Dec;26(4):949-66

GI Unit, Massachusetts General Hospital, GRJ724, 55 Fruit Street, Boston, MA 02114, USA.

Recent advances in understanding of the molecular characteristics of the hepatitis C virus have led to the development of novel antiviral therapeutics. Direct-acting antivirals are designed to inhibit viral targets, whereas host-targeted antivirals block host factors that are used by the virus for its own life cycle. The rapid development of agents in multiple classes has led to the promise of shorter therapy duration, an improved side effect profile, and eventually interferon-sparing regimens. This article reviews novel hepatitis C virus therapeutics in development, including mechanism of action, efficacy, and adverse effects.
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http://dx.doi.org/10.1016/j.idc.2012.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624290PMC
December 2012

Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana.

J Infect Dis 2012 Dec 12;206(11):1695-705. Epub 2012 Oct 12.

Department of Medicine, Brigham and Women's Hospital, Berlin, Germany.

Background: It is unknown whether adverse birth outcomes are associated with maternal highly active antiretroviral therapy (HAART) in pregnancy, particularly in resource-limited settings.

Methods: We abstracted obstetrical records at 6 sites in Botswana for 24 months. Outcomes included stillbirths (SBs), preterm delivery (PTD), small for gestational age (SGA), and neonatal death (NND). Among human immunodeficiency virus (HIV)-infected women, comparisons were limited to HAART exposure status at conception, and those with similar opportunities for outcomes. Comparisons were adjusted for CD4(+) lymphocyte cell count.

Results: Of 33,148 women, 32,113 (97%) were tested for HIV, of whom 9504 (30%) were HIV infected. Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected women, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among women initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9). Low CD4(+) was independently associated with SB and SGA, and maternal hypertension during pregnancy with PTD, SGA, and SB.

Conclusions: HAART receipt during pregnancy was associated with increased PTD, SGA, and SB.
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http://dx.doi.org/10.1093/infdis/jis553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488194PMC
December 2012

Dissipation monitoring for assessing EGF-induced changes of cell adhesion.

Biosens Bioelectron 2012 Oct-Dec;38(1):375-81. Epub 2012 Jun 19.

Department of Chemistry, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.

Epidermal growth factor (EGF)-induced cell de-adhesion has been implicated as a critical step of normal embryonic development, wound repair, inflammatory response, and tumor cell metastasis. Like many other cellular processes, this cell de-adhesion exhibits a complex, time-dependent pattern. A comprehensive understanding of this process requires a quantitative, real-time assessment of cell-substrate interactions at the molecular level. We employed the quartz crystal microbalance with dissipation monitoring (QCM-D) to successfully track the EGF-induced changes in energy dissipation factor, ΔD, of a monolayer of MCF10A cells in real time. This time-dependent ΔD response correlates well both qualitatively and quantitatively with sequential events of a rapid disassembly, transition, and slow reassembly of focal adhesions of the cells in response to EGF exposure. Based on this strong correlation, we utilized the QCM-D to demonstrate that this dynamic focal-adhesion restructuring is regulated temporally by the downstream pathways of EGFR signaling such as the PI3K, MAPK/ERK, and PLC pathways. Because the QCM-D is a noninvasive technique, this novel approach potentially has a broad range of applications in the fundamental study of cellular processes, such as cell signaling and trafficking and mechanotransduction, and holds promise for drug and biomarker screening.
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http://dx.doi.org/10.1016/j.bios.2012.06.018DOI Listing
December 2012

Extended therapy with pegylated interferon and weight-based ribavirin for HCV-HIV coinfected patients.

HIV Clin Trials 2012 Mar-Apr;13(2):70-82

Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Background: It is unknown whether extended treatment with pegylated interferon (PEG) and weight-based ribavirin (WBR) results in higher rates of sustained viro-logic response (SVR) among HCV-HIV coinfected patients compared with standard duration therapy.

Objective: The study aimed to measure rates of SVR among coinfected patients who received extended therapy with PEG plus WBR.

Methods: HCVHIV coinfected subjects were treated with PEG and WBR, and those who achieved early virologic response (EVR; ≥ 2 log decrease in HCV RNA from baseline or HCV RNA<600 IU/mL) at week 12 were eligible to continue treatment for 72 weeks. SVR (HCV RNA<60 IU/mL) was measured 24 weeks after treatment discontinuation. Predictors of SVR were assessed in simple and multivariate logistic regression.

Results: A total of 329 subjects enrolled at 36 sites. Of 184 subjects who achieved EVR, 169 entered Step 3: 89% male, 52% White, 29% Black, and 71% HCV treatment naïve. The overall SVR rate was 27% (95% CI, 22%-32%) among all subjects, and 33% (95% CI, 27%-40%) among the 223 who were HCV treatment naïve. In exploratory analyses, among 120 treatment-naïve subjects who entered Step 3, the SVR rate was 62% (95% CI, 52%-70%). In this subgroup, predictors of SVR were HCV genotype 2 or 3 (P = .03), HCV RNA <800,000 IU/mL at study entry (P = .05), and achievement of complete EVR (HCV RNA<600 IU/mL at week 12;P < .0001).

Conclusion: Among all subjects, we observed a comparable overall SVR rate to prior studies of subjects treated for 48 weeks. Extended treatment with PEG and WBR may be beneficial to subsets of coinfected patients, specifically those who are treatment naïve and achieve complete EVR.
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http://dx.doi.org/10.1310/hct1302-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367320PMC
June 2012

Characterization of mechanical behavior of an epithelial monolayer in response to epidermal growth factor stimulation.

Exp Cell Res 2012 Mar 29;318(5):521-6. Epub 2011 Dec 29.

Department of Electrical and Computer Engineering, Michigan State University, East Lansing, Michigan 48824, United States.

Cell signaling often causes changes in cellular mechanical properties. Knowledge of such changes can ultimately lead to insight into the complex network of cell signaling. In the current study, we employed a combination of atomic force microscopy (AFM) and quartz crystal microbalance with dissipation monitoring (QCM-D) to characterize the mechanical behavior of A431 cells in response to epidermal growth factor receptor (EGFR) signaling. From AFM, which probes the upper portion of an individual cell in a monolayer of cells, we observed increases in energy dissipation, Young's modulus, and hysteresivity. Increases in hysteresivity imply a shift toward a more fluid-like mechanical ordering state in the bodies of the cells. From QCM-D, which probes the basal area of the monolayer of cells collectively, we observed decreases in energy dissipation factor. This result suggests a shift toward a more solid-like state in the basal areas of the cells. The comparative analysis of these results indicates a regionally specific mechanical behavior of the cell in response to EGFR signaling and suggests a correlation between the time-dependent mechanical responses and the dynamic process of EGFR signaling. This study also demonstrates that a combination of AFM and QCM-D is able to provide a more complete and refined mechanical profile of the cells during cell signaling.
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http://dx.doi.org/10.1016/j.yexcr.2011.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288599PMC
March 2012

Evaluating Inhibition of the Epidermal Growth Factor (EGF)-Induced Response of Mutant MCF10A Cells with an Acoustic Sensor.

Biosensors (Basel) 2012 Nov 13;2(4):448-64. Epub 2012 Nov 13.

Department of Chemistry, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA.

Many cancer treatments rely on inhibition of epidermal growth factor (EGF)-induced cellular responses. Evaluating drug effects on such responses becomes critical to the development of new cancer therapeutics. In this report, we have employed a label-free acoustic sensor, the quartz crystal microbalance with dissipation monitoring (QCM-D), to track the EGF-induced response of mutant MCF10A cells under various inhibitory conditions. We have identified a complex cell de-adhesion process, which can be distinctly altered by inhibitors of signaling pathways and cytoskeleton formation in a dose-dependent manner. The dose dependencies of the inhibitors provide IC50 values which are in strong agreement with the values reported in the literature, demonstrating the sensitivity and reliability of the QCM-D as a screening tool. Using immunofluorescence imaging, we have also verified the quantitative relationship between the ΔD-response (change in energy dissipation factor) and the level of focal adhesions quantified with the areal density of immunostained vinculin under those inhibitory conditions. Such a correlation suggests that the dynamic restructuring of focal adhesions can be assessed based on the time-dependent change in ΔD-response. Overall, this report has shown that the QCM-D has the potential to become an effective sensing platform for screening therapeutic agents that target signaling and cytoskeletal proteins.
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http://dx.doi.org/10.3390/bios2040448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263556PMC
November 2012

Birth weight for gestational age norms for a large cohort of infants born to HIV-negative women in Botswana compared with norms for U.S.-born black infants.

BMC Pediatr 2011 Dec 16;11:115. Epub 2011 Dec 16.

Beth Israel Deaconess Medical Center, Division of Infectious Disease, Boston, MA 02115, USA.

Background: Standard values for birth weight by gestational age are not available for sub-Saharan Africa, but are needed to evaluate incidence and risk factors for intrauterine growth retardation in settings where HIV, antiretrovirals, and other in utero exposures may impact birth outcomes.

Methods: Birth weight data were collected from six hospitals in Botswana. Infants born to HIV-negative women between 26-44 weeks gestation were analyzed to construct birth weight for gestational age charts. These data were compared with published norms for black infants in the United States.

Results: During a 29 month period from 2007-2010, birth records were reviewed in real-time from 6 hospitals and clinics in Botswana. Of these, 11,753 live infants born to HIV-negative women were included in the analysis. The median gestational age at birth was 39 weeks (1st quartile 38, 3rd quartile 40 weeks), and the median birth weight was 3100 grams (1st quartile 2800, 3rd quartile 3400 grams). We constructed estimated percentile curves for birth weight by gestational age which demonstrate increasing slope during the third trimester and leveling off beyond 40 weeks. Compared with black infants in the United States, Botswana-born infants had lower median birth weight for gestational age from weeks 37 through 42 (p < .02).

Conclusions: We present birth weight for gestational age norms for Botswana, which are lower at term than norms for black infants in the United States. These findings suggest the importance of regional birth weight norms to identify and define risk factors for higher risk births. These data serve as a reference for Botswana, may apply to southern Africa, and may help to identify infants at risk for perinatal complications and inform comparisons among infants exposed to HIV and antiretrovirals in utero.
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http://dx.doi.org/10.1186/1471-2431-11-115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271964PMC
December 2011

Engaging HIV-infected patients in antiretroviral therapy services: CD4 cell count testing after HIV diagnosis from 2005 to 2009 in Yunnan and Guangxi, China.

Chin Med J (Engl) 2011 May;124(10):1488-92

Division of Treatment and Care, National Center for AIDS/STD Control and Prevention, Chinese Center for Diseases Control and Prevention, Beijing 100050, China.

Background: The initiation and expansion of China's national free antiretroviral therapy program has led to significant improvement of survival among its participants. Success of further scaling up treatment coverage rests upon intensifying HIV screening and efficient linkage of care. Timely CD4 cell count testing after HIV diagnosis is necessary to determine whether a patient meets criteria for antiretroviral treatment, and represents a crucial link to engage HIV-infected patients in appropriate care, which has not been evaluated in China.

Methods: We evaluated all patients ≥ 16 years who tested HIV positive from 2005 to 2009 in Yunnan and Guangxi. Multivariate Logistic regression models were applied to identify factors associated with lack of CD4 cell count testing within 6 months after HIV diagnosis.

Results: A total of 83 556 patients were included. Over the study period, 30 635 (37%) of subjects received a CD4 cell count within 6 months of receiving the HIV diagnosis. The rate of CD4 cell count testing within 6 months of HIV diagnosis increased significantly from 7% in 2005 to 62% in 2009. Besides the earlier years of HIV diagnosis, negative predictors for CD4 cell count testing in multivariate analyses included older age, not married or unclear marriage status, incarceration, diagnosis at sexual transmitted disease clinics, mode of HIV transmission classified as men who have sex with men, intravenous drug users or transmission route unclear, while minority ethnicity, receipt of high school or higher education, diagnosis at voluntary counseling and testing clinics, and having HIV positive parents were protective.

Conclusions: Significant progress has been made in increasing CD4 testing among newly diagnosed HIV positive patients in Yunnan and Guangxi from 2005 - 2009. However, a sizable proportion of HIV positive patients still lack CD4 testing within 6 months of diagnosis. Improving CD4 testing, particularly among patients with identified risk factors, is essential to link patients with ART services and optimize treatment coverage.
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May 2011

Real-time and label-free detection of cellular response to signaling mediated by distinct subclasses of epidermal growth factor receptors.

Anal Chem 2011 Apr 25;83(8):3141-6. Epub 2011 Mar 25.

Chemistry Department, Drexel University, 3141 Chestnut Street, Philadelphia, Pennsylvania 19104, USA.

Epidermal growth factor receptors (EGFRs) have often shown two distinct binding affinities for epidermal growth factor. It is the high-affinity EGFR that is predominantly responsible for mediating the cell signaling that plays an indispensable role in cell growth, proliferation, motility, and differentiation. We applied the quartz crystal microbalance with dissipation monitoring (QCM-D) to track short-term cellular responses to EGFR signaling in human carcinoma A431 cells. Cellular responses to high- and low-affinity EGFR signaling were detected individually as well as simultaneously based on changes in mass and viscoelasticity of cells. These responses are associated with EGF-induced biological processes including the cytoskeleton remodeling and calcium influx. QCM-D provides a label-free sensor technology that can be exploited to investigate the role of high-affinity EGFR in cancer development and cancer prognosis.
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http://dx.doi.org/10.1021/ac200160uDOI Listing
April 2011

Can we use the "C" word with confidence? Cure for chronic hepatitis C.

Gastroenterology 2011 Mar 21;140(3):766-8. Epub 2011 Jan 21.

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http://dx.doi.org/10.1053/j.gastro.2011.01.018DOI Listing
March 2011

Antiretroviral treatment initiation among HIV-infected pregnant women with low CD4(+) cell counts in Gaborone, Botswana.

J Acquir Immune Defic Syndr 2010 May;54(1):102-6

Harvard Medical School, Boston, MA, USA.

Background: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4(+) cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4 cell count testing, and HAART initiation during pregnancy.

Methods: From October 2007 through June 2008, we reviewed obstetric and laboratory records of women at Princess Marina Hospital in Gaborone, Botswana.

Results: We recorded information from 3056 women. Of 2675 women eligible for the PMTCT program, 2623 (98%) had a documented HIV status, of whom 793 (30%) were HIV infected. Among women who were treatment naive at pregnancy conception, 397 (59%) had recorded CD4(+) cell counts, of whom 62 (16%) had a CD4(+) cell count <200 cells per cubic millimeter. Among this subset, 23 (37%) initiated HAART during pregnancy, 26 (42%) received zidovudine prophylaxis, and 13 (21%) received no therapy.

Conclusions: We observed low rates of CD4(+) cell count testing and HAART initiation during pregnancy. Antenatal clinics should prioritize CD4(+) cell count testing and referral of women who qualify for HAART to maximize benefits of maternal treatment and PMTCT.
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http://dx.doi.org/10.1097/QAI.0b013e3181c080bfDOI Listing
May 2010

Monitoring the implementation of Consultation Planning, Recording, and Summarizing in a breast care center.

Patient Educ Couns 2008 Dec 28;73(3):536-43. Epub 2008 Aug 28.

University of California, San Francisco, United States.

Objective: We implemented and monitored a clinical service, Consultation Planning, Recording and Summarizing (CPRS), in which trained facilitators elicit patient questions for doctors, and then audio-record, and summarize the doctor-patient consultations.

Methods: We trained 8 schedulers to offer CPRS to breast cancer patients making treatment decisions, and trained 14 premedical interns to provide the service. We surveyed a convenience sample of patients regarding their self-efficacy and decisional conflict. We solicited feedback from physicians, schedulers, and CPRS staff on our implementation of CPRS.

Results: 278 patients used CPRS over the 22-month study period, an exploitation rate of 32% compared to our capacity. 37 patients responded to surveys, providing pilot data showing improvements in self-efficacy and decisional conflict. Physicians, schedulers, and premedical interns recommended changes in the program's locations; delivery; products; and screening, recruitment and scheduling processes.

Conclusion: Our monitoring of this implementation found elements of success while surfacing recommendations for improvement.

Practice Implications: We made changes based on study findings. We moved Consultation Planning to conference rooms or telephone sessions; shortened the documents produced by CPRS staff; diverted slack resources to increase recruitment efforts; and obtained a waiver of consent in order to streamline and improve ongoing evaluation.
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http://dx.doi.org/10.1016/j.pec.2008.07.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2622737PMC
December 2008

Reproductive care and rates of pregnancy in teenagers with negative pregnancy test results.

J Adolesc Health 2006 Mar;38(3):222-9

Yale University School of Nursing, New Haven, Connecticut 06536-0740, USA.

Purpose: The purpose of this study was to follow-up adolescent girls with negative pregnancy tests (NPTs) through an 18-month follow-up analysis of health services received, patterns of contraception use, and pregnancy outcomes.

Method: This study involved a retrospective review of medical records of 129 adolescent patients who had a NPT result from clinical sites in an urban medical center during a 3-month period in 1997. A stratified random sample of participants was selected from adolescents who received care at 2 school-based health centers, a women's health center, and an adolescent health clinic associated with a large academic medical center.

Findings: Analysis of the 129 cases indicated that the cohort of adolescents with NPTs appears to be a higher risk group of girls than suggested by previous studies. Of the multi-ethnic sample with a mean age of 16.2 +/- 1.4 years at the time of the NPT, 47% had already had 1 or more pregnancies and 25% had 1 child. Thirty percent of the subjects were offered condoms, and 50% were offered hormonal contraception at the time of the NPT; only 46% were given a return appointment. By 18 months after the index pregnancy test, 36% of the subjects had 1 or more pregnancies, and the majority of the subjects had used no form of contraception or had used contraception inconsistently.

Conclusions: Comprehensive reproductive health services often are not offered to adolescents who receive NPT results. Sexually active teenagers need thorough reproductive care and consistent follow-up evaluation to avoid sexually transmitted infections (STIs) and unintended pregnancies.
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http://dx.doi.org/10.1016/j.jadohealth.2004.10.007DOI Listing
March 2006