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1.  High sustained virological response rates using imported generic direct acting antiviral treatment for hepatitis C 
Journal of Virus Eradication  null;3(4):200-203.
High prices of direct acting antivirals (DAAs) for hepatitis C virus (HCV) can lead to restrictions on access to treatment in high- and middle-income countries. An increasing number of people in these countries are treating their HCV infection with generic drugs produced in India, China, Bangladesh or Egypt. This analysis assessed the efficacy of generic imported DAAs.
Patients sourced generic versions of sofosbuvir (SOF), ledipasvir (LDV) and daclatasvir (DCV) from suppliers in India, Bangladesh, China and Egypt via three buyers’ clubs. The choice of DAAs and the length of treatment were determined on baseline RNA levels, HCV genotype and stage of fibrosis. Patient HCV RNA levels were evaluated pre-treatment, during treatment, at end of treatment (EOT) and then for sustained virological response (SVR) at 4, 12, and 24 weeks, normally by a treating clinician.
Overall 616 patients submitted results: 199 from an Australian buyers’ club, 205 from a South-east Asian buyers’ clubs, and 212 from an Eastern European buyers’ club. Of the 616 patients treated, 276 received SOF/LDV (35 with ribavirin [RBV]) and 340 received SOF/DCV (61 with RBV). At baseline, 61% were male, 52% had HCV genotype 1 and 11% had liver cirrhosis. The mean age was 44.3 years and the mean baseline HCV RNA was 6.9 log10 IU/mL. A rapid virological response (RVR) was observed in 314/375 (84%) of the patients treated. Based on currently available data, the percentage of patients with HCV RNA below the lower limit of quantification (LLoQ) was 99% (234/237) at EOT, 99% (299/303) at SVR4 and 99% (247/250) at SVR12.
In this analysis, treatment with imported generic DAAs achieved high rates of HCV RNA undetectability at the end of treatment, and SVR12 in 99% of patients evaluated to date. Mass treatment with generic DAAs is a feasible and economical alternative route of accessing curative DAAs, where the high prices for branded alternatives prevent access to treatment.
PMCID: PMC5632545
hepatitis C, direct acting antivirals, sofosbuvir, ledipasvir, daclatasvir
2.  InterPrEP. Internet-based pre-exposure prophylaxis with generic tenofovir DF/emtricitabine in London: an analysis of outcomes in 641 patients 
Journal of Virus Eradication  null;3(4):218-222.
HIV pre-exposure prophylaxis (PrEP) is not available on the National Health Service (NHS) in England. People are buying generic versions of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) on the internet, which is legal under UK import laws.
HIV-negative individuals attending our clinic who reported purchasing generic PrEP online were provided with risk-reduction advice and were evaluated for HIV, hepatitis B and C, renal function and sexually transmitted infections (STIs)on their first visit. They were offered regular follow-up visits every 3 months and given risk-reduction advice. Plasma therapeutic drug monitoring (TDM) for tenofovir and FTC was also offered.
641 individuals accessed the service during 2016–2017. Median time on generic PrEP was 202 days. All were MSM, 81% were white, 75% used PrEP daily and 14% on an event-driven basis, and 67% were on generic TDF/FTC manufactured by Cipla Ltd. There were no serious adverse events. Thirty-nine percent of individuals (191/494) reported using recreational drugs in the 12 months before starting PrEP, and 29% (127/443) reported this while taking PrEP. During follow-up, 26% (142/552) of individuals were diagnosed with an STI at one or more follow-up visits. In 336 person-years of follow-up, there were no cases of HIV infection (0%, 95% CI 0%–1.1%). There were no new cases of hepatitis B and two new cases of hepatitis C.
There were no new cases of HIV in 641 individuals using generic PrEP. At the same centre, new HIV diagnoses fell from 69 per month in October 2015 to 15 per month in June 2017. We believe that our support for individuals taking generic PrEP has contributed to this fall. There was a 10% increase in STI diagnoses during PrEP compared to baseline. Strategies to reduce STIs remain crucial.
PMCID: PMC5632549
HIV infection, pre-exposure prophylaxis, generic, antiretroviral drugs
3.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
PMCID: PMC5606215
4.  Geographical Variation in Prevalence of Cryptococcal Antigenemia among HIV-infected Treatment-Naïve Patients in Nigeria: A multicenter cross-sectional study 
Worldwide, HIV-associated cryptococcal meningitis affects approximately 1 million persons and causes 600,000 deaths each year mostly in sub-Sharan Africa. Limited data exist on cryptococcal meningitis and antigenemia in Nigeria, and most studies are geographically restricted. We determined the prevalence of cryptococcal antigenemia (CrAg) among HIV-infected treatment-naïve individuals in Nigeria.
This was a retrospective, cross-sectional study across four geographic regions in Nigeria. We performed CrAg testing using a lateral flow immunoassay on archived whole blood samples collected from HIV-infected participants at US PEPFAR-supported sites selected to represent the major geographical and ethnic diversity in Nigeria. Eligible samples were (1) stored in an -80° freezer; (2) collected from consenting patients (>15 years) naïve to antiretroviral therapy with CD4+ count less than 200 cells/mm3.
A total of 2,752 stored blood samples were retrospectively screened for CrAg. A majority of samples were from participants aged 30 - 44 (57.6%), and 1,570 (57.1%) were from women. The prevalence of CrAg positivity in specimens with CD4 < 200 cells/mm3 was 2.3% (95% CI = 1.8%-3.0%), and varied significantly across the four regions (p < 0.001). At 4.4% (3.2%-5.9%), the South East contained the highest prevalence.
The significant regional variation in CrAg prevalence found in Nigeria should be taken into consideration as plans are made to integrate routine screening into clinical care for HIV-infected patients.
PMCID: PMC4981538  PMID: 27144527
AIDS; cryptococcal antigen (CrAg); cryptococcal meningitis; retrospective cross-sectional study; sub-Saharan Africa; Nigeria
5.  Community Pharmacy Staff Perceptions on Preventing Alcohol and Medication Interactions in Older Adults 
To examine rural/urban pharmacy staff perceptions on messaging, barriers, and motivators for preventing alcohol and medication interactions (AMI) in older adults (65+ years).
A survey was distributed through the local pharmacist association and statewide pharmacy registry in Kentucky.
A total of N=255 responses were received from pharmacists, pharmacy technicians, and pharmacy students.
Across rural/urban regions alike, among the AMI prevention messages provided, participants identified the most important messages to be: AMI can be potentially dangerous and life threatening, emergency rooms should be used when experiencing an AMI, and doctors and pharmacists should be consulted about AMI. The most common AMI prevention barriers indicated were stigma, costs, and low perceived risks. The most common AMI prevention motivators indicated were physical health improvement/promoting a healthy lifestyle, convenient setting, and financial incentives.
Irrespective of geography, participants similarly rated the presented AMI prevention messages, barriers, and motivators. Using the findings, the development of an AMI prevention program is suggested utilizing messaging surrounding AMI threat, behavioral management, and behavioral prevention.
PMCID: PMC5013263  PMID: 27594107
Aging; Alcohol; Medication Safety; Medication Interactions; Substance Use
6.  Gabapentin misuse, abuse, and diversion: A systematic review 
Addiction (Abingdon, England)  2016;111(7):1160-1174.
Background and Aims
Since its market release, gabapentin has been presumed to have no abuse potential and subsequently has been prescribed widely off-label, despite increasing reports of gabapentin misuse. This review estimates and describes the prevalence and effects of, motivations behind, and risk factors for gabapentin misuse, abuse, and diversion.
Databases were searched for peer-reviewed articles demonstrating gabapentin misuse, characterized by taking a larger dosage than prescribed or taking gabapentin without a prescription, and diversion. All types of studies were considered; grey literature was excluded. Thirty-three articles met inclusion criteria, consisting of 23 case studies and 11 epidemiological reports. Published reports came from the USA, the UK, Germany, Finland, India, South Africa, and France, and two analyzed websites not specific to a particular country.
Prevalence of gabapentin misuse in the general population was reported to be 1%, 40–65% among individuals with prescriptions, and between 15–22% within populations of people who abuse opioids. An array of subjective experiences reminiscent of opioids, benzodiazepines, and psychedelics were reported over a range of doses, including those within clinical recommendations. Gabapentin was primarily misused for recreational purposes, self-medication, or intentional self-harm and was misused alone or in combination with other substances, especially opioids, benzodiazepines, and/or alcohol. Individuals with histories of drug abuse were most often involved in its misuse.
Epidemiological and case report evidence suggests that the antiepileptic and analgesic medication gabapentin is being misused internationally at a rate of about 1%, with substance abuse populations at special risk for misuse/abuse.
PMCID: PMC5573873  PMID: 27265421
gabapentin; prescription drug misuse; systematic review; diversion; substance abuse
7.  A comprehensive method for identification of suitable reference genes in extracellular vesicles 
Reverse transcription–quantitative polymerase chain reaction (RT-qPCR) is one of the most sensitive, economical and widely used methods for evaluating gene expression. However, the utility of this method continues to be undermined by a number of challenges including normalization using appropriate reference genes. The need to develop tailored and effective strategies is further underscored by the burgeoning field of extracellular vesicle (EV) biology. EVs contain unique signatures of small RNAs including microRNAs (miRs). In this study we develop and validate a comprehensive strategy for identifying highly stable reference genes in a therapeutically relevant cell type, cardiosphere-derived cells. Data were analysed using the four major approaches for reference gene evaluation: NormFinder, GeNorm, BestKeeper and the Delta Ct method. The weighted geometric mean of all of these methods was obtained for the final ranking. Analysis of RNA sequencing identified miR-101-3p, miR-23a-3p and a previously identified EV reference gene, miR-26a-5p. Analysis of a chip-based method (NanoString) identified miR-23a, miR-217 and miR-379 as stable candidates. RT-qPCR validation revealed that the mean of miR-23a-3p, miR-101-3p and miR-26a-5p was the most stable normalization strategy. Here, we demonstrate that a comprehensive approach of a diverse data set of conditions using multiple algorithms reliably identifies stable reference genes which will increase the utility of gene expression evaluation of therapeutically relevant EVs.
PMCID: PMC5549828
Extracellular vesicles; microRNAs; cardiosphere-derived cells; CDCs; miRs; reference genes; qPCR; stem cells; RT-qPCR
8.  Accumbens nNOS Interneurons Regulate Cocaine Relapse 
The Journal of Neuroscience  2017;37(4):742-756.
Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ∼1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction.
SIGNIFICANCE STATEMENT Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus accumbens. We demonstrate the sequence of events that mediates synaptic potentiation and reinstated cocaine seeking induced by cocaine-conditioned cues. Activation of prefrontal inputs to the accumbens by cues initiates spillover of synaptic glutamate, which stimulates metabotropic glutamate receptor 5 (mGluR5) on a small population of interneurons (∼1%) expressing neuronal nitric oxide synthase. Stimulating these glutamate receptors increases nitric oxide (NO) production, which stimulates matrix metalloprotease-2 (MMP-2) and MMP-9 activity in the extracellular space. Manipulating the interaction between mGluR5, NO production, or MMP-2 and MMP-9 pharmacologically or genetically is sufficient to recapitulate transient synaptic potentiation and reinstate cocaine seeking.
PMCID: PMC5296777  PMID: 28123012
cocaine; glutamate; metabotropic glutamate receptor; MMP; nitric oxide; relapse
9.  Development of Cortical Shape in the Human Brain from 6 to 24 Months of Age via a Novel Measure of Shape Complexity 
NeuroImage  2016;135:163-176.
The quantification of local surface morphology in the human cortex is important for examining population differences as well as developmental changes in neurodegenerative or neurodevelopmental disorders. We propose a novel cortical shape measure, referred to as the ‘shape complexity index’ (SCI), that represents localized shape complexity as the difference between the observed distributions of local surface topology, as quantified by the shape index (SI) measure, to its best fitting simple topological model within a given neighborhood. We apply a relatively small, adaptive geodesic kernel to calculate the SCI. Due to the small size of the kernel, the proposed SCI measure captures fine differences of cortical shape. With this novel cortical feature, we aim to capture comparatively small local surface changes that capture a) the widening versus deepening of sulcal and gyral regions, as well as b) the emergence and development of secondary and tertiary sulci. Current cortical shape measures, such as the gyrification index (GI) or intrinsic curvature measures, investigate the cortical surface at a different scale and are less well suited to capture these particular cortical surface changes. In our experiments, the proposed SCI demonstrates higher complexity in the gyral/sulcal wall regions, lower complexity in wider gyral ridges and lowest complexity in wider sulcal fundus regions. In early postnatal brain development, our experiments show that SCI reveals a pattern of increased cortical shape complexity with age, as well as sexual dimorphisms in the insula, middle cingulate, parieto-occipital sulcal and Broca's regions. Overall, sex differences were greatest at 6 months of age and were reduced at 24 months, with the difference pattern switching from higher complexity in males at 6 months to higher complexity in females at 24months. This is the first study of longitudinal, cortical complexity maturation and sex differences, in the early postnatal period from 6 to 24 months of age with fine scale, cortical shape measures. These results provide information that complement previous studies of gyrification index in early brain development.
PMCID: PMC4915970  PMID: 27150231
Shape Complexity Index; Shape Index; Earth Mover Distance; Age Effect; Sexual Dimorphism
10.  Concurrent alcohol and medication poisoning hospital admissions among older rural and urban residents 
Alcohol and medications interactions are projected to increase due to the growth of older adults that are unsafely consuming alcohol and medications. Plus, aging adults who reside in rural areas are at the highest risk of experiencing medication interactions.
Estimate concurrent alcohol and medication (alcohol/medication) hospitalizations in adults 50+ years, comparing age groups and rural/urban regions.
Kentucky non-federal, acute care inpatient hospital discharge electronic records for individuals aged 50+ years from 2001 to 2012 were examined. Rate differences were estimated across age and regional strata. Differences in the underlying principal diagnosis, intent, and medications were also examined.
There were 2,168 concurrent alcohol/medication hospitalizations among 50+ year olds identified. There was a 187% increase in alcohol/medication hospitalizations from 2001 (n=104) to 2012 (n=299). The per capita alcohol/medication hospitalization rate increased from 8.91 (per 100,000) in 2001 to 19.98 (per 100,000) in 2012, a 124 % increase. The characteristics of the hospitalizations included 75% principal diagnosis as medication poisoning, self-harm as the primary intent (55%) in 50–64 year olds, and unintentional intent (41%) in 65+ adults. Benzodiazepines were most often involved in the poisonings (36.5%).
Concurrent alcohol/medication hospitalizations in Kentucky are increasing among aging adults. Greater increases in rural areas and the 65+ aged adults were seen, although there were also higher alcohol/medication hospitalizations in urban and 50–64 aged adults. These findings indicate the need for public health prevention and clinical intervention to better educate and manage alcohol consuming older adults on safe medication and alcohol practices.
PMCID: PMC4998842  PMID: 27184414
Aging; alcohol; medication safety; mental health; substance misuse
11.  Platelet-rich plasma induces post-natal maturation of immature articular cartilage and correlates with LOXL1 activation 
Scientific Reports  2017;7:3699.
Platelet-rich plasma (PRP) is used to stimulate the repair of acute and chronic cartilage damage even though there is no definitive evidence of how this is achieved. Chondrocytes in injured and diseased situations frequently re-express phenotypic biomarkers of immature cartilage so tissue maturation is a potential pathway for restoration of normal structure and function. We used an in vitro model of growth factor-induced maturation to perform a comparative study in order to determine whether PRP can also induce this specific form of remodeling that is characterised by increased cellular proliferation and tissue stiffness. Gene expression patterns specific for maturation were mimicked in PRP treated cartilage, with chondromodulin, collagen types II/X downregulated, deiodinase II and netrin-1 upregulated. PRP increased cartilage surface cell density 1.5-fold (P < 0.05), confirmed by bromodeoxyuridine incorporation and proportionate increases in proliferating cell nuclear antigen gene expression. Atomic force microscopy analysis of PRP and growth factor treated cartilage gave a 5-fold increase in stiffness correlating with a 10-fold upregulation of lysyl oxidase like-1 gene expression (P < 0.001). These data show PRP induces key aspects of post-natal maturation in immature cartilage and provides the basis to evaluate a new biological rationale for its activity when used clinically to initiate joint repair.
PMCID: PMC5473810  PMID: 28623328
12.  Enteroaggregative Escherichia coli Adherence Fimbriae Drive Inflammatory Cell Recruitment via Interactions with Epithelial MUC1 
mBio  2017;8(3):e00717-17.
Enteroaggregative Escherichia coli (EAEC) causes diarrhea and intestinal inflammation worldwide. EAEC strains are characterized by the presence of aggregative adherence fimbriae (AAF), which play a key role in pathogenesis by mediating attachment to the intestinal mucosa and by triggering host inflammatory responses. Here, we identify the epithelial transmembrane mucin MUC1 as an intestinal host cell receptor for EAEC, demonstrating that AAF-mediated interactions between EAEC and MUC1 facilitate enhanced bacterial adhesion. We further demonstrate that EAEC infection also causes elevated expression of MUC1 in inflamed human intestinal tissues. Moreover, we find that MUC1 facilitates AAF-dependent migration of neutrophils across the epithelium in response to EAEC infection. Thus, we show for the first time a proinflammatory role for MUC1 in the host response to an intestinal pathogen.
EAEC is a clinically important intestinal pathogen that triggers intestinal inflammation and diarrheal illness via mechanisms that are not yet fully understood. Our findings provide new insight into how EAEC triggers host inflammation and underscores the pivotal role of AAFs—the principal adhesins of EAEC—in driving EAEC-associated disease. Most importantly, our findings add a new dimension to the signaling properties of the transmembrane mucin MUC1. Mostly studied for its role in various forms of cancer, MUC1 is widely regarded as playing an anti-inflammatory role in response to infection with bacterial pathogens in various tissues. However, the role of MUC1 during intestinal infections has not been previously explored, and our results describe the first report of MUC1 as a proinflammatory factor following intestinal infection.
PMCID: PMC5461410
Escherichia coli; fimbriae; inflammation; mucin
13.  Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene 
Addiction biology  2015;21(3):530-546.
Abused inhalants are voluntary inhaled at high concentrations to produce intoxicating effects. Results from animal studies show that the abused inhalant toluene triggers behaviors, such as self-administration and conditioned place preference that are commonly associated with addictive drugs. Little is known however about how toluene affects neurons within the nucleus accumbens (NAc), a brain region within the basal ganglia that mediates goal-directed behaviors and is implicated in the development and maintenance of addictive behaviors. Here, we report that toluene inhibits a component of the after-hyperpolarization potential (AHP), and dose-dependently inhibits NMDA-mediated currents in rat NAc medium spiny neurons (MSN). Moreover, using the multivariate statistical technique, partial least squares discriminative analysis (PLS-DA) to analyze electrophysiological measures from rat NAc MSNs, we show that toluene induces a persistent depression of AMPA-mediated currents in one subtype of NAc medium spiny neurons, and that the electrophysiological features of MSN neurons predicts their sensitivity to toluene. The CB1 receptor antagonist AM281 blocked the toluene-induced long-term depression of AMPA currents, indicating that this process is dependent on endocannabinoid signaling. The neuronal identity of recorded cells was examined using dual histochemistry and shows that toluene-sensitive NAc neurons are dopamine D2 MSNs that express preproenkephalin mRNA. Overall, the results from these studies indicate that physiological characteristics obtained from NAc MSNs during whole-cell patch clamp recordings reliably predict neuronal phenotype, and that the abused inhalant toluene differentially depresses excitatory neurotransmission in NAc neuronal subtypes.
PMCID: PMC4561223  PMID: 25752326
Abused Inhalants; D2R Medium Spiny Neurons; Endocannabinoids; Nucleus Accumbens; Toluene; Whole-Cell Patch Clamp
14.  RCT of the effect of berryfruit polyphenolic cultivar extract in mild steroid-naive asthma: a cross-over, placebo-controlled study 
BMJ Open  2017;7(3):e013850.
There is preclinical evidence that consumption of berryfruit extract may reduce chronic airways inflammation and modify airway remodelling in allergen-induced models of lung inflammation. We investigated the effect of berryfruit extract on the fractional expired nitric oxide (FeNO), a biomarker of eosinophilic airways inflammation, in adults with steroid-naïve asthma.
Randomised placebo-controlled cross-over double-blind trial.
Single-centre community-based trial.
28 steroid-naïve mild asthmatics with Feno >40 ppb, of whom 25 completed both study interventions.
Participants were randomised to receive, according to the cross-over design, 100 mg berryfruit polyphenolic extract (BFPE) or placebo for 4 weeks, with a 4-week washout period between the interventions.
Primary outcome measure
The primary outcome variable was FeNO at 4 weeks, analysed by a mixed linear model, with a random effect for participant and baseline FeNo as a covariate.
The mean (SD) natural logarithm transformed (ln) FeNO after 4 weeks of treatment for the BFPE and placebo groups was 4.28 (0.47) and 4.22 (0.47), respectively. The paired change from baseline mean (SD) BFPE minus placebo ln FeNO was −0.03 (0.39), N=25. The mixed linear model estimate, with baseline covariate adjustment, difference in ln FeNO, was −0.002 (95% CI −0.15 to 0.14), p=0.98. This is equivalent to a ratio of geometric mean FeNO of 1.0 (95% CI 0.86 to 1.15).
In steroid-naïve participants with mild asthma and elevated FeNO, there was no effect of BFPE on FeNO, a biomarker of eosinophilic airways inflammation. Caution is required in the extrapolation of apparent benefit in murine models of lung eosinophilia to clinical efficacy in patients with asthma.
Trial registration number
ANZCTR: 12613000451707; Results.
PMCID: PMC5372143  PMID: 28320793
Animal models; Clinical respiratory medicine
15.  Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL‐10 expression and secretion 
EMBO Molecular Medicine  2017;9(3):337-352.
Cardiosphere‐derived cells (CDCs) reduce myocardial infarct size via secreted extracellular vesicles (CDC‐EVs), including exosomes, which alter macrophage polarization. We questioned whether short non‐coding RNA species of unknown function within CDC‐EVs contribute to cardioprotection. The most abundant RNA species in CDC‐EVs is a Y RNA fragment (EV‐YF1); its relative abundance in CDC‐EVs correlates with CDC potency in vivo. Fluorescently labeled EV‐YF1 is actively transferred from CDCs to target macrophages via CDC‐EVs. Direct transfection of macrophages with EV‐YF1 induced transcription and secretion of IL‐10. When cocultured with rat cardiomyocytes, EV‐YF1‐primed macrophages were potently cytoprotective toward oxidatively stressed cardiomyocytes through induction of IL‐10. In vivo, intracoronary injection of EV‐YF1 following ischemia/reperfusion reduced infarct size. A fragment of Y RNA, highly enriched in CDC‐EVs, alters Il10 gene expression and enhances IL‐10 protein secretion. The demonstration that EV‐YF1 confers cardioprotection highlights the potential importance of diverse exosomal contents of unknown function, above and beyond the usual suspects (e.g., microRNAs and proteins).
PMCID: PMC5331234  PMID: 28167565
extracellular vesicle; macrophage; RNA; stem cells; Cardiovascular System; Stem Cells
16.  Three Cases of Neurologic Syndrome Caused by Donor-Derived Microsporidiosis  
Emerging Infectious Diseases  2017;23(3):387-395.
Encephalitozoon cuniculi was transmitted from an infected donor to 3 solid organ recipients, 1 of whom died.
In April 2014, a kidney transplant recipient in the United States experienced headache, diplopia, and confusion, followed by neurologic decline and death. An investigation to evaluate the possibility of donor-derived infection determined that 3 patients had received 4 organs (kidney, liver, heart/kidney) from the same donor. The liver recipient experienced tremor and gait instability; the heart/kidney and contralateral kidney recipients were hospitalized with encephalitis. None experienced gastrointestinal symptoms. Encephalitozoon cuniculi was detected by tissue PCR in the central nervous system of the deceased kidney recipient and in renal allograft tissue from both kidney recipients. Urine PCR was positive for E. cuniculi in the 2 surviving recipients. Donor serum was positive for E. cuniculi antibodies. E. cuniculi was transmitted to 3 recipients from 1 donor. This rare presentation of disseminated disease resulted in diagnostic delays. Clinicians should consider donor-derived microsporidial infection in organ recipients with unexplained encephalitis, even when gastrointestinal manifestations are absent.
PMCID: PMC5382757  PMID: 28220747
organ transplants; microsporidia; microsporidiosis; communicable diseases; neurologic syndrome; meningitis/encephalitis; fungi
18.  Slow lung clearance and limited translocation of four sizes of inhaled iridium nanoparticles 
Concerns have been expressed that inhaled nanoparticles may behave differently to larger particles in terms of lung clearance and translocation, with potential implications for their toxicity. Studies undertaken to investigate this have typically involved limited post-exposure periods. There is a shortage of information on longer-term clearance and translocation patterns and their dependence on particle size, which this study aimed to address.
Rats were exposed (<3 h) nose-only to aerosols of spark-generated radioactive iridium-192 nanoparticles of four sizes: 10 nm, 15 nm, 35 nm and 75 nm (count median diameter) (aerosol mass concentrations 17, 140, 430, and 690 μg/m3, respectively). The content of iridium-192 in the whole animal, organs, tissues, and excreta was measured at various times post-exposure to ≥ 1 month. Limited toxicological investigations were undertaken for the 10 nm aerosol using bronchoalveolar lavage fluid. Elemental maps of tissue samples were produced using laser ablation inductively coupled plasma mass spectrometry and synchrotron micro-focus x-ray fluorescence. The chemical speciation of the iridium was explored using synchrotron micro focus x-ray near-edge absorption spectroscopy.
Long-term lung retention half-times of several hundred days were found, which were not dependent on particle size. There was significant variation between individual animals. Analysis of bronchoalveolar lavage fluid for the 10 nm aerosol indicated a limited inflammatory response resolving within the first 7 days. Low levels of, particle size dependent, translocation to the kidney and liver were found (maximum 0.4% of the lung content). Any translocation to the brain was below the limits of detection (i.e. < 0.01% of the lung content). The kidney content increased to approximately 30 days and then remained broadly constant or decreased, whereas the content in the liver increased throughout the study. Laser ablation inductively coupled plasma mass spectrometry analysis indicated homogeneous iridium distribution in the liver and within the cortex in the kidney.
Slow lung clearance and a pattern of temporally increasing concentrations in key secondary target organs has been demonstrated for inhaled iridium aerosol particles < 100 nm, which may have implications for long-term toxicity, especially in the context of chronic exposures.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-017-0185-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5304551  PMID: 28187746
Nanoparticles; Inhalation exposure; In vivo study; Rat; Tissue distribution; Lung clearance; Toxicity
19.  Day-time variation of serum periostin in asthmatic adults treated with ICS/LABA and adults without asthma 
We aimed to determine the effect of sampling time during the day on serum periostin levels in adult participants with and without asthma.
Serum periostin was measured at 2-h intervals from 0800 to 1800 h in 16 adult participants with stable asthma prescribed inhaled corticosteroid and long-acting beta-agonist therapy, and in 16 otherwise healthy participants without asthma. Mixed linear models were used to compare time zero (08:00 h) with subsequent measurement time for serum periostin for both groups.
In both asthma and non-asthma, the mean (SD) serum periostin levels continuously reduced during the day from 53.5 (13.6) ng/mL at 0800 h to 50.9 (13.4) ng/mL at 1800 h (difference log periostin −0.05, P ≤ 0.001) and 50.5 (13.0) ng/mL at 0800 h to 46.2 (11.5) ng/mL at 1800 h (difference log periostin −0.08, P ≤ 0.001) respectively.
Periostin values are higher in the morning compared with the afternoon in asthmatic and non-asthmatic adults. The small magnitude of the variation in serum periostin levels suggests that the time of day in which the serum periostin measurements are made is unlikely to influence treatment decisions if a specific serum periostin level is used to predict treatment responsiveness.
Trial registration Australia New Zealand Trials Registry (ACTRN12614000072617)
Electronic supplementary material
The online version of this article (doi:10.1186/s13223-017-0182-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5299725
Asthma; Biomarker; Daytime variation; Periostin
20.  ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) Trial: Rationale and Design 
Cell Transplantation  2017;26(2):205-214.
Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo-controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a doubleblind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by magnetic resonance imaging. The ALLSTAR trial employs a “seamless” WOVE 1 design that enables continuous enrollment from phase 1 to phase 2 and will evaluate the safety of intracoronary administration of allogeneic CDCs and its efficacy in decreasing infarct size in post-MI patients.
PMCID: PMC5657761  PMID: 27543900
Stem cells; ST elevation MI; Trial design; Myocardial infarction (MI); Regenerative medicine
21.  Support Seeking or Familial Obligation: An Investigation of Motives for Disclosing Genetic Test Results 
Health communication  2015;31(6):668-678.
Genetic test results reveal not only personal information about a person’s likelihood of certain medical conditions but also information about their genetic relatives (Annas, Glantz, & Roche, 1995). Given the familial nature of genetic information, one’s obligation to protect family members may be a motive for disclosing genetic test results, but this claim has not been methodically tested. Existing models of disclosure decision-making presume self-interested motives, such as seeking social support, instead of other-interested motives, like familial obligation. This study investigated young adults’ (N = 173) motives to share a genetic-based health condition, alpha-1 antitrypsin deficiency, after reading a hypothetical vignette. Results show that social support and familial obligation were both reported as motives for disclosure. In fact, some participants reported familial obligation as their primary motivator for disclosure. Finally, stronger familial obligation predicted increased likelihood of disclosing hypothetical genetic test results. Implications of these results were discussed in reference to theories of disclosure decision-making models and the practice of genetic disclosures.
PMCID: PMC5139682  PMID: 26507777
disclosure; decision-making; familial obligation; genetics; motives
22.  Preparing for Antibiotic Resistance Campaigns: A Person-centered Approach to Audience Segmentation 
Journal of health communication  2015;20(12):1433-1440.
Antibiotic resistance is growing threat to public health threat that calls for urgent attention. However, creating campaigns to slow the emergence and spread of drug-resistant pathogens is challenging because the goal—antibiotic stewardship—encompasses multiple behaviors. This study provided a novel approach to audience segmentation for a multifaceted goal, by using a person-centered approach to identify profiles of US adults based on shared stewardship intentions. The latent class analysis identified three groups: Stewards, Stockers, and Demanders. The findings suggest campaigns with goals aimed at encouraging Stewards to follow through on their intentions, encouraging Stockers to dispose of their leftover antibiotics, and convincing Demanders to accept provider’s evidence-based judgment when a prescription for antibiotics is not indicated. Covariate analysis showed that people who held more inaccurate beliefs about what antibiotics can treat had higher odds of being Demanders and Stockers instead of Stewards. People with stronger health mavenism also had higher odds of being Stockers instead of Stewards. The covariate analysis provided theoretical insight into the strategies to pursue in campaigns targeting these three groups.
PMCID: PMC4697945  PMID: 26181623
antibiotic resistance; audience segmentation; latent class analysis; misattributions; health mavens
23.  Evaluation of a Public-sector, Provider-initiated Cryptococcal Antigen Screening and Treatment Program, Western Cape, South Africa 
Screening for serum cryptococcal antigen (CrAg) may identify those at risk for disseminated cryptococcal disease (DCD), and pre-emptive fluconazole treatment may prevent progression to DCD. In August 2012, the Western Cape Province (WC), South Africa, adopted provider-initiated CrAg screening. We evaluated the implementation and effectiveness of this large-scale public-sector program during its first year, September 1, 2012—August 31, 2013.
We used data from the South African National Health Laboratory Service, WC provincial HIV program, and nationwide surveillance data for DCD. We assessed the proportion of eligible patients screened for CrAg (CrAg test done within 30 days of CD4 date) and the prevalence of CrAg positivity. Incidence of DCD among those screened was compared with those not screened.
Of 4,395 eligible patients, 26.6% (n=1170) were screened. The proportion of patients screened increased from 15.9% in September 2012 to 36.6% in August 2013. The prevalence of positive serum CrAg was 2.1%. Treatment data were available for 13 of 24 CrAg-positive patients; nine of 13 were treated with fluconazole. Nine (0.8%) incident cases of DCD occurred among the 1170 patients who were screened for CrAg vs. 49 (1.5%) incident cases among the 3225 patients not screened (p=0.07).
Relatively few eligible patients were screened under the WC provider-initiated CrAg screening program. Unscreened patients were nearly twice as likely to develop DCD. CrAg screening can reduce the burden of DCD, but needs to be implemented well. To improve screening rates, countries should consider laboratory-based reflexive screening when possible.
PMCID: PMC4871265  PMID: 26926942
South Africa; Cryptococcal meningitis; Cryptococcal antigen; CrAg; Screening; Fluconazole prophylaxis; Prevention
24.  NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype 
Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24+/CD44+, CD133+, and aldehyde dehydrogenasebright) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.
PMCID: PMC4781667  PMID: 26363055
25.  Gq-DREADD Selectively Initiates Glial Glutamate Release and Inhibits Cue-induced Cocaine Seeking 
Biological psychiatry  2015;78(7):441-451.
Glial cells of the central nervous system directly influence neuronal activity by releasing neuroactive small molecules, including glutamate. Long-lasting cocaine-induced reductions in extracellular glutamate in the nucleus accumbens core (NAcore) affect synaptic plasticity responsible for relapse vulnerability.
We transduced NAcore astrocytes with an AAV viral vector expressing hM3Dq (Gq) DREADD under control of the glial fibrillary acidic protein (GFAP) promoter in 62 male Sprague Dawley rats, 4 dnSNARE mice and 4 wild type littermates. Using glutamate biosensors we measured NAcore glutamate levels following intracranial or systemic administration of clozapine-N-oxide (CNO), and tested the ability of systemic CNO to inhibit reinstated cocaine or sucrose seeking following self-administration (SA) and extinction training.
Administration of CNO in GFAP-Gq-DREADD transfected animals increased NAcore extracellular glutamate levels in vivo. The glial origin of released glutamate was validated by an absence of CNO-mediated release in mice expressing a dominant-negative SNARE variant in glia. Also, CNO-mediated release was relatively insensitive to N-type calcium channel blockade. Systemic administration of CNO inhibited cue-induced reinstatement of cocaine seeking in rats extinguished from cocaine, but not sucrose SA. The capacity to inhibit reinstated cocaine-seeking was prevented by systemic administration of the group II metabotropic glutamate receptor (mGluR2/3) antagonist LY341495.
DREADD-mediated glutamate gliotransmission inhibited cue-induced reinstatement of cocaine seeking by stimulating release-regulating mGluR2/3 autoreceptors to inhibit cue-induced synaptic glutamate spillover.
PMCID: PMC4547911  PMID: 25861696
Cocaine; Glutamate; Astrocytes; DREADD; Reinstatement; Biosensor

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