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1.  Automated telephone interventions for problematic alcohol use in clinical and population samples: a randomized controlled trial 
BMC Research Notes  2017;10:624.
Objective
The primary objective was to evaluate 6-month outcomes for brief and extensive automated telephony interventions targeting problematic alcohol use, in comparison to an assessment-only control group. The secondary objective was to compare levels of problematic alcohol use (hazardous, harmful or probable dependence), gender and age among study participants from clinical psychiatric and addiction outpatient settings and from population-based telephone helpline users and Internet help-seeker samples.
Results
The Alcohol Use Disorders Identification Test (AUDIT) was used for screening of problematic alcohol use and 6-month follow-up assessment. A total of 248 of help-seekers with at least hazardous use (AUDIT scores of ≥ 6/≥ 8 for women/men) were recruited from clinical and general population settings. Minor recruitment group differences were identified with respect to AUDIT scores and age at baseline. One hundred and sixty persons (64.5%) did not complete the follow-up assessment. The attrition group had a higher proportion of probable dependence (71% vs. 56%; p = 0.025), and higher scores on the total AUDIT, and its subscales for alcohol consumption and alcohol problems. At follow up, within-group problem levels had declined across all three groups, but there were no significant between-group differences.
Trial registration ClinicalTrials.gov NCT01958359, Registered October 9, 2013. Retrospectively registered
doi:10.1186/s13104-017-2955-4
PMCID: PMC5704400  PMID: 29183357
Alcohol; Hazardous; Dependence; Randomized; Intervention; Telephone; Automated; Outpatient; Psychiatry; Addiction; Help seekers
2.  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
doi:10.1186/s13722-017-0087-8
PMCID: PMC5606215
3.  Skills Training via Smartphone App for University Students with Excessive Alcohol Consumption: a Randomized Controlled Trial 
Purpose
University students in a study on estimated blood alcohol concentration (eBAC) feedback apps were offered participation in a second study, if reporting continued excessive consumption at 6-week follow-up. This study evaluated the effects on excessive alcohol consumption of offering access to an additional skills training app.
Method
A total of 186 students with excessive alcohol consumption were randomized to an intervention group or a wait list group. Both groups completed online follow-ups regarding alcohol consumption after 6 and 12 weeks. Wait list participants were given access to the intervention at 6-week follow-up. Assessment-only controls (n = 144) with excessive alcohol consumption from the ongoing study were used for comparison.
Results
The proportion of participants with excessive alcohol consumption declined in both intervention and wait list groups compared to controls at first (p < 0.001) and second follow-ups (p = 0.054). Secondary analyses showed reductions for the intervention group in quantity of drinking at first follow-up (−4.76, 95% CI [−6.67, −2.85], Z = −2.09, p = 0.037) and in frequency of drinking at both follow-ups (−0.83, 95% CI [−1.14, −0.52], Z = −2.04, p = 0.041; −0.89, 95% CI [−1.16, −0.62], Z = −2.12, p = 0.034). The odds ratio for not having excessive alcohol consumption among men in the intervention group compared to male controls was 2.68, 95% CI [1.37, 5.25] (Z = 2.88, p = 0.004); the figure for women was 1.71, 95% CI [1.11, 2.64] (Z = 2.41, p = 0.016).
Conclusion
Skills training apps have potential for reducing excessive alcohol use among university students. Future research is still needed to disentangle effects of app use from emailed feedback on excessive alcohol consumption and study participation.
Trial Registration
NCT02064998
Electronic supplementary material
The online version of this article (doi:10.1007/s12529-016-9629-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s12529-016-9629-9
PMCID: PMC5608866  PMID: 28224445
Randomized controlled trial; Problem drinking; Alcohol abuse; College; University; Smartphone; Mobile phone; eHealth; mHealth; Brief intervention; Relapse prevention
4.  Interactive Voice Response with Feedback Intervention in Outpatient Treatment of Substance Use Problems in Adolescents and Young Adults: A Randomized Controlled Trial 
Purpose
Substance use disorders and problematic substance use are common problems in adolescence and young adulthood. Brief personalized feedback has been suggested for treatment of alcohol and drug problems and poor mental health. This repeated measurement randomized controlled trial examines the effect of an interactive voice response (IVR) system for assessing stress, depression, anxiety and substance use.
Methods
The IVR system was used twice weekly over 3 months after treatment initiation, with or without addition of a personalized feedback intervention on stress and mental health symptoms. Both IVR assessment only (control group) and IVR assessment including feedback (intervention group) were provided as an add-on to treatment-as-usual procedures (TAU) in outpatient treatment of substance use problems in adolescents and young adults (N = 73).
Results
By using a mixed models approach, differences in change scores were analyzed over the three-month assessment period. Compared to the control group, the intervention group demonstrated significantly greater improvement in the Arnetz and Hasson stress score (AHSS, p = 0.019), the total Symptoms Checklist 8 score (SCL-8D, p = 0.037), the SCL-8D anxiety sub-score (p = 0.017), and on a summarized feedback score (p = 0.026), but not on the depression subscale. There were no differences in global substance use scores between the intervention group (feedback on mental health symptoms) and the control group.
Conclusion
In conclusion, IVR may be useful for follow-up and repeated interventions as an add-on to regular treatment, and personalized feedback could potentially improve mental health in adolescents and young adults with problematic substance use.
doi:10.1007/s12529-016-9625-0
PMCID: PMC5608891  PMID: 28028732
Randomized controlled trial (RCT); Interactive voice response (IVR); Outpatient treatment; Adolescents; Young adults; Substance use disorder; Mental health problems
5.  Large-scale ligand-based predictive modelling using support vector machines 
The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-016-0151-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-016-0151-5
PMCID: PMC4980776  PMID: 27516811
Predictive modelling; Support vector machine; Bioclipse; Molecular signatures; QSAR
6.  Mobile Interventions Targeting Risky Drinking Among University Students: A Review 
Current Addiction Reports  2016;3:166-174.
Mobile interventions based on text messages, automated telephone programs (interactive voice response (IVR)), and smartphone apps offer a new approach targeting hazardous alcohol use in university students. This review covers seven recent studies involving college or university students that evaluated intervention efficacy in comparison to controls: four using text messages, one using IVR, and two smartphone apps. Only the study evaluating IVR reported positive results for the primary outcome. Two of the text message studies reported positive results on secondary outcomes, while the other two reported no differences in comparison to control groups. For smartphone apps, one study reported positive results on secondary outcomes, while the other showed no differences in comparison to controls for a web-based app and negative results for a native app. Further development of mobile interventions is needed for this at-risk population, both in terms of intervention content and use of robust research designs.
doi:10.1007/s40429-016-0099-6
PMCID: PMC4856712  PMID: 27226948
Review; Alcohol; Hazardous drinking; University/college students; Intervention; Text messages; Automated telephony; Smartphone apps
7.  Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice 
Abstract
Objective
The lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.
Methods
Here, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.
Results
Chronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.
Interpretation
Our data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.
doi:10.1002/acn3.245
PMCID: PMC4693626  PMID: 26817023
8.  Mobile Phone Apps for University Students With Hazardous Alcohol Use: Study Protocol for Two Consecutive Randomized Controlled Trials 
JMIR Research Protocols  2015;4(4):e139.
Background
About 50% of university students overconsume alcohol, and drinking habits in later adulthood are to some extent established during higher educational studies. Several studies have demonstrated that Internet-based interventions have positive effects on drinking habits among university students. Our recent study evaluated two mobile phone apps targeting drinking choices at party occasions via personalized feedback on estimated blood alcohol concentration (eBAC) for students with hazardous drinking. No changes in drinking parameters were found over a seven-week period apart from an increase in number of drinking occasions among men for one of the apps tested. Up to 30% of the study participants drank at potentially harmful levels: higher than the national recommended number of standard drinks per week (a maximum of 9 for women and 14 for men) in Sweden.
Objective
(1) To evaluate improved versions of the two mobile phone apps tested in our prior trial, in a new, 3-armed randomized controlled trial among university students with at least hazardous drinking habits according to the Alcohol Use Disorders Identifications Test (AUDIT; Study 1). (2) After 6 weeks, to target study participants showing alcohol consumption higher than the national recommended levels for standard drinks per week by offering them participation in a second, 2-armed randomized trial evaluating an additional mobile phone app with skill enhancement tasks (Study 2). (3) To follow participants at 6, 12 and 18 weeks after recruitment to Study 1 and at 6 and 12 weeks after recruitment to Study 2.
Methods
Two randomized controlled trials are conducted. Study 1: Students are recruited at four Swedish universities, via direct e-mail and advertisements on Facebook and student union web sites. Those who provide informed consent, have a mobile phone, and show at least hazardous alcohol consumption according to the AUDIT (≥6 for women; ≥8 points for men) are randomized into three groups. Group 1 has access to the Swedish government alcohol monopoly’s app, Promillekoll, offering real-time estimated eBAC calculation; Group 2 has access to a Web-based app, PartyPlanner, developed by the research group, offering real-time eBAC calculation with planning and follow-up functions; and Group 3 participants are controls. Follow-up is conducted at 6, 12 and 18 weeks. Study 2. Participants who at the first 6-week follow-up show drinking levels higher than 9 (W) or 14 (M) standard drinks (12 g alcohol) per week, are offered participation in Study 2. Those who consent are randomized to either access to a skills training app, TeleCoach or to a wait-list control group.
Results
Latent Markov models for Study 1 and mixed models analyses for Study 2 will be performed. Study 2 data will be analyzed for publication during the spring of 2016; Study 1 data will be analyzed for publication during the fall of 2016.
Conclusions
If mobile phone interventions for reducing hazardous alcohol use are found to be effective, the prospects for positively influencing substance use-related health among university students can considerably improve.
Trial Registration
ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02064998 (Archived by WebCite at http://www.webcitation.org/6dy0AlVRP)
doi:10.2196/resprot.4894
PMCID: PMC4704963  PMID: 26693967
randomized controlled trial, universities, alcohol abuse, prevention, mobile phone, eHealth, mHealth
9.  Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice 
Abstract
Objective
The lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.
Methods
Here, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.
Results
Chronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.
Interpretation
Our data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.
doi:10.1002/acn3.245
PMCID: PMC4693626  PMID: 26817023
10.  Effects of Baseline Problematic Alcohol and Drug Use on Internet-Based Cognitive Behavioral Therapy Outcomes for Depression, Panic Disorder and Social Anxiety Disorder 
PLoS ONE  2014;9(8):e104615.
Purpose
Patients’ problematic substance use prevalence and effects were explored in relation to internet-based cognitive behavioral therapy (ICBT) outcomes for depression, panic disorder and social anxiety disorder.
Methods
At baseline and treatment conclusion, 1601 ICBT patients were assessed with self-rated measures for alcohol and drug use (AUDIT/DUDIT), depressive symptoms (MADRS-S), panic disorder symptoms (PDSS-SR) and social anxiety symptoms (LSAS-SR).
Results
Problematic substance use (AUDIT ≥8 for men, ≥6 for women; DUDIT ≥1) occurred among 32.4% of the patients; 24.1% only alcohol, 4.6% only drugs, and 3.7% combined alcohol and drug use. Hazardous alcohol use and probable alcohol dependence negatively affected panic disorder outcomes, and hazardous drug use led to worse social anxiety outcomes. Depression outcomes were not affected by substance use. Treatment adherence was negatively affected by problematic drug use among men and 25–34 year olds; combined substance use negatively affected adherence for women and 35–64 year olds.
Conclusion
Problematic substance use does not preclude ICBT treatment but can worsen outcomes, particularly problematic alcohol use for panic disorder patients and hazardous drug use for social anxiety patients. ICBT clinicians should exercise particular caution when treating men and younger patients with problematic drug use, and women or older patients with combined substance use.
doi:10.1371/journal.pone.0104615
PMCID: PMC4133364  PMID: 25122509
11.  Evaluation of Interactive Voice Response (IVR) and postal survey in follow-up of children and adolescents discharged from psychiatric outpatient treatment: a randomized controlled trial 
SpringerPlus  2014;3:77.
Systematic evaluation of child and adolescent psychiatric outpatient treatment is important but time-consuming. The aim of this paper was to study whether Interactive Voice Response (IVR) is a more effective method than a questionnaire sent by post when following up outpatient treatment in child and adolescent psychiatry. Eighty patients were recruited from a child and adolescent psychiatric outpatient unit in Sweden. One parent of each of the patients was randomized to complete the BCFPI follow-up form, using either IVR (n = 40) or postal survey (n = 40) one month after discharge. The response rate for complete answers was 65% in the IVR group and 38% in the postal survey group (p = 0.014). There was less need for reminders in the IVR group (p = 0.000). IVR is a promising and cost-effective method for evaluating evidence-based treatment in child and adolescent psychiatric care.
doi:10.1186/2193-1801-3-77
PMCID: PMC3926947  PMID: 24567883
Child and adolescent psychiatry; Evaluation; Interactive voice response (IVR); Postal survey; Brief child and family phone interview (BCFPI)
12.  Mobile phone brief intervention applications for risky alcohol use among university students: a randomized controlled study 
Background
Brief interventions via the internet have been shown to reduce university students’ alcohol intake. This study tested two smartphone applications (apps) targeting drinking choices on party occasions, with the goal of reducing problematic alcohol intake among Swedish university students.
Methods
Students were recruited via e-mails sent to student union members at two universities. Those who gave informed consent, had a smartphone, and showed risky alcohol consumption according to the Alcohol Use Disorders Identification Test (AUDIT) were randomized into three groups. Group 1 had access to the Swedish government alcohol monopoly’s app, Promillekoll, offering real-time estimated blood alcohol concentration (eBAC) calculation; Group 2 had access to a web-based app, PartyPlanner, developed by the research group, offering real-time eBAC calculation with planning and follow-up functions; and Group 3 participants were controls. Follow-up was conducted at 7 weeks.
Results
Among 28574 students offered participation, 4823 agreed to join; 415 were excluded due to incomplete data, and 1932 fulfilled eligibility criteria for randomization. Attrition was 22.7–39.3 percent, higher among heavier drinkers and highest in Group 2. Self-reported app use was higher in Group 1 (74%) compared to Group 2 (41%). Per-protocol analyses revealed only one significant time-by-group interaction, where Group 1 participants increased the frequency of their drinking occasions compared to controls (p = 0.001). Secondary analyses by gender showed a significant difference among men in Group 1 for frequency of drinking occasions per week (p = 0.001), but not among women. Among all participants, 29 percent showed high-risk drinking, over the recommended weekly drinking levels of 9 (women) and 14 (men) standard glasses.
Conclusions
Smartphone apps can make brief interventions available to large numbers of university students. The apps studied using eBAC calculation did not, however, seem to affect alcohol consumption among university students and one app may have led to a negative effect among men. Future research should: 1) explore ways to increase user retention, 2) include apps facilitating technical manipulation for evaluation of added components, 3) explore the effects of adapting app content to possible gender differences, and 4) offer additional interventions to high-risk users.
Trial registration
clinicaltrials.gov: NCT01958398.
doi:10.1186/1940-0640-9-11
PMCID: PMC4091647  PMID: 24985342
Randomized controlled trial; Problem drinking; Alcohol abuse; College; University; Smartphone; Mobile phone; eHealth; mHealth; Brief intervention
13.  Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance 
BMC Cancer  2013;13:374.
Background
Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells.
Methods
The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays.
Results
One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model.
Conclusions
The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance.
doi:10.1186/1471-2407-13-374
PMCID: PMC3751689  PMID: 23919498
Screening; Myeloma cell lines; Primary cultures; Drug resistance; Tubulin inhibition
14.  Interactive voice response - an automated follow-up technique for adolescents discharged from acute psychiatric inpatient care: a randomised controlled trial 
SpringerPlus  2013;2:146.
Follow-up methods must be easy for young people to handle. We examine Interactive Voice Response (IVR) as a method for collecting self-reported data. Sixty inpatients were recruited from a child and adolescent psychiatric emergency unit in Malmö, Sweden and called every second (N = 30) or every fourth (N = 30) day from discharge until first visit in outpatient care. A pre-recorded voice asked them to evaluate their current mood using their mobile phones. Average response rate was 91%, and 71% had a 100% response rate. Gender, age and length of inpatient treatment did not affect response rate, nor did randomisation. Boys estimated their current mood on average as 3.52 units higher than girls, CI = (2.65, 4.48). Automated IVR is a feasible method of collecting follow-up data among adolescents discharged from a psychiatric emergency unit.
doi:10.1186/2193-1801-2-146
PMCID: PMC3639352  PMID: 23641319
16.  Multiplexed Homogeneous Proximity Ligation Assays for High-throughput Protein Biomarker Research in Serological Material* 
Molecular & Cellular Proteomics : MCP  2011;10(4):M110.004978.
A high throughput protein biomarker discovery tool has been developed based on multiplexed proximity ligation assays in a homogeneous format in the sense of no washing steps. The platform consists of four 24-plex panels profiling 74 putative biomarkers with sub-pm sensitivity each consuming only 1 μl of human plasma sample. The system uses either matched monoclonal antibody pairs or the more readily available single batches of affinity purified polyclonal antibodies to generate the target specific reagents by covalently linking with unique nucleic acid sequences. These paired sequences are united by DNA ligation upon simultaneous target binding forming a PCR amplicon. Multiplex proximity ligation assays thereby converts multiple target analytes into real-time PCR amplicons that are individually quantified using microfluidic high capacity qPCR in nano liter volumes. The assay shows excellent specificity, even in multiplex, by its dual recognition feature, its proximity requirement, and most importantly by using unique sequence specific reporter fragments on both antibody-based probes. To illustrate the potential of this protein detection technology, a pilot biomarker research project was performed using biobanked plasma samples for the detection of colorectal cancer using a multivariate signature.
doi:10.1074/mcp.M110.004978
PMCID: PMC3069344  PMID: 21242282
17.  A strand specific high resolution normalization method for chip-sequencing data employing multiple experimental control measurements 
Background
High-throughput sequencing is becoming the standard tool for investigating protein-DNA interactions or epigenetic modifications. However, the data generated will always contain noise due to e.g. repetitive regions or non-specific antibody interactions. The noise will appear in the form of a background distribution of reads that must be taken into account in the downstream analysis, for example when detecting enriched regions (peak-calling). Several reported peak-callers can take experimental measurements of background tag distribution into account when analysing a data set. Unfortunately, the background is only used to adjust peak calling and not as a pre-processing step that aims at discerning the signal from the background noise. A normalization procedure that extracts the signal of interest would be of universal use when investigating genomic patterns.
Results
We formulated such a normalization method based on linear regression and made a proof-of-concept implementation in R and C++. It was tested on simulated as well as on publicly available ChIP-seq data on binding sites for two transcription factors, MAX and FOXA1 and two control samples, Input and IgG. We applied three different peak-callers to (i) raw (un-normalized) data using statistical background models and (ii) raw data with control samples as background and (iii) normalized data without additional control samples as background. The fraction of called regions containing the expected transcription factor binding motif was largest for the normalized data and evaluation with qPCR data for FOXA1 suggested higher sensitivity and specificity using normalized data over raw data with experimental background.
Conclusions
The proposed method can handle several control samples allowing for correction of multiple sources of bias simultaneously. Our evaluation on both synthetic and experimental data suggests that the method is successful in removing background noise.
doi:10.1186/1748-7188-7-2
PMCID: PMC3371767  PMID: 22248020
18.  Brunn: An open source laboratory information system for microplates with a graphical plate layout design process 
BMC Bioinformatics  2011;12:179.
Background
Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data.
Results
A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves.
Conclusions
Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.
doi:10.1186/1471-2105-12-179
PMCID: PMC3123236  PMID: 21599898
19.  Impaired Lysosomal Trimming of N-Linked Oligosaccharides Leads to Hyperglycosylation of Native Lysosomal Proteins in Mice with α-Mannosidosis ▿  
Molecular and Cellular Biology  2009;30(1):273-283.
α-Mannosidosis is caused by the genetic defect of the lysosomal α-d-mannosidase (LAMAN), which is involved in the breakdown of free α-linked mannose-containing oligosaccharides originating from glycoproteins with N-linked glycans, and thus manifests itself in an extensive storage of mannose-containing oligosaccharides. Here we demonstrate in a model of mice with α-mannosidosis that native lysosomal proteins exhibit elongated N-linked oligosaccharides as shown by two-dimensional difference gel electrophoresis, deglycosylation assays, and mass spectrometry. The analysis of cathepsin B-derived oligosaccharides revealed a hypermannosylation of glycoproteins in mice with α-mannosidosis as indicated by the predominance of extended Man3GlcNAc2 oligosaccharides. Treatment with recombinant human α-mannosidase partially corrected the hyperglycosylation of lysosomal proteins in vivo and in vitro. These data clearly demonstrate that LAMAN is involved not only in the lysosomal catabolism of free oligosaccharides but also in the trimming of asparagine-linked oligosaccharides on native lysosomal proteins.
doi:10.1128/MCB.01143-09
PMCID: PMC2798300  PMID: 19884343
20.  Cross-Cultural Patterns in College Student Drinking and its Consequences—A Comparison between the USA and Sweden 
Aims: The aim of the study was to compare alcohol use, consequences and common risk factors between American and Swedish college students. Methods: A secondary comparative analysis from one American and two Swedish studies in college settings. Results: Swedish freshmen report higher alcohol use than US freshmen students. Swedish residence hall students report higher alcohol use than US residence hall students, but lower than American fraternity/sorority members. US students were less likely to be drinkers. Controlling for age, country moderated the relationship between family history and harmful drinking scores for women (stronger in the USA), and between expectancies and harmful drinking scores for men (stronger in Sweden), though in both cases this represented a small effect and patterns were similar overall. Conclusions: Swedish students are at higher risk for alcohol use than US students, but similar patterns between aetiological predictors and outcomes in both countries suggest that research from the USA is generalizable to Swedish students and vice versa. More research is needed to better understand unique relationships associated with age and family history.
doi:10.1093/alcalc/agn055
PMCID: PMC2570849  PMID: 18593864
21.  Revealing cell cycle control by combining model-based detection of periodic expression with novel cis-regulatory descriptors 
BMC Systems Biology  2007;1:45.
Background
We address the issue of explaining the presence or absence of phase-specific transcription in budding yeast cultures under different conditions. To this end we use a model-based detector of gene expression periodicity to divide genes into classes depending on their behavior in experiments using different synchronization methods. While computational inference of gene regulatory circuits typically relies on expression similarity (clustering) in order to find classes of potentially co-regulated genes, this method instead takes advantage of known time profile signatures related to the studied process.
Results
We explain the regulatory mechanisms of the inferred periodic classes with cis-regulatory descriptors that combine upstream sequence motifs with experimentally determined binding of transcription factors. By systematic statistical analysis we show that periodic classes are best explained by combinations of descriptors rather than single descriptors, and that different combinations correspond to periodic expression in different classes. We also find evidence for additive regulation in that the combinations of cis-regulatory descriptors associated with genes periodically expressed in fewer conditions are frequently subsets of combinations associated with genes periodically expression in more conditions. Finally, we demonstrate that our approach retrieves combinations that are more specific towards known cell-cycle related regulators than the frequently used clustering approach.
Conclusion
The results illustrate how a model-based approach to expression analysis may be particularly well suited to detect biologically relevant mechanisms. Our new approach makes it possible to provide more refined hypotheses about regulatory mechanisms of the cell cycle and it can easily be adjusted to reveal regulation of other, non-periodic, cellular processes.
doi:10.1186/1752-0509-1-45
PMCID: PMC2200664  PMID: 17939860
22.  Bayesian detection of periodic mRNA time profiles without use of training examples 
BMC Bioinformatics  2006;7:63.
Background
Detection of periodically expressed genes from microarray data without use of known periodic and non-periodic training examples is an important problem, e.g. for identifying genes regulated by the cell-cycle in poorly characterised organisms. Commonly the investigator is only interested in genes expressed at a particular frequency that characterizes the process under study but this frequency is seldom exactly known. Previously proposed detector designs require access to labelled training examples and do not allow systematic incorporation of diffuse prior knowledge available about the period time.
Results
A learning-free Bayesian detector that does not rely on labelled training examples and allows incorporation of prior knowledge about the period time is introduced. It is shown to outperform two recently proposed alternative learning-free detectors on simulated data generated with models that are different from the one used for detector design. Results from applying the detector to mRNA expression time profiles from S. cerevisiae showsthat the genes detected as periodically expressed only contain a small fraction of the cell-cycle genes inferred from mutant phenotype. For example, when the probability of false alarm was equal to 7%, only 12% of the cell-cycle genes were detected. The genes detected as periodically expressed were found to have a statistically significant overrepresentation of known cell-cycle regulated sequence motifs. One known sequence motif and 18 putative motifs, previously not associated with periodic expression, were also over represented.
Conclusion
In comparison with recently proposed alternative learning-free detectors for periodic gene expression, Bayesian inference allows systematic incorporation of diffuse a priori knowledge about, e.g. the period time. This results in relative performance improvements due to increased robustness against errors in the underlying assumptions. Results from applying the detector to mRNA expression time profiles from S. cerevisiae include several new findings that deserve further experimental studies.
doi:10.1186/1471-2105-7-63
PMCID: PMC1413563  PMID: 16469110

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