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Forsberg, Pia
Publications (10 of 79) Show all publications
Gyllemark, P., Forsberg, P., Ernerudh, J. & Henningsson, A. J. (2017). Intrathecal Th17- and B cell-associated cytokine and chemokine responses in relation to clinical outcome in Lyme neuroborreliosis: a large retrospective study.. Journal of Neuroinflammation, 14(1)
Open this publication in new window or tab >>Intrathecal Th17- and B cell-associated cytokine and chemokine responses in relation to clinical outcome in Lyme neuroborreliosis: a large retrospective study.
2017 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, no 1Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: B cell immunity, including the chemokine CXCL13, has an established role in Lyme neuroborreliosis, and also, T helper (Th) 17 immunity, including IL-17A, has recently been implicated.

METHODS: We analysed a set of cytokines and chemokines associated with B cell and Th17 immunity in cerebrospinal fluid and serum from clinically well-characterized patients with definite Lyme neuroborreliosis (group 1, n = 49), defined by both cerebrospinal fluid pleocytosis and Borrelia-specific antibodies in cerebrospinal fluid and from two groups with possible Lyme neuroborreliosis, showing either pleocytosis (group 2, n = 14) or Borrelia-specific antibodies in cerebrospinal fluid (group 3, n = 14). A non-Lyme neuroborreliosis reference group consisted of 88 patients lacking pleocytosis and Borrelia-specific antibodies in serum and cerebrospinal fluid.

RESULTS: Cerebrospinal fluid levels of B cell-associated markers (CXCL13, APRIL and BAFF) were significantly elevated in groups 1, 2 and 3 compared with the reference group, except for BAFF, which was not elevated in group 3. Regarding Th17-associated markers (IL-17A, CXCL1 and CCL20), CCL20 in cerebrospinal fluid was significantly elevated in groups 1, 2 and 3 compared with the reference group, while IL-17A and CXCL1 were elevated in group 1. Patients with time of recovery <3 months had lower cerebrospinal fluid levels of IL-17A, APRIL and BAFF compared to patients with recovery >3 months.

CONCLUSIONS: By using a set of markers in addition to CXCL13 and IL-17A, we confirm that B cell- and Th17-associated immune responses are involved in Lyme neuroborreliosis pathogenesis with different patterns in subgroups. Furthermore, IL-17A, APRIL and BAFF may be associated with time to recovery after treatment.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-134633 (URN)10.1186/s12974-017-0789-6 (DOI)000397149000001 ()28148307 (PubMedID)
Note

Funding agencies: Medical Research Council of Southeast Sweden (FORSS); Futurum-the Academy for Health and Care; Division of Medical Services, Region Jonkoping County; EU-Interreg project ScandTick Innovation

Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2018-04-18
Wilhelmsson, P., Fryland, L., Lindblom, P., Sjöwall, J., Ahlm, C., Berglund, J., . . . Lindgren, P.-E. (2016). A prospective study on the incidence of Borrelia infection after a tick bite in Sweden and on the Åland Islands, Finland (2008-2009). Ticks and Tick-borne Diseases, 7(1), 71-79
Open this publication in new window or tab >>A prospective study on the incidence of Borrelia infection after a tick bite in Sweden and on the Åland Islands, Finland (2008-2009)
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2016 (English)In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 7, no 1, p. 71-79Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis (LB) is a common and increasing tick-borne disease in Europe. The risk of acquiring a Borrelia infection after a tick bite is not fully known. Therefore, we investigated the incidence of Borrelia infection after a tick bite and if the Borrelia load and/or the duration of tick-feeding influenced the risk of infection. During 2008-2009, ticks and blood samples were collected from 1546 tick-bitten persons from Sweden and the Åland Islands, Finland. Follow-up blood samples were taken three months after the tick bite. The duration of tick feeding was microscopically estimated and Borrelia was detected and quantified in ticks by real-time PCR. Anti-Borrelia antibodies were detected in sera using ELISA assays and immunoblot.

Even though 28 % of the participants were bitten by a Borrelia-positive tick, only 7.5% (32/428) of them developed a Borrelia infection, half of them LB. All who seroconverted removed “their” ticks significantly later than those who did not. The Borrelia load in the ticks did not explain the risk of seroconversion. Regional as well as gender differences in the Borrelia seroprevalence were found. The risk of developing a Borrelia infection after a bite by a Borrelia-infected tick is small but increases with the duration of tick feeding.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
Borrelia burgdorferi sensu lato; tick bite; incidence of infection; Lyme borreliosis; asymptomatic infection; bacterial load; tick-feeding.
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-105475 (URN)10.1016/j.ttbdis.2015.08.009 (DOI)000366953400012 ()
Note

Funding agencies: Swedish Research Council Branch of Medicine [K2008-58X-14631-06-3]; Medical Research Council of South-East Sweden [FORSS-8967, FORSS-12573, FORSS-29021, FORSS-86911]; EU Interreg IV A project ScandTick [167226]; County Council of Ostergotland [LIO-56191];

Available from: 2014-03-25 Created: 2014-03-25 Last updated: 2017-05-03Bibliographically approved
Johansson, J., Sahin, C., Pestoff, R., Ignatova, S., Forsberg, P., Edsjö, A., . . . Stenmark Askmalm, M. (2015). A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia.. Case Reports in Gastrointestinal Medicine, 2015, 1-5, Article ID 140616.
Open this publication in new window or tab >>A Novel SMAD4 Mutation Causing Severe Juvenile Polyposis Syndrome with Protein Losing Enteropathy, Immunodeficiency, and Hereditary Haemorrhagic Telangiectasia.
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2015 (English)In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2015, p. 1-5, article id 140616Article in journal (Refereed) Published
Abstract [en]

Juvenile polyposis syndrome (JPS) is a rare genetic disorder characterized by juvenile polyps of the gastrointestinal tract. We present a new pathogenic mutation of the SMAD4 gene and illustrate the need for a multidisciplinary health care approach to facilitate the correct diagnosis. The patient, a 47-year-old Caucasian woman, was diagnosed with anaemia at the age of 12. During the following 30 years, she developed numerous gastrointestinal polyps. The patient underwent several operations, and suffered chronic abdominal pain, malnutrition, and multiple infections. Screening of the SMAD4 gene revealed a novel, disease-causing mutation. In 2012, the patient suffered hypoalbuminemia and a large polyp in the small bowel was found. Gamma globulin was given but the patient responded with fever and influenza-like symptoms and refused more treatment. The patient underwent surgery in 2014 and made an uneventful recovery. At follow-up two months later albumin was 38 g/L and IgG was 6.9 g/L. Accurate diagnosis is essential for medical care. For patients with complex symptomatology, often with rare diseases, this is best provided by multidisciplinary teams including representatives from clinical genetics. Patients with a SMAD4 mutation should be followed up both for JPS and haemorrhagic hereditary telangiectasia and may develop protein loosing enteropathy and immunodeficiency.

National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-115933 (URN)10.1155/2015/140616 (DOI)25705527 (PubMedID)
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2017-12-04
Grankvist, A., Labbe Sandelin, L., Andersson, J., Fryland, L., Wilhelmsson, P., Lindgren, P.-E., . . . Wenneras, C. (2015). Infections with Candidatus Neoehrlichia mikurensis and Cytokine Responses in 2 Persons Bitten by Ticks, Sweden. Emerging Infectious Diseases, 21(8), 1462-1465
Open this publication in new window or tab >>Infections with Candidatus Neoehrlichia mikurensis and Cytokine Responses in 2 Persons Bitten by Ticks, Sweden
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2015 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 21, no 8, p. 1462-1465Article in journal (Refereed) Published
Abstract [en]

The prevalence of Candidatus Neoehrlichia mikurensis infection was determined in 102 persons bitten by ticks in Sweden. Two infected women had erythematous rashes; 1 was co-infected with a Borrelia sp., and the other showed seroconversion for Anaplasma phagocytophilum. Both patients had increased levels of Neoehrlichia DNA and serum cytokines for several months.

Place, publisher, year, edition, pages
Centers for Disease Control and Prevention, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120731 (URN)10.3201/eid2108.150060 (DOI)000358458300031 ()26197035 (PubMedID)
Note

Funding Agencies|ALF-Goteborg [71580]; Cancer and Allergy Foundation [149781]; Vastra Gotaland Region Research and Development [94510]; Laboratory Medicine at Sahlgrenska University Hospital [6333]; Medical Research Council of South-East Sweden [FORSS-297311, FORSS-307591, FORSS-87231]; Swedish Research Council/Medicine [2011-345]; ALF-Ostergotland

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2017-12-04
Henningsson, A. J., Wilhelmsson, P., Gyllemark, P., Kozak Ljunggren, M., Matussek, A., Nyman, D., . . . Forsberg, P. (2015). Low risk of seroconversion or clinical disease in humans after a bite by an Anaplasma phagocytophilum-infected tick. Ticks and Tick-borne Diseases, 6(6), 787-792
Open this publication in new window or tab >>Low risk of seroconversion or clinical disease in humans after a bite by an Anaplasma phagocytophilum-infected tick
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2015 (English)In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 6, no 6, p. 787-792Article in journal (Refereed) Published
Abstract [en]

The risk of contracting human granulocytic anaplasmosis (HGA) after a tick bite is mainly unknown. In this study we investigated the clinical and serological response in 30 humans bitten by ticks positive for Anaplasma phagocytophilum (Group A), 30 humans bitten by Borrelia burgdorferi sensu lato (s.l.)-positive ticks (Group B), and 30 humans bitten by ticks negative for both A. phagocytophilum and B. burgdorferi s.l. (Group C). Ticks, blood samples and questionnaires were collected from tick-bitten humans at 34 primary healthcare centres in Sweden and in the Åland Islands, Finland, at the time of the tick bite and after three months. A total of 2553 ticks detached from humans in 2007-2009 were analyzed by polymerase chain reaction, and 31 (1.2%) were positive for A. phagocytophilum, 556 (21.8%) were positive for B. burgdorferi s.l., and eight (0.3%) were co-infected by A. phagocytophilum and B. burgdorferi s.l. The overall prevalence of Anaplasma IgG antibodies in the included participants (n=90) was 17%, and there was no significant difference between the groups A-C. Only one of the participants (in Group C) showed a four-fold increase of IgG antibodies against A. phagocytophilum at the three-month follow-up, but reported no symptoms. The frequency of reported symptoms did not differ between groups A-C, and was unrelated to the findings of A. phagocytophilum and B. burgdorferi s.l. in the detached ticks. We conclude that the risk for HGA or asymptomatic seroconversion after a tick bite in Sweden or in the Åland Islands is low, even if the tick is infected by A. phagocytophilum.

Place, publisher, year, edition, pages
Elsevier, 2015
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-122245 (URN)10.1016/j.ttbdis.2015.07.005 (DOI)000362143800015 ()26187418 (PubMedID)
Note

Funding text: Swedish Research Council; Medical Research Council of Southeast Sweden (FORSS); Futurum Academy of Healthcare; Jonkoping County Council; Interreg IV A Programme ScandTick; Division of Medical Services, Ryhov County Hospital, Jonkoping

Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2018-01-10
Dessau, R. B., Fryland, L., Wilhelmsson, P., Ekerfelt, C., Nyman, D., Forsberg, P. & Lindgren, P.-E. (2015). Study of a Cohort of 1,886 Persons To Determine Changes in Antibody Reactivity to Borrelia burgdorferi 3 Months after a Tick Bite. Clinical and Vaccine Immunology, 22(7), 823-827
Open this publication in new window or tab >>Study of a Cohort of 1,886 Persons To Determine Changes in Antibody Reactivity to Borrelia burgdorferi 3 Months after a Tick Bite
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2015 (English)In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 22, no 7, p. 823-827Article in journal (Refereed) Published
Abstract [en]

Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi. The most frequent clinical manifestation is a rash called erythema migrans. Changes in antibody reactivity to B. burgdorferi 3 months after a tick bite are measured using enzyme-linked immunosorbent assays (ELISAs). One assay is based on native purified flagellum antigen (IgG), and the other assay is based on a recombinant antigen called C6 (IgG or IgM). Paired samples were taken at the time of a tick bite and 3 months later from 1,886 persons in Sweden and the Åland Islands, Finland. The seroconversion or relative change is defined by dividing the measurement units from the second sample by those from the first sample. The threshold for the minimum level of significant change was defined at the 2.5% level to represent the random error level. The thresholds were a 2.7-fold rise for the flagellar IgG assay and a 1.8-fold rise for the C6 assay. Of 1,886 persons, 102/101 (5.4%) had a significant rise in antibody reactivity in the flagellar assay or the C6 assay. Among 40 cases with a diagnosis of Lyme borreliosis, the sensitivities corresponding to a rise in antibodies were 33% and 50% for the flagellar antigen and the C6 antigen, respectively. Graphical methods to display the antibody response and to choose thresholds for a rise in relative antibody reactivity are shown and discussed. In conclusion, 5.4% of people with tick bites showed a rise in Borrelia-specific antibodies above the 2.5% threshold in either ELISA but only 40 (2.1%) developed clinical Lyme borreliosis.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-120003 (URN)10.1128/CVI.00026-15 (DOI)000356863200016 ()25994550 (PubMedID)
Available from: 2015-07-02 Created: 2015-07-02 Last updated: 2017-10-31
Nordberg, M., Forsberg, P., Berglund, J., Bjöersdorff, A., Ernerudh, J., Garpmo, U., . . . Eliasson, I. (2014). Aetiology of Tick-Borne Infections in an Adult Swedish Population—Are Co-Infections with Multiple Agents Common?. Open Journal of Clinical Diagnostics, 4(1), 31-40
Open this publication in new window or tab >>Aetiology of Tick-Borne Infections in an Adult Swedish Population—Are Co-Infections with Multiple Agents Common?
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2014 (English)In: Open Journal of Clinical Diagnostics, ISSN 2162-5816, E-ISSN 2162-5824, Vol. 4, no 1, p. 31-40Article in journal (Refereed) Published
Abstract [en]

In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria; 1) patients with unspecific symptoms, i.e. fever (≥38.0℃) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM), following an observed tick bite or tick exposure within one month prior to onset of symptoms. A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical co-infection with Anaplasma phagocytophilum, based on serology. Both TBE cases had co-infections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.

Place, publisher, year, edition, pages
Scientific Research Publishing, 2014
Keywords
Epidemiology, Tick-Borne Infections, Tick-Borne Encephalitis, Lyme Borreliosis, Human Granulocytic Anaplasmosis
National Category
Health Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-109614 (URN)10.4236/ojcd.2014.41007 (DOI)
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2017-12-05Bibliographically approved
Hedin Skogman, B., Forsberg, P., Vene, S. & Åkerlind, B. (2014). Are There Undiagnosed TBE-, Herpes- or Enteroviral Infections among Children Being Evaluated for Lyme Neuroborreliosis?. Open Journal of Clinical Diagnostics, 4(3), 123-129
Open this publication in new window or tab >>Are There Undiagnosed TBE-, Herpes- or Enteroviral Infections among Children Being Evaluated for Lyme Neuroborreliosis?
2014 (English)In: Open Journal of Clinical Diagnostics, ISSN 2162-5816, E-ISSN 2162-5824, Vol. 4, no 3, p. 123-129Article in journal (Refereed) Published
Abstract [en]

Lyme neuroborreliosis (LNB) in children is a challenging diagnosis based on clinical manifestations and laboratory findings. The aim of this study was to investigate whether herpes simplex virus (HSV) 1 or 2, varicella zoster virus (VZV), enterovirus or tick-borne encephalitis virus (TBEV) could be identified in cerebrospinal fluid (CSF) or serum from children being evaluated for LNB, in order to elucidate whether such infectious diseases may be missed by the clinician. Methods: Ninety-nine pediatric patients (n = 99) were retrospectively included from a previous study on LNB in southeast of Sweden. They had been diagnosed as “Possible LNB” or “Not determined” due to negative Borrelia antibody index in CSF. Routine polymerase chain reaction (PCR) methods were used for detection of herpes viral RNA or enteroviral DNA in CSF. An ELISA assay was used for detection of anti-TBEV antibodies (IgM and IgG) in serum. Results: One patient showed elevated anti-TBEV IgM and IgG antibodies in serum, indicating a current TBE infection. No positive PCR reactions for HSV 1 or 2, VZV or enterovirus were detected in CSF from any of the patients. In conclusion, our results suggest that undiagnosed herpes- or enteroviral infections are unlikely to explain CNS symptoms in children being evaluated for LNB, whereas missed TBE infections may occur. TBEV serology should be included when evaluating children for LNB in TBE endemic areas.

Place, publisher, year, edition, pages
Scientific Research Publishing, 2014
Keywords
Enterovirus, Herpes Simplex Virus, Lyme Neuroborreliosis, Varicella Zoster Virus, Tick-Borne Encephalitis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-110996 (URN)10.4236/ojcd.2014.43020 (DOI)
Available from: 2014-10-02 Created: 2014-10-02 Last updated: 2017-12-05
Lindblom, P., Wilhelmsson, P., Fryland, L., Matussek, A., Haglund, M., Sjöwall, J., . . . Lindgren, P.-E. (2014). Determining factors for successful vaccination against tick-borne encephalitis virus in older individuals.
Open this publication in new window or tab >>Determining factors for successful vaccination against tick-borne encephalitis virus in older individuals
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

We performed a cross-sectional study including 533 persons (median age 61) from the highly TBE endemic Åland Islands in the archipelago between Sweden and Finland. Blood samples, questionnaires and vaccination records were obtained from all study participants. The aim was to investigate if there was any association between TBEV antibody titer and 14 healthrelated factors: [age, gender, number of vaccine doses (0-5), time since last vaccine dose, previous TBE disease, vaccination against other flaviviruses, ≥2 tick-bites during the previous 3 months, pet-ownership, asthma, smoking, allergy, diabetes, medication, and previous tumor]. Measurement of TBEV IgG antibodies was performed using two commercial ELISA assays (Enzygnost and Immunozym), and a third in-house rapid fluorescent focus inhibition test was used to measure TBEV neutralizing antibodies. The age of the person and the number of vaccine doses were the two most important factors determining successful vaccination. The response to each vaccine dose declined linearly with increased age. A 35 year age difference corresponds to a vaccine dose increment from 3 to 4 to achieve the same response. Participants receiving medication and participants previously vaccinated against other flaviviruses had lower TBEV antibody titers on average, while those with self-reported asthma had higher titers. By comparing the 3 serological assays we show that the Enzygnost and Immunozym assay differ due to choice of cutoffs, but not in overall accuracy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105919 (URN)
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2014-04-14Bibliographically approved
Sandholm, K., Henningsson, A. J., Säve, S., Bergström, S., Forsberg, P., Jonsson, N., . . . Ekdahl, K. N. (2014). Early cytokine release in response to live Borrelia burgdorferi Sensu Lato Spirochetes is largely complement independent. PloS one, 9(9), e108013
Open this publication in new window or tab >>Early cytokine release in response to live Borrelia burgdorferi Sensu Lato Spirochetes is largely complement independent
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2014 (English)In: PloS one, ISSN 1932-6203, Vol. 9, no 9, p. e108013-Article in journal (Refereed) Published
Abstract [en]

AIM: Here we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78, which is resistant to complement-mediated lysis, and Borrelia garinii LU59, which is complement-sensitive.

METHODS: Borrelia spirochetes were incubated in hirudin plasma, or hirudin-anticoagulated whole blood. Complement activation was measured as the generation of C3a and sC5b-9. Binding of the complement components C3, factor H, C4, and C4BP to the bacterial surfaces was analyzed. The importance of complement activation on phagocytosis, and on the release of cytokines and chemokines, was investigated using inhibitors acting at different levels of the complement cascade.

RESULTS: 1) Borrelia garinii LU59 induced significantly higher complement activation than did Borrelia afzelii K78. 2) Borrelia afzelii K78 recruited higher amounts of factor H resulting in significantly lower C3 binding. 3) Both Borrelia strains were efficiently phagocytized by granulocytes and monocytes, with substantial inhibition by complement blockade at the levels of C3 and C5. 4) The release of the pro-inflammatory cytokines and chemokines IL-1β, IL-6, TNF, CCL20, and CXCL8, together with the anti-inflammatory IL-10, were increased the most (by>10-fold after exposure to Borrelia). 5) Both strains induced a similar release of cytokines and chemokines, which in contrast to the phagocytosis, was almost totally unaffected by complement blockade.

CONCLUSIONS: Our results show that complement activation plays an important role in the process of phagocytosis but not in the subsequent cytokine release in response to live Borrelia spirochetes.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-112749 (URN)10.1371/journal.pone.0108013 (DOI)000345745400038 ()25265036 (PubMedID)
Available from: 2014-12-12 Created: 2014-12-12 Last updated: 2015-10-09
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