| 1. |
- Henningsson, Anna J, 1972-
(författare)
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Clinical, epidemiological and immunological aspects of Lyme borreliosis with special focus on the role of the complement system
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lyme borreliosis (LB) is the most common vector-borne disease in the Northern Hemisphere. The infection is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and it is transmitted to humans by ticks. LB is associated with several clinical manifestations, of which erythema migrans (EM) and neuroborreliosis (NB) are the most common inEurope. The course of the disease is usually benign, but can vary between individuals. The underlying pathogenic mechanisms are not fully understood, but the prognosis is probably determined by a complex interplay between the bacteria and the host’s immune response. Previous studies have indicated that a strong initial T helper (Th) 1-response followed by a Th2 response is beneficial for the clinical outcome in LB.The aims of this thesis were to follow the incidence of NB inJönköping County,Sweden, over time, to search for clinical and laboratory markers associated with the risk of developing long-lasting post-treatment symptoms, and to explore the role of the complement system as well as the relative balance between Th-associated cytokine/chemokine responses in LB.The number of NB cases, diagnosed by cerebrospinal fluid (CSF) analysis, increased from 5 to 10/100,000 inhabitants/year in Jönköping County during 2000-2005. Post-treatment symptoms persisting more than 6 months occurred in 13 %, and were associated with higher age, longer-lasting symptoms prior to treatment, higher levels of Borrelia-specific IgG in CSF, and reported symptoms of radiculitis. Facial palsy, headache and fever were frequent manifestations in children, whereas unspecific muscle and joint pain were the most commonly reported symptoms in older patients.Complement activation occurred both locally in the skin in EM and in CSF of NB patients. However, no activation could be detected in blood in NB patients. Elevated levels of C1q, C4 and C3a in CSF, along with correlation between C1q and C3a levels, suggest complement activation via the classical pathway locally in the central nervous system in NB. In vitro experiments with two clinical Borrelia isolates revealed that B. garinii LU59 induced higher complement activation in human plasma compared to B. afzelii K78 that recruited more of complement regulator factor H. To elucidate the role of complement in the phagocytosis process, experiments were performed using whole blood from healthy donors incubated with fluorescence-labelled spirochetes and different complement inhibitors. The results illustrated a central role of complement for phagocytosis of Borrelia spirochetes.We also studied the relative contribution of different Th-associated cytokines/chemokine responses in NB. The results support the notion that early NB is dominated by a Th1 response, eventually accompanied by a Th2 response. IL-17A was increased in CSF in half of the patients with confirmed NB, suggesting a hitherto unknown role of Th17 in NB.In conclusion, the risk of developing long-lasting post-treatment symptoms tend to increase mainly with age and duration of symptoms prior to treatment in NB. The complement system seems to play an important role in host defence to recognize and kill Borrelia spirochetes. However, complement activation in inappropriate sites or to an excessive degree may cause tissue damage, and therefore, the role of complement in relation to disease course needs to be studied further. Likewise, the role of Th17 in LB pathogenesis and host defence should be further evaluated in prospective studies.
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| 2. |
- Labbé Sandelin, Lisa, 1977-
(författare)
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Neoehrlichia mikurensis in Sweden : An emerging tick-borne human pathogen
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neoehrlichia mikurensis is an emerging tick-borne human pathogen, causing neoehrlichiosis in immunosuppressed and immunocompetent individuals. It targets the vascular endothelium, leading to thromboembolic and vascular events, but can also pass without symptoms. As symptoms easily are misinterpreted, immunosuppressive treatment or chemotherapy is often incorrectly initiated. Diagnostic delay can be considerable.The overall aim of this thesis was to gain a better understanding on N. mikurensis in Sweden, focusing on human infections and public health aspects. The prevalence of N. mikurensis in different populations was examined. The symptomatology of neoehrlichiosis and the risk of transfusion-mediated transmission was studied. N. mikurensis was observed in low prevalences in ticks collected from migratory birds, in tick-bitten individuals, in patients with persistent symptoms attributed to presumed tick-bite exposure, and in blood donors. Fourteen N. mikurensis-positive individuals were identified. The majority were immunocompetent and asymptomatic. Both spontaneous clearance and persistence was observed. Two of 102 tick-bitten individuals were N. mikurensis-positive. Both presented with erythema migrans, but borreliosis was a more probable cause in both. The findings do not support a change in practice regarding first-line treatment of erythema migrans, but further studies are warranted.Persistence of N. mikurensis in blood raises questions regarding the possibility of transmission by transfusion and the risk of activating the infection if immune status is altered. N. mikurensis was identified in seven out of 1 006 blood donors. Look-back and tracing identified 12 recipients who were transfused with blood components from N. mikurensis-positive donors. Several recipients had multiple risk factors for severe neoehrlichiosis, but transfusion-transmitted neoehrlichiosis was not detected. Nevertheless, the possibility that N. mikurensis can be transmitted by transfusion cannot be excluded.Isolates from birds and blood donors were identical to previously reported Swedish human isolates. Migrating birds can act as dispersal vectors of N. mikurensis, but their role as transmission hosts is still unclear.The disease burden and public health impact of neoehrlichiosis is probably small, but information is lacking in several areas. Suspicion of neoehrlichiosis is warranted in immunocompromised and/or splenectomised patients with persistent fever, with or without thromboembolic and vascular events. Furthermore, neoehrlichiosis should be included in the differential diagnosis of anaplasmosis. Besides raised awareness, a possible mandatory notification is proposed as well as a comprehensive surveillance system for transfusion-transmitted infections. One of the priority issues is the possible need for screening of patients living in N. mikurensis-endemic areas before and during immunosuppressive treatment.
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| 3. |
- Philipson, Anna, 1978-
(författare)
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Health economic aspects of emotional problems and pain symptoms in childhood and adolescence : Long-term outcomes, efficacy and cost-effectiveness of interventions
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Emotional problems and pain symptoms among children and adolescents are a global public health challenge that imposes a great burden on the individuals affected and on society. Because resources are limited, allocation and prioritization are needed. Health economic analysis can constitute a foundation for such decisions.The overall aim of this thesis is to estimate long-term outcomes associated with adolescent depression and to evaluate interventions for emotional problems and pain symptoms in childhood and adolescence from a health economic perspective. The thesis is based on four papers: paper I is a longitudinal cohort study of 539 participants, showing that adolescent depression is associated with reduced earnings in adulthood, papers II, III, and IV are based on two randomized controlled trials of interventions. In paper II, a dance intervention for 112 adolescent females with internalizing symptoms were evaluated. A cost–utility analysis was performed, indicating that the intervention was costeffective given a willingness-to-pay threshold of USD 50,000 with an incremental cost-effectiveness ratio of USD 3830/quality-adjusted life year. Papers III and IV evaluated a dance and yoga intervention for 121 girls, 9–13 years old, with functional abdominal pain disorders. Paper III showed that the intervention group decreased their abdominal pain more than did the control group. In paper IV, the cost–utility analysis of the trial indicated a negative incremental cost-effectiveness ratio, investigated from a societal perspective, over both one and ten years.In conclusion, this thesis identifies a need for preventive as well as treatment interventions for emotional problems in adolescence, to decrease the prevalence of emotional problems and mitigate negative outcomes. Dance or dance and yoga combined can be effective and cost-effective early treatment interventions for emotional problems and pain symptoms among females in childhood and adolescence. These findings may assist decision-makers in resource allocation within this area
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| 4. |
- Hagberg, Niklas, 1977-
(författare)
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The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, which can eventually lead to immune complex (IC)-mediated organ damage. Due to the stimulation of plasmacytoid dendritic cells (pDC) by nucleic acid-containing ICs (DNA- or RNA-IC), patients with SLE have an ongoing interferon (IFN)-α production. IFN-α induces a general activation of the immune system that may initiate or propagate an autoimmune process if not properly regulated. Previous studies have shown that natural killer (NK) cells potently enhance the IFN-α production by pDCs.In study I, the mechanisms behind the NK cell-mediated increased IFN-α production by RNA-IC-stimulated pDCs were investigated. ICs triggered CD56dim NK cells via FcγRIIIA to the secretion of cytokines (e.g. MIP-1β) that promoted IFN-α production. Additionally, an LFA-1-dependent cell-cell interaction between pDCs and NK cells strongly contributed to the increased production of IFN-α. In study II, the RNA-IC-induced regulation of surface molecules on pDCs and NK cells was investigated. The expression of CD319 and CD229, which are two SLAM family receptors genetically associated with SLE, was induced on pDCs and NK cells by RNA-IC. IFN-α-producing pDCs displayed an increased expression of CD319 and CD229, whereas pDCs from patients with SLE had a decreased expression of CD319. In study III, we serendipitously identified an SLE patient harboring autoantibodies to the NK cell receptor CD94/NKG2A. In study IV, sera from 203 patients with SLE were analyzed for autoantibodies to the CD94/NKG2A, CD94/NKG2C and NKG2D receptors. Seven patients harbored anti-CD94/NKG2A autoantibodies, and two of these patient’s autoantibodies also reacted with CD94/NKG2C. Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with the HLA-E-mediated regulation of NK cell cytotoxicity, and facilitated the elimination of target cells expressing these receptors. Furthermore, these autoantibodies were found in a group of severely diseased SLE patients and their titers closely followed disease activity.In conclusion, this thesis provides insights to molecular mechanisms whereby NK cells regulate the IFN-α production, it further links the SLAM receptors to SLE, and it describes novel autoantibodies to receptors regulating NK cell cytotoxicity. Together these findings strengthen the assumption that NK cells are involved in the pathogenesis of SLE.
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| 5. |
- Ljunghill Hedberg, Anna, 1972-
(författare)
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Impact of the inflammatory response on specific immunity in neurosurgical patients
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vaccination with a T-cell-dependent pneumococcal conjugate vaccine (PCV) followed by a T-cell-independent pneumococcal polysaccharide vaccine (PPSV) is recommended after basilar skull fracture to reduce the risk of meningitis. The optimal time frame for vaccination has not yet been established and varies widely in practice. Because the risk of meningitis is at its peak shortly after the trauma incident, early vaccination might be more desirable. After trauma and central nervous system (CNS) injury, T-cell defects leading to trauma and CNS injury-induced immune deficiency syndromes may affect the vaccine response. In light of the above information, the overall aim of this thesis was to investigate the impact of neurotrauma and neurosurgery on the response to T-cell-dependent and T-cell-independent vaccines.In Paper I, we compared the antibody response to a T-cell-dependent conjugate vaccine in patients vaccinated within 10 days after neurotrauma or neurosurgery with those vaccinated after >3 weeks. To avoid interference with pneumococcal vaccination, a conjugate vaccine against Haemophilus influenzae type b (Hib) was chosen for the study. The majority of the patients responded to the vaccination, although the number of responders was significantly lower in patients vaccinated early.In Paper II, we investigated the antibody response to the T-cell-independent vaccine PPSV in patients vaccinated within 10 days after neurotrauma or neurosurgery and in patients vaccinated after >3 weeks. Patients vaccinated early responded similarly to those vaccinated after the acute period, indicating that PPSV can be administered early after neurotrauma or neurosurgery.In Paper III, we compared the response to Hib vaccine with the response to PPSV. We also examined whether individual clinical or immunological parameters might predict the response to T-cell-dependent vaccine and thereby help identify non-responders before vaccination. No correlation between Hib vaccine and PPSV responses was found, indicating that B-cell function is not similarly depressed as T-cell function. It was not possible to predict the T-cell-dependent vaccine response by standardized grading of the trauma or by parameters reflecting the innate immune response.In Paper IV, we found a significant reduction in the ex vivo CD4+ T-lymphocyte response to PCV in patients after neurotrauma or neurosurgery as compared with healthy controls.Our results suggest that PPSV might be a viable alternative to T-cell-dependent PCV in early vaccination after neurotrauma.
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| 6. |
- Duberg, Anna, 1976-
(författare)
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Dance Intervention for Adolescent Girls with Internalizing Problems : Effects and Experiences
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Globally, psychological health problems are currently among the most serious public health challenges. Adolescent girls suffer from internalizing problems, such as somatic symptoms and mental health problems, at higher rates than in decades. By age 15, over 50 % of all girls experience multiple health complaints more than once a week and one in five girls reports fair or poor health.The overall aim of this study was to investigate the effects of and experiences with an after-school dance intervention for adolescent girls with internalizing problems. The intervention comprised dance that focused on resources twice weekly for 8 months. Specifically, this thesis aimed to: I) investigate the effects on self-rated health (SRH), adherence and over-all experience; II) evaluate the effects on somatic symptoms, emotional distress and use of medication; III) explore the experiences of those participating in the intervention; and IV) assess the cost-effectiveness.A total of 112 girls aged 13 to 18 years were included in a randomized controlled trial. The dance intervention group comprised 59 girls, and the control group 53. In paper I, the dance group showed increased SRH scores compared to the control group (p = .02). Girls in the intervention group showed high adherence and a positive overall experience. In paper II, the dance group exhibited a decrease in somatic symptoms (p = .021), emotional distress (p = .023) and use of medication (p = .020) compared to the control group. In paper III, a strategic sample of 24 girls was interviewed. Qualitative content analysis was performed, and five generic categories emerged. Two were “An Oasis from Stress” and “Supportive Togetherness”, which was shown to represent the fundamental basis and setting of the intervention. The main category, participants’ central experience, was understood as “Finding embodied self-trust that opens new doors”. Paper IV revealed that, due to decreased number of visits to the school nurse and an increase in health related quality of life; the intervention was considered to be cost-effective (combined with the usual school health services). In summary, the results of this thesis show that this dance intervention for adolescent girls with internalizing problems generated positive health effects and proved to be cost-effective. For this target group, a non-judgmental environment and supportive togetherness proved to be of importance for participation. The results of this study may provide practical information for school health care staff and caregivers in designing future interventions.
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| 7. |
- Ssegonja, Richard, et al.
(författare)
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Depressive disorders in adolescence, recurrence in early adulthood, and healthcare usage in mid-adulthood : A longitudinal cost-of-illness study
- 2019
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Ingår i: Journal of Affective Disorders. - : ELSEVIER. - 0165-0327 .- 1573-2517. ; 258, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depression in adolescence is associated with increased healthcare consumption in adulthood, but prior research has not recognized the heterogeneity of depressive disorders. This paper investigated the additional healthcare usage and related costs in mid-adulthood for individuals with adolescent depression, and examined the mediating role of subsequent depression in early adulthood.Methods: This study was based on the Uppsala Longitudinal Adolescent Depression Study, initiated in Sweden in the early 1990s. Depressive disorders were assessed in adolescence (age 16-17) and early adulthood (age 19-30). Healthcare usage and related costs in mid-adulthood (age 31-40) were estimated using nationwide population-based registries. Participants with specific subtypes of adolescent depression (n = 306) were compared with matched non-depressed peers (n = 213).Results: Women with persistent depressive disorder (PDD) in adolescence utilized significantly more healthcare resources in mid-adulthood. The association was not limited to psychiatric care, and remained after adjustment for individual and parental characteristics. The total additional annual cost for a single age group of females with a history of PDD at a population level was estimated at 3.10 million USD. Depression recurrence in early adulthood mediated the added costs for psychiatric care, but not for somatic care.Limitations: Primary health care data were not available, presumably resulting in an underestimation of the true healthcare consumption. Estimates for males had limited precision due to a relatively small male proportion.Conclusions: On a population level, the additional healthcare costs incurred in mid-adulthood in females with a history of adolescent PDD are considerable. Early treatment and prevention should be prioritized.
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| 8. |
- Israelsson, Charlotte, 1969-
(författare)
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Molecular Characterization of Experimental Traumatic Brain Injury
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Traumatic brain injury (TBI) is the most common cause of mortality and disability in the younger (<50 years) Swedish population with an incidence rate of 20,000 cases per year. This thesis aims to increase the understanding of brain injury mechanisms, especially in a molecular and cellular context. Bone morphogenetic protein (BMP) signalling was examined in three genetically modified mice (two “loss-of-function”, one “gain-of-function”) exposed to TBI (controlled cortical impact, CCI) with CaMKII used as promoter for Cre-driven recombination in postnatal forebrain neurons. The mice survived, developed normally and did not show any obvious phenotypes except for an upregulation in Mtap2 mRNA in mice with impaired BMP signalling. Reactive Gfap and Timp1 mRNA expression measured using quantitative RT-PCR (qRT-PCR) was reduced in the mice overexpressing BMP signals. The BMP signalling pathway was further studied in cultured PC12 cells with BMP4 and NGF added. Egr3 expression was substantially increased by these growth factors. Blocking Egr or Junb functions reduced neurite outgrowth. TBI-induced mRNA expression changes in 100 selected genes in C57BL/6J mouse neocortex and hippocampus were measured using qRT-PCR at different time points post-injury. Several distinct gene clusters with similar expression patterns were identified. GeneChip analysis (Affymetrix) of the injured mouse neocortex at three days revealed 146 transcripts significantly upregulated, confirming and extending the qRT-PCR results. The findings demonstrate marked increases after injury among chemokine transcripts and activation of many genes involved in inflammation. In conclusion, the present study has revealed transcriptional changes in specific signalling pathways after brain injury. The results may help to identify novel targets for neuroprotective interventions after traumatic brain injury.
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| 9. |
- Jansson, Markus, 1982-, et al.
(författare)
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Cost-effectiveness of antibiotic prophylaxis in elective cesarean section
- 2018
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Ingår i: Cost Effectiveness and Resource Allocation. - : BMC. - 1478-7547. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: The proportion of pregnant women delivered by cesarean section has increased steadily during the past three decades. The risk of infection is 10-fold augmented after elective cesarean section compared to vaginal delivery. Antibiotic prophylaxis may reduce endometritis by 62% and superficial wound infection by 38% after elective cesarean section. International guidelines recommend antibiotic prophylaxis in elective cesarean section, but this procedure is not routinely followed in Sweden. Studies of costs of antibiotic prophylaxis in cesarean section show conflicting results and are based on substantially different incidence of postoperative infections. No study of costs of antibiotic prophylaxis in elective cesarean section in a Swedish or Nordic context has been pursued. The aim of this study was to investigate if antibiotic prophylaxis is cost-reducing in elective cesarean section in orebro County, Sweden.Methods: All women undergoing elective cesarean in the Region orebro County health care system during 2011-2012 were eligible for inclusion. Postoperative infections and risk factors for infections were registered. A hypothetical situation in which all participants had received antibiotic prophylaxis was compared to the actual situation, in which none of them had received antibiotic prophylaxis. The reduction in the risk of postoperative infections resulting from antibiotic prophylaxis was based on a meta-analysis. Costs for in-patient care of postoperative infections were extracted from the accounting system, and costs for out-patient care were calculated according to standard costs. Costs for antibiotic prophylaxis were calculated and compared with the cost reduction that would be implied by the introduction of such prophylaxis.Results: The incidences of deep and superficial surgical site infection were 3.5% and 1.3% respectively. Introduction of antibiotic prophylaxis would reduce health care costs by 31 Euro per cesarean section performed (95% credible interval 4-58 Euro). The probability of cost-saving was 99%.Conclusions: Antibiotic prophylaxis in elective cesarean section is cost-reducing in this health care setting. Our results indicate that the introduction of antibiotic prophylaxis in elective cesarean section can also be cost-saving in low infection rate settings.Trial registration Ethical approval was given by the Regional Ethical Review Board in Uppsala (registration number 2013/484).
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| 10. |
- Ssegonja, Richard, et al.
(författare)
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Cost-effectiveness of an indicated preventive intervention for depression in adolescents: a model to support decision making
- 2020
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Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 277, s. 789-799
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adolescent depression has negative health and economic outcomes in the shortand long-term. Indicated preventive interventions, in particular group based cognitive behavioural therapy (GB-CBT), are ef-fective in preventing depression in adolescents with subsyndromal depression. However, little is known about the cost-effectiveness of these interventions. Methods: A Markov cohort model was used to conduct cost-effectiveness analyses comparing a GB-CBT indicated preventive intervention for depression, to a no-intervention option in a Swedish setting. Taking a time horizon of 5and 10 years, incremental differences in societal costs and health benefits expressed as differences in the proportion of cases of depression prevented, and as quality adjusted life years (QALYs) gained were estimated. Through univariate and probabilistic sensitivity analyses, the robustness of the results was explored. Costs, presented in 2018 USD, and effects were discounted at a yearly rate of 3%. Results: The base-case analysis showed that GB-CBT indicated preventive intervention incurred lower costs, prevented a larger proportion of cases of depression and generated higher QALYs compared to the no -intervention option for both time horizons. Offering the intervention was even a cost saving strategy and demonstrated a probability of being cost-effective of over 95%. In the sensitivity analyses, these results were robust to the modelling assumptions. Limitations: The study considered a homogeneous cohort and assumed a constant annual decay rate of the relative treatment effect. Conclusions: GB-CBT indicated preventive interventions for depression in adolescence can generate good value for money compared to leaving adolescents with subsyndromal depression untreated.
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