Model-based predictions on health benefits and budget impact of implementing empagliflozin in people with type 2 diabetes and established cardiovascular disease.

AIM: To perform a model-based analysis of the short- and long-term health benefits and costs of further increased implementation of empagliflozin for people with type 2 diabetes and established cardiovascular disease (eCVD) in Sweden. MATERIALS AND METHODS: The validated Institute for Health Economics Diabetes Cohort Model (IHE-DCM) was used to estimate health benefits and a 3-year budget impact, and lifetime costs per quality-adjusted life years (QALY) gained of increased implementation of adding empagliflozin to standard of care (SoC) for people with type 2 diabetes and eCVD in a Swedish setting. Scenarios with 100%/75%/50% implementation were explored. Analyses were based on 30 model cohorts with type 2 diabetes and eCVD (n = 131 412 at baseline) from national health data registers. Sensitivity analyses explored the robustness of results. RESULTS: Over 3 years, SoC with empagliflozin (100% implementation) versus SoC before empagliflozin resulted in 7700 total life years gained and reductions in cumulative incidence of cardiovascular deaths by 30% and heart failures by 28%. Annual costs increased by 15% from higher treatment costs and increased survival. Half of these benefits and costs are not yet reached with current implementation below 50%. SoC with empagliflozin yielded 0.37 QALYs per person, with an incremental cost-effectiveness ratio of 16 000 EUR per QALY versus SoC before empagliflozin. CONCLUSIONS: Model simulations using real-world data and trial treatment effects indicated that a broader implementation of empagliflozin, in line with current guidelines for treatment of people with type 2 diabetes and eCVD, would lead to further benefits even from a short-term perspective.

Pain, depression and anxiety in people with haemophilia from three Nordic countries: Cross-sectional survey data from the MIND study.

INTRODUCTION: People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life. AIM: To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130). METHODS: PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety. RESULTS: There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed. CONCLUSIONS: Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies.

Serosurvey of spotted fever group Rickettsia in equids from western Pará, Amazon, Brazil.

From a previous large epidemiological survey, we randomly selected 474 serum samples (463 horses and 11 mules) distributed among four municipalities of Pará state, Amazon region, Brazil, and from three types: farm animal, urban carthorse, and sport horse. Samples were tested by indirect fluorescence antibody test (IFAT ≥ 64) for antibodies reactive to spotted fever group (SFG) rickettsiae using Rickettsia rickettsii as crude antigens. From the 474 equids tested, 149 (31.4%) had ticks attached during sampling, belonging mostly to the species Dermacentor nitens. The overall seroprevalence for SFG rickettsiae was 31.4% (95% confidence interval: 27.3-35.9%) with 149 seropositive animals out of 474 screened. Notably, 77 equids (16.2%) had high endpoint titers ranging from 512 to 16,384, indicating that they had been exposed to SFG rickettsiae not long before sampling. Animal type affected rickettsial seroprevalence, with significantly higher values among farm horses when compared with urban and sport animals. Presence of dogs and tick infestation were negatively associated with equid seropositivity to R. rickettsii. This is the first report of SFG rickettsiae-reactive antibodies in equids from Pará state, Brazilian Amazon.

Swedish guidelines for device-aided therapies in Parkinson's disease -Economic evaluation and implementation.

OBJECTIVES: The National Board of Health and Welfare in Sweden published the national guidelines for Parkinson's Disease 2016. The aim of this study was to summarize this evidence review and development of the guidelines, focusing on the economic evaluation of device-aided therapies (deep brain stimulation, pump-based infusion of levodopa-carbidopa intestinal gel or apomorphine) for Parkinson's disease, and the rate of implementation after 3 years in Sweden. MATERIAL AND METHODS: The evidence review underlying the guidelines-including systematic literature searches of clinical and economic evidence, model-based economic evaluation, and formal analysis and guideline development-was examined, condensed, and translated. The impact of the guidelines was assessed with treatment use statistics from 2009 to 2019. RESULTS: All device-aided therapies were assigned high priority. Based on a relatively low proportion of device-aided therapies (30%) in Parkinson's disease, a 5-year increase of 500 patients was recommended. This was estimated to reduce total costs by SEK 14 million (€1.7 million). Follow-up data found an increase of 217 patients between 2017 and 2019, following the same trend as before the guidelines. CONCLUSION: Three years after the guidelines were published, the use of device-aided therapies has increased in Sweden, albeit not in pace with recommendations. One reason for slow implementation may be poor incentivization related to budget silos in which the costs for device-aided therapies are borne by the regions but the cost offsets (eg, reduced need for home care) are reaped by local stakeholders.

Costs of diabetes complications: hospital-based care and absence from work for 392,200 people with type 2 diabetes and matched control participants in Sweden.

AIMS/HYPOTHESIS: The risk of complications and medical consequences of type 2 diabetes are well known. Hospital costs have been identified as a key driver of total costs in studies of the economic burden of type 2 diabetes. Less evidence has been generated on the impact of individual diabetic complications on the overall societal burden. The objective of this study was to analyse costs of hospital-based healthcare (inpatient and outpatient care) and work absence related to individual macrovascular and microvascular complications of type 2 diabetes in Sweden in 2016. METHODS: Data for 2016 were retrieved from a Swedish national retrospective observational database cross-linking individual-level data for 1997-2016. The database contained information from population-based health, social insurance and socioeconomic registers for 392,200 people with type 2 diabetes and matched control participants (5:1). Presence of type 2 diabetes and of diabetes complications were derived using all years, 1997-2016. Costs of hospital-based care and of absence from work due to diabetes complications were estimated for the year 2016. Regression analysis was used for comparison with control participants to attribute absence from work to individual complications, and to account for joint presence of complications. RESULTS: Use of hospital care for complications was higher in type 2 diabetes compared with control participants in 2016: 26% vs 12% had ≥1 hospital contact; there were 86,104 vs 24,608 outpatient visits per 100,000 people; and there were 9894 vs 2546 inpatient admissions per 100,000 people (all p < 0.001). The corresponding total costs of hospital-based care for complications were €919 vs €232 per person (p < 0.001), and 74.7% of costs were then directly attributed to diabetes (€687 per person). Regression analyses distributed the costs of days absent from work across diabetes complications per se, basic type 2 diabetes effect and unattributed causes. Diabetes complications amounted to €1317 per person in 2016, accounting for possible complex interactions (25% of total costs of days absent). Key drivers of costs were the macrovascular complications angina pectoris, heart failure and stroke; and the microvascular complications eye diseases, including retinopathy, kidney disease and neuropathy. Early mortality in working ages cost an additional €579 per person and medications used in risk-factor treatment amounted to €418 per person. CONCLUSIONS/INTERPRETATION: The economic burden of complications in type 2 diabetes is substantial. Costs of absence from work in this study were found to be greater than of hospital-based care, highlighting the need for considering treatment consequences in a societal perspective in research and policy. Graphical abstract.

Days absent from work as a result of complications associated with type 2 diabetes: Evidence from 20 years of linked national registry data in Sweden.

AIMS: To analyse days absent from work related to individual microvascular, macrovascular and other complications of type 2 diabetes (T2D) and to identify key drivers of absence. MATERIALS AND METHODS: National health and socio-economic individual-level data were analysed for the years 1997 to 2016 for people with T2D, and age-, sex- and residential region-matched controls (5:1) using linkage to Swedish national administrative registers, based on personal identity numbers. Regression analyses accounting for individual-level clustering and education were estimated to obtain days absent by individual complications. Alternative analyses, for example, workforce indicator and age subgroups, were explored for robustness and comparison purposes. RESULTS: A total of 413 000 people with T2D aged <66 years, comprising 4.9 million person-years, was included. The crude proportion with any absence was higher among those with T2D compared to controls (47% vs. 26%) in the index year, and the median (IQR) number of days was higher (223 [77;359] vs. 196 [59;352]) if any absence. Regression analyses showed that complications per se were a key driver of days absent: stroke (+102 days); end-stage renal disease (+70 days); severe vision loss (+56 days); and angina pectoris, heart failure, and osteoarthritis (+53 days each). The alternative analyses showed similar levels of days absent and age subgroups differed in expected directions. CONCLUSIONS: This study provides evidence of the persisting impact on productivity from complications that supports continued efforts to reduce risk factors in T2D. Future studies on burden of disease and economic evaluations of new therapies and disease management may use this new set of complication-specific estimates to improve understanding of the value of reducing complications.

Socioeconomic inequalities in breast cancer incidence and mortality in Europe-a systematic review and meta-analysis.

BACKGROUND: Breast cancer is the leading cause of female cancer in Europe and is estimated to affect more than one in 10 women. Higher socioeconomic status has been linked to higher incidence but lower case fatality, while the impact on mortality is ambiguous. METHODS: We performed a systematic literature review and meta-analysis on studies on association between socioeconomic status and breast cancer outcomes in Europe, with a focus on effects of confounding factors. Summary relative risks (SRRs) were calculated. RESULTS: The systematic review included 25 articles of which 8 studied incidence, 10 case fatality and 8 mortality. The meta-analysis showed a significantly increased incidence (SRR 1.25, 1.17-1.32), a significantly decreased case fatality (SRR 0.72, 0.63-0.81) and a significantly increased mortality (SRR 1.16, 1.10-1.23) for women with higher socioeconomic status. The association for incidence became insignificant when reproductive factors were included. Case fatality remained significant after controlling for tumour characteristics, treatment factors, comorbidity and lifestyle factors. Mortality remained significant after controlling for reproductive factors. CONCLUSION: Women with higher socioeconomic status show significantly higher breast cancer incidence, which may be explained by reproductive factors, mammography screening, hormone replacement therapy and lifestyle factors. Lower case fatality for women with higher socioeconomic status may be partly explained by differences in tumour characteristics, treatment factors, comorbidity and lifestyle factors. Several factors linked to breast cancer risk and outcome, such as lower screening attendance for women with lower socioeconomic status, are suitable targets for policy intervention aimed at reducing socioeconomic-related inequalities in health outcomes.

The fluorescent ligand bTVBT2 reveals increased p-tau uptake by retinal microglia in Alzheimer's disease patients and AppNL-F/NL-F mice.

BACKGROUND: Amyloid beta (Aß) deposits and hyperphosphorylated tau (p-tau) accumulation have been identified in the retina of Alzheimer's disease (AD) patients and transgenic AD mice. Previous studies have shown that retinal microglia engulf Aß, but this property decreases in AD patients. Whether retinal microglia also take up p-tau and if this event is affected in AD is yet not described. In the current study, we use the p-tau-specific thiophene-based ligand bTVBT2 to investigate the relationship between disease progression and p-tau uptake by microglia in the retina of AD patients and AppNL-F/NL-F knock-in mice, an AD mouse model known to demonstrate extracellular Aß plaques and dystrophic neurites in the brain from 6 months of age. METHODS: Evaluation of bTVBT2 specificity and its presence within microglia was assessed by immunofluorescent staining of hippocampal sections and flat-mount retina samples from non-demented controls, AD patients, 3-, 9-, and 12-month-old AppNL-F/NL-F knock-in mice and 12- and 18-month-old wild type (WT) mice. We used ImageJ to analyze the amount of bTVBT2 inside Iba1-positive microglia. Co-localization between the ligand and p-tau variant Ser396/Ser404 (PHF-1), Aß, phosphorylated TAR DNA binding protein 43 (pTDP-43), and islet amyloid polypeptide (IAPP) in the brain and retina was analyzed using confocal imaging. RESULTS: Confocal imaging analysis showed that bTVBT2 binds to PHF-1- and AT8-positive aggregates inside retinal microglia, and not to Aß, pTDP-43, or IAPP. The density of bTVBT2-positive microglia was higher in cases with a high Aß load compared to those with a low Aß load. This density correlated with the neurofibrillary tangle load in the brain, but not with retinal levels of high molecular weight (aggregated) Aß40 or Aß42. Analysis of AppNL-F/NL-F knock-in mouse retina further showed that 50% of microglia in 3-month-old AppNL-F/NL-F knock-in mice contained bTVBT2. The percentage significantly increased in 9- and 12-month-old mice. CONCLUSION: Our study suggests that the microglial capability to uptake p-tau in the retina persists and intensifies with AD progression. These results also highlight bTVBT2 as a ligand of interest in future monitoring of retinal AD pathology.

Treatment Preferences for Acute Allergic Reactions: A Discrete Choice Experiment.

Background: Timely treatment of acute allergic reactions (AARs) is important to minimize reaction severity. Corticosteroid tablets dissolved in water are commonly used in mainstay treatment. A new oral film that dissolves on the tongue provides a faster and less cumbersome alternative to tablets for corticosteroid administration during AARs. This study evaluated patients' preferences for attributes related to administration mode of corticosteroids in AARs. Methods: A web-based survey was sent to a sample from the adult Swedish population (≥18 years) with experience of corticosteroid treatment for AAR. We assessed the willingness to pay (WTP) for attributes related to corticosteroid treatment by applying a discrete choice experiment (DCE) approach. DCE attributes were administration mode, time to symptom relief, and price. The WTP for each attribute was derived using the attribute's coefficient in a logistic regression analysis. We specified a forced choice (FC) and an unforced choice (UC) model. In the FC model, the respondents chose between 2 hypothetical treatments and in the UC model, between any of 2 hypothetical treatments and their current treatment. Results: The final study population included 348 subjects, of which 80% were women. All the evaluated DCE attributes were significant predictors for the treatment choice (p<.001). In the FC model, the incremental WTP for an oral film compared with tablets was 409 Swedish kronor (SEK [≈€36.7]), with no other factors considered. In the UC model, the incremental WTP for the oral film compared with tablets was 574 SEK (≈€51.7). After considering the value of the respondents' current treatment, the WTP for the oral film decreased to 336 SEK (≈€30.3). The total WTP was reduced by 17 SEK (≈€1.5) per minute of shorter time to symptom relief. Subgroup analyses showed that people with circulatory symptoms and experience of swallowing difficulties related to allergy medication had higher WTP for the oral film than the average respondent. Conclusion: The findings show a substantial economic benefit of the oral film vs tablets for patients with AARs in Sweden. This result remained also after compensation for the full value of the patients' current treatment.

Disease burden and unmet need for acute allergic reactions - A patient perspective.

Background: Acute allergic reactions (AARs) occur shortly after exposure to an allergen, and the severity is on a continuum. Systemic corticosteroids (CS) are mainstay treatment of moderate to severe AARs, whereas those at risk of the most severe AARs (ie, anaphylaxis) are also recommended prescription of epinephrine autoinjectors. There is limited research on the impact of AARs not fulfilling the criteria for anaphylaxis. We have characterized a sample with a history of moderate to severe AARs and evaluated their self-reported disease burden (ie, daily life impact, anxiety, and treatment impediments). Methods: Survey study of adults with experience of AARs treated with CS. Participants recruited from a web-based panel and using social media were asked to complete a questionnaire related to their allergy and experience of AARs. The results were summarized for the whole sample and across subgroups with and without prescription of epinephrine. Results: The final study sample included 387 participants (80% women, mean age 41), of which 129 (33%) had at some point been prescribed epinephrine. The most common symptoms were respiratory (80%) and skin (78%) manifestations, and the mean (standard deviation, SD) self-rated severity score (scale from 0 [very mild] to 10 [very severe]) of the most recent AAR was 6.1 (2.0). More than 80% had experience of AARs interrupting daily activities and 50% of AARs that had limited work/studies or participation in leisure activities. Most of the respondents reported some degree of anxiety related to AARs and 43% had feared for their lives. Moreover, difficulties swallowing allergy medicine at an AAR was experienced by 26% and not having the medicine available when needed by 66%. Participants with prescription of epinephrine experienced more severe AARs than those without such prescription (mean [SD] severity 6.8 [2.1] vs 5.8 [1.8], p < 0.0001); however, also those without epinephrine prescription reported considerable anxiety and impact on daily life and to a similar degree as those with prescription. Conclusions: In this sample, subjects with experience of AARs treated with CS showed a considerable disease burden with anxiety and interruption on daily life, as well as problems related to access to, and swallowing of, medication. Although respondents with epinephrine prescription had more severe disease, a high disease burden was also evident among those without epinephrine. The study increases the knowledge of people with moderate to severe AARs, a patient population that has previously been underrepresented in the research literature.

Analgesic efficacy of sleep-promoting pharmacotherapy in patients with chronic pain: a systematic review and meta-analysis.

Dysregulation of sleep heightens pain sensitivity and may contribute to pain chronification. Interventions which consolidate and lengthen sleep have the potential to improve pain control. The main objective of this systematic review was to examine the effects of sleep-promoting pharmacotherapy on pain intensity in patients with chronic pain. Multiple electronic databases were searched from inception to January 2022 to identify relevant randomized controlled trials (RCTs). Two independent reviewers screened titles, abstracts, and full-text articles; extracted data; and assessed risk of bias for each included study. The GRADE approach was used to determine the strength of evidence. The search identified 624 articles. After full-text screening, 10 RCTs (n = 574 randomized participants) involving 3 pharmacologic interventions (melatonin, zopiclone, and eszopiclone) and 7 different chronic pain populations were included. Minimum clinically significant pain reduction ≥30% was reported in 4 studies. There is low-quality evidence (downgraded due to inconsistency and imprecision) that 2 to 8 weeks treatment with a sleep-promoting medication alone or in combination with an analgesic (6 trials, n = 397) decreases pain intensity compared with placebo or the same analgesic treatment alone (SMD -0.58 [95% confidence interval -1.00, -0.17], P = 0.006). Analyses of associations between changes in sleep and pain outcomes were only provided in 2 articles, with inconsistent findings. Notably, pain-relieving effects were most consistent in melatonin trials. Only 3 studies implemented polysomnography to obtain objective sleep measures. Low-quality evidence indicates that pharmacologic sleep promotion may decrease pain intensity in chronic pain populations. More research is needed to fully understand the influence of sleep-targeting interventions on pain control.

Cerebral Aß deposition precedes reduced cerebrospinal fluid and serum Aß42/Aß40 ratios in the AppNL-F/NL-F knock-in mouse model of Alzheimer's disease.

BACKGROUND: Aß42/Aß40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer's disease (AD), but their temporal and correlative relationship with cerebral Aß pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. METHODS: CSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL-F/NL-F knock-in mice (n = 48) and 2-18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aß42 and Aß40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aß plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aß42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. RESULTS: In AppNL-F/NL-F knock-in mice, Aß42/Aß40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aß pathology, in which a more widespread Aß plaque burden and increased levels of Aß42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aß42/Aß40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aß plaque burden as well as the levels of both soluble and insoluble Aß42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aß plaque pathology were found in AppNL/NL knock-in mice during the observation time. CONCLUSIONS: Our findings suggest a temporal sequence of events in AppNL-F/NL-F knock-in mice, in which initial deposition of Aß aggregates in the brain is followed by a decline of the Aß42/Aß40 ratio in CSF and serum once the cerebral Aß pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aß pathology when assessed in CSF compared with serum.

Galectin-3 ablation does not affect infarct size or inflammatory cytokines after experimental stroke in 24-month-old female mice.

BACKGROUND: The tissue damage following a focal stroke causes an inflammatory response that is thought to aggravate the disease state. Galectin-3 is a proinflammatory molecule that has been shown to play a significant role in the inflammatory responses in brain diseases and following experimental stroke. In most animal experiments, young animals are used, although attempts are often made to model diseases that affect the elderly. Therefore, in this project, we intended to investigate the role of Galectin-3 in experimental stroke in older mice. METHODS: In this project, 24-month-old (aged) female mice were subjected to an experimental stroke (permanent middle cerebral artery occlusion) 7 days before sacrifice. We wanted to investigate whether the absence of the inflammatory protein Galectin-3 could affect motor phenotype, neuroinflammation and infarct size. Number of mice without Galectin-3 (Galectin-3 KO) = 9, number of wildtype controls of the same age = 6. RESULTS: In our aged female mice, we could not observe any significant differences between Galectin-3 KO and wildtype regarding the inclined plane test or cylinder test. We could not observe different infarct sizes between the two genotypes. In brain homogenates, we measured levels of 10 inflammatory cytokines, but we could not see any significant differences in any of them. CONCLUSION: In summary, it can be said that the absence of the inflammatory mediator Galectin-3 does not seem to have a strong poststroke effect in aged females. Unfortunately, we could not analyze these mice with immunohistochemistry, which limited our study.

Current and future costs of obesity in Sweden.

BACKGROUND: Obesity is a growing health issue. This study estimated the costs of obesity among people aged 25-84 years in Sweden using disease and non-disease specific attributable fractions from published data. A prognosis of costs of obesity in 2030 is presented. METHODS AND MATERIALS: Diseases related to obesity and their respective risks and population attributable fraction were retrieved by literature review. Longitudinal data on age and sex related prevalence of obesity was used to construct three scenarios for costs of obesity in 2030. RESULTS: Nearly 4% of all deaths among people 25-84 years in 2016 (n = 3,400) were attributed to obesity. Obesity cost EUR 2.7 billion in 2016, or EUR 377 per inhabitant aged ≥25 years. Non-health care costs were dominant and represented 80% of total societal costs. Main drivers were premature mortality (28%) and permanent sick leave (37%). If the proportion of obese remain at 2016 level, costs will increase 9% by 2030, but with continued linear growth, costs will increase by 66%. CONCLUSIONS: The responsibility, costs and treatment fall on several actors with a considerable burden falling on the individual and the society at large. New health promoting interventions and policy programs are needed and must be evaluated in terms of resource use and expected return.

Risk sharing in managed entry agreements-A review of the Swedish experience.

BACKGROUND: In 2014 managed entry agreements (MEA) between Swedish health care payers (county councils), the reimbursement authority (the Dental and Pharmaceutical Benefits Agency (TLV)) and pharmaceutical companies were introduced to facilitate early and equal access to treatments. MEAs complement the value-based pricing system for out-patient drugs and enables stake-holders to negotiate risk-sharing agreements. AIM: The aim of the study was to review existing agreements, describe the type of uncertainty dealt with, and to analyze incentives created using the literature on performance-based reimbursement schemes in Sweden. METHOD: A document review of all agreements made in the period January 2015 to August 2019 was conducted, classifying agreements by the type of uncertainty dealt with. RESULTS: Agreements were made for 56 products during the studied time period (45 ongoing), mainly in the fields of hepatitis C (n = 10) and oncology (n = 14). Uncertainties addressed in ongoing agreements included size of treated population (10), treatment duration (13), and effectiveness (9). The mechanism for risk-sharing was limited to refunds based on patient numbers, duration or just flat-rate refunds. The estimated refund in 2018 was 50 % of total sales. DISCUSSION: This review show that the main driver behind risk sharing in Sweden so far have seem to be affordability rather than managing uncertainty.

Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer's disease.

Physical exercise has been suggested to reduce the risk of developing Alzheimer's disease (AD) as well as ameliorate the progression of the disease. However, we recently published results from two large epidemiological studies showing no such beneficial effects on the development of AD. In addition, long-term, voluntary running in the 5xFAD mouse model of AD did not affect levels of soluble amyloid beta (Aß), synaptic proteins or cognitive function. In this follow-up study, we investigate whether running could impact other pathological aspects of the disease, such as insoluble Aß levels, the neuroinflammatory response and non-cognitive behavioral impairments. We investigated the effects of 24 weeks of voluntary wheel running in female 5xFAD mice (n = 30) starting at 2-3 months of age, before substantial extracellular plaque formation. Running mice developed hindlimb clasping earlier (p = 0.009) compared to sedentary controls. Further, running exacerbated the exploratory behavior in Elevated plus maze (p = 0.001) and anxiety in Open field (p = 0.024) tests. Additionally, microglia, cytokines and insoluble Aß levels were not affected. Taken together, our findings suggest that voluntary wheel running is not a beneficial intervention to halt disease progression in 5xFAD mice.

Blood and cerebrospinal fluid neurofilament light differentially detect neurodegeneration in early Alzheimer's disease.

Cerebrospinal fluid (CSF) neurofilament light (NfL) concentration has reproducibly been shown to reflect neurodegeneration in brain disorders, including Alzheimer's disease (AD). NfL concentration in blood correlates with the corresponding CSF levels, but few studies have directly compared the reliability of these 2 markers in sporadic AD. Herein, we measured plasma and CSF concentrations of NfL in 478 cognitively unimpaired (CU) subjects, 227 patients with mild cognitive impairment, and 113 patients with AD dementia. We found that the concentration of NfL in CSF, but not in plasma, was increased in response to Aß pathology in CU subjects. Both CSF and plasma NfL concentrations were increased in patients with mild cognitive impairment and AD dementia. Furthermore, only NfL in CSF was associated with reduced white matter microstructure in CU subjects. Finally, in a transgenic mouse model of AD, CSF NfL increased before serum NfL in response to the development of Aß pathology. In conclusion, NfL in CSF may be a more reliable biomarker of neurodegeneration than NfL in blood in preclinical sporadic AD.

Aß deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease.

The links between ß-amyloid (Aß) and tau in Alzheimer's disease are unclear. Cognitively unimpaired persons with signs of Aß pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aß pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aß aggregation started. These results show that Aß pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

Physical Activity Reduces Epilepsy Incidence: a Retrospective Cohort Study in Swedish Cross-Country Skiers and an Experimental Study in Seizure-Prone Synapsin II Knockout Mice.

BACKGROUND: Epilepsy patients commonly exercise less than the general population. Animal studies indicate beneficial effects of physical activity in established epilepsy, while its effect on the development is currently less known. METHODS: Here, we investigated the incidence of epilepsy during 20 years in a cohort of participants from the long-distance Swedish cross-country ski race Vasaloppet (n = 197,685) and compared it to the incidence of non-participating-matched controls included in the Swedish population register (n = 197,684). Individuals diagnosed with diseases such as stroke and epilepsy before entering the race were excluded from both groups. Experimentally, we also determined how physical activity could affect the development of epilepsy in epilepsy-prone synapsin II knockout mice (SynIIKO), with and without free access to a running wheel. RESULTS: We identified up to 40-50% lower incidence of epilepsy in the Vasaloppet participants of all ages before retirement. A lower incidence of epilepsy in Vasaloppet participants was seen regardless of gender, education and occupation level compared to controls. The participants included both elite and recreational skiers, and in a previous survey, they have reported a higher exercise rate than the general Swedish population. Sub-analyses revealed a significantly lower incidence of epilepsy in participants with a faster compared to slower finishing time. Dividing participants according to specified epilepsy diagnoses revealed 40-50% decrease in focal and unspecified epilepsy, respectively, but no differences in generalized epilepsy. Voluntary exercise in seizure-prone SynIIKO mice for 1 month before predicted epilepsy development decreased seizure manifestation from > 70 to 40%. Brain tissue analyses following 1 month of exercise showed increased hippocampal neurogenesis (DCX-positive cells), while microglial (Iba1) and astrocytic activation (GFAP), neuronal Map2, brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B intensity were unaltered. Continued exercise for additionally 2 months after predicted seizure onset in SynIIKO mice resulted in a 5-fold reduction in seizure manifestation (from 90 to 20%), while 2 months of exercise initiated at the time of predicted seizure development gave no seizure relief, suggesting exercise-induced anti-epileptogenic rather than anti-convulsive effect. CONCLUSION: The clinical study and the experimental findings in mice indicate that physical activity may prevent or delay the development of epilepsy.

Midlife physical activity is associated with lower incidence of vascular dementia but not Alzheimer's disease.

BACKGROUND: Physical activity might reduce the risk of developing dementia. However, it is still unclear whether the protective effect differs depending on the subtype of dementia. We aimed to investigate if midlife physical activity affects the development of vascular dementia (VaD) and Alzheimer's disease (AD) differently in two large study populations with different designs. METHODS: Using a prospective observational design, we studied whether long-distance skiers of the Swedish Vasaloppet (n = 197,685) exhibited reduced incidence of VaD or AD compared to matched individuals from the general population (n = 197,684) during 21 years of follow-up (median 10, interquartile range (IQR) 5-15 years). Next, we studied the association between self-reported physical activity, stated twice 5 years apart, and incident VaD and AD in 20,639 participants in the Swedish population-based Malmo Diet and Cancer Study during 18 years of follow-up (median 15, IQR 14-17 years). Finally, we used a mouse model of AD and studied brain levels of amyloid-ß, synaptic proteins, and cognitive function following 6 months of voluntary wheel running. RESULTS: Vasaloppet skiers (median age 36.0 years [IQR 29.0-46.0], 38% women) had lower incidence of all-cause dementia (adjusted hazard ratio (HR) 0.63, 95% CI 0.52-0.75) and VaD (adjusted HR 0.49, 95% CI 0.33-0.73), but not AD, compared to non-skiers. Further, faster skiers exhibited a reduced incidence of VaD (adjusted HR 0.38, 95% CI 0.16-0.95), but not AD or all-cause dementia compared to slower skiers. In the Malmo Diet and Cancer Study (median age 57.5 years [IQR 51.0-63.8], 60% women), higher physical activity was associated with reduced incidence of VaD (adjusted HR 0.65, 95% CI 0.49-0.87), but not AD nor all-cause dementia. These findings were also independent of APOE-ε4 genotype. In AD mice, voluntary running did not improve memory, amyloid-ß, or synaptic proteins. CONCLUSIONS: Our results indicate that physical activity in midlife is associated with lower incidence of VaD. Using three different study designs, we found no significant association between physical activity and subsequent development of AD.