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Abstract Objectives For drugs reimbursed with limited evidence of patient benefits, confirmatory evidence of overall survival (OS) and quality of life (QoL) benefits is important. For QoL data to serve as valuable input to patients and decision-makers, it must be measured and analyzed using appropriate methods. We aimed to assess the measurement and analyses of post-reimbursement QoL data for cancer drugs introduced in Swedish healthcare with limited evidence at the time of reimbursement. Methods We reviewed any published post-reimbursement trial data on QoL for cancer drugs reimbursed in Sweden between 2010 and 2020 with limited evidence of improvement in QoL and OS benefits at the time of reimbursement. We extracted information on the instruments used, frequency of measurement, extent of missing data, statistical approaches, and the use of pre-registration and study protocols. Results Out of 22 drugs satisfying our inclusion criteria, we identified published QoL data for 12 drugs in 22 studies covering multiple cancer types. The most frequently used QoL instruments were EORTC QLQ-C30 and EQ-5D-3/5L. We identified three areas needing improvement in QoL measurement and analysis: (i) motivation for the frequency of measurements, (ii) handling of the substantial missing data problem, and (iii) inclusion and adherence to QoL analyses in clinical trial pre-registration and study protocols. Conclusions Our review shows that the measurements and analysis of QoL data in our sample of cancer trials covering drugs initially reimbursed without any confirmed QoL or OS evidence have significant room for improvement. The increasing use of QoL assessments must be accompanied by a stricter adherence to best-practice guidelines to provide valuable input to patients and decision-makers.

Abstract Background Cardiovascular diseases (CVDs) are the leading cause of death in Indonesia, accounting for 38% of the total mortality in 2019. Moreover, healthcare spending on CVDs has been at the top of the spending under the National Health Insurance (NHI) implementation. This study analyzed the association between the presence of CVDs with or without other chronic disease comorbidities and healthcare costs among adults (> 30 years old) and if the association differed between NHI members in the subsidized group (poorer) and non-subsidized households group (better-off) in Indonesia. Methods This retrospective cohort study analyzed the NHI database from 2016–2018 for individuals with chronic diseases (n = 271,065) ascertained based on ICD-10 codes. The outcome was measured as healthcare costs in USD value for 2018. We employed a three-level multilevel linear regression, with individuals at the first level, households at the second level, and districts at the third level. The outcome of healthcare costs was transformed with an inverse hyperbolic sine to account for observations with zero costs and skewed data. We conducted a cross-level interaction analysis to analyze if the association between individuals with different diagnosis groups and healthcare costs differed between those who lived in subsidized and non-subsidized households. Results The mean healthcare out- and inpatient costs were higher among patients diagnosed with CVDs and multimorbidity than patients with other diagnosis groups. The predicted mean outpatient costs for patients with CVDs and multimorbidity were more than double compared to those with CVDs but no comorbidity (USD 119.5 vs USD 49.1, respectively for non-subsidized households and USD 79.9 vs USD 36.7, respectively for subsidized households). The NHI household subsidy status modified relationship between group of diagnosis and healthcare costs which indicated a weaker effect in the subsidized household group (β = -0.24, 95% CI -0.29, -0.19 for outpatient costs in patients with CVDs and multimorbidity). At the household level, higher out- and inpatient costs were associated with the number of household members with multimorbidity. At the district level, higher healthcare costs was associated with the availability of primary healthcare centres. Conclusions CVDs and multimorbidity are associated with higher healthcare costs, and the association is stronger in non-subsidized NHI households. Households' subsidy status can be construed as indirect socioeconomic inequality that hampers access to healthcare facilities. Efforts to combat cardiovascular diseases (CVDs) and multimorbidity should consider their distinct impacts on subsidized households. The effort includes affirmative action on non-communicable disease (NCD) management programs that target subsidized households from the early stage of the disease.

Introduction Although breast reconstruction is an integral part of breast cancer treatment, there is little high-quality evidence to indicate which method is the most effective. Randomised controlled trials (RCTs) are generally thought to provide the most solid scientific evidence, but there are significant barriers to conducting RCTs in breast reconstruction, making both recruitment and achieving unbiased and generalisable results a challenge. The objective of this study is to compare implant-based and autologous breast reconstruction in non-irradiated patients. Moreover, the study aims to improve the evidence for trial decision-making in breast reconstruction.Methods and analysis The study design partially randomised patient preference trial might be a way to overcome the aforementioned challenges. In the present study, patients who consent to randomisation will be randomised to implant-based and autologous breast reconstruction, whereas patients with strong preferences will be able to choose the method. The study is designed as a superiority trial based on the patient-reported questionnaire BREAST-Q and 124 participants will be randomised. In the preference cohort, patients will be included until 62 participants have selected the least popular alternative. Follow-up will be 60 months. Embedded qualitative studies and within-trial economic evaluation will be performed. The primary outcome is patient-reported breast-specific quality of life/satisfaction, and the secondary outcomes are complications, factors affecting satisfaction and cost-effectiveness.Ethics and dissemination The study has been approved by the Swedish Ethical Review Authority (2023-04754-01). Results will be published in peer-reviewed scientific journals and presented at peer-reviewed scientific meetings.Trial registration number NCT06195865.

Abstract Background The COVID-19 pandemic has disrupted healthcare utilization globally, but little is known about the effects among patients with cardiovascular diseases (CVDs) and other multimorbidities. This study analyzed the impacts of COVID-19 on healthcare utilization for patients aged 30 years and older with cardiovascular diseases (CVDs) with or without other chronic disease comorbidities in Indonesia. Methods We designed a retrospective cohort study based on the Indonesian National Health Insurance (NHI) sample data from 2016–2020. We defined healthcare utilization as monthly outpatient and inpatient visits related to chronic diseases at the hospital and primary healthcare levels per 10,000 NHI members. We used interrupted time series analysis to evaluate how the healthcare utilization patterns had changed due to the COVID-19 pandemic. Results Overall, hospital outpatient visits decreased by 39% when the pandemic occurred (95% Confidence Interval (CI): 0.48,0.76), inpatient visits by 28% (95% CI: 0.62,0.83), and primary healthcare visits by 34% (95% CI:0.55, 0.81). For patients with CVDs and multimorbidity, hospital outpatient and inpatient visit rates were reduced by 36% and 38%, respectively and primary healthcare visits by 32%. Some insignificant differences in the reduction of out-and inpatient visits were observed across diagnosis groups and regions. Conclusion Healthcare utilization among patients with chronic diseases decreased significantly during COVID-19 and consistently across different chronic diseases and regions. To cope with the unmet needs of healthcare utilization in the context of the pandemic, the healthcare system needs to be strengthened to cater to the needs of the population-at-risk, especially for patients with CVDs and multimorbidity.

Abstract Background Stroke is a common and costly disease affecting the person with stroke and their relatives. If the negative effect on the health of informal caregivers to a person with stroke translates into an increased healthcare consumption has not yet been studied. Further, the importance of including costs and health consequences of informal caregiving in health economic evaluation supporting decision-making is an ongoing discussion. Therefore, this study aims to estimate the long-term effect on healthcare utilisation among spouses of persons with a first-ever stroke. Method The study population consists of spouses of persons with first-ever stroke events in 2010–2011 and a reference population matched on age, sex and municipality of residence. We have access to information on healthcare utilisation five years before and five years after the stroke event for the whole study population. Using a difference-in-difference approach, the main analysis estimates the effects on primary and specialist outpatient care visits and days with inpatient care per year. Further, we analyse the healthcare utilisation among spouses depending on the modified Rankin Scale (mRS) of the person with stroke. Results Our main analysis indicates that spouses have slightly more days with inpatient care five years after the stroke event than the reference population (p = 0.03). In contrast, spouses have fewer primary and specialist outpatient care visits than the reference population following the stroke event. In the analysis where spouses’ healthcare utilisation is analysed according to the mRS status of the person with stroke, we identify the most notable change in the number of visits to specialist outpatient and days with inpatient care among spouses of persons with mRS 3 (dependency in daily activities). Conclusion Our study suggests that being the spouse of a person with stroke has minor effects on healthcare utilisation. Further, healthcare utilisation is most affected among the spouses of persons with stroke and dependency in daily activities (mRS 3). According to our results, it does not seem vital to include spouses of persons with stroke healthcare utilisation in health economic evaluations.

Abstract Background Astrocytes respond to injury and disease through a process known as reactive astrogliosis, of which inflammatory signaling is one subset. This inflammatory response is heterogeneous with respect to the inductive stimuli and the afflicted central nervous system region. This is of plausible importance in e.g. traumatic axonal injury (TAI), where lesions in the brainstem carries a particularly poor prognosis. In fact, astrogliotic forebrain astrocytes were recently suggested to cause neuronal death following axotomy. We therefore sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro. Methods We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of mouse embryonic stem cells (ES). We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α and clinically relevant inflammatory mediators. In co-cultures with reactive ES-astrocytes and motor neurons, we assessed neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions. Results We confirmed the brainstem/rostroventral ES-astrocyte identity using RNA-sequencing, immunocytochemistry, and by comparison with primary subventricular zone-astrocytes. Following cytokine stimulation, the c-Jun N-terminal kinase pathway down-stream product phosphorylated c-Jun was increased, thus demonstrating ES-astrocyte reactivity. These reactive ES-astrocytes conferred a contact-dependent neurotoxic effect upon co-culture with motor neurons. When exposed to IL-1β and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following human severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. Activation of ES-astrocytes by these cytokines was associated with pathways relating to endoplasmic reticulum stress and altered regulation of MYC. Conclusions Ventral brainstem and rostroventral spinal cord astrocytes differentiated from mouse ES can exert neurotoxic effects in vitro. This highlights how neuroinflammation following CNS lesions can exert region- and cell-specific effects. Our in vitro model system, which uniquely portrays astrocytes and neurons from one niche, allows for a detailed and translationally relevant model system for future studies on how to improve neuronal survival in particularly vulnerable CNS regions following e.g. TAI.

Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients (n?=?7; GCS 3?8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI.

Abstract Background Uganda has a high population growth rate of 3%, partly due to limited access to and low usage of contraception. This study assessed the cost-effectiveness of the family planning benefits cards (FPBC) program compared to standard of care (SOC). The FPBC program was initiated to increase access to modern contraception among young women in slums in Kampala, Uganda. Methods We developed a decision-analytic model (decision tree) and parameterized it using primary intervention data together with previously published data. In the base case, a sexually active woman from an urban slum, aged 18 to 30 years, was modelled over a one-year time horizon from both the modified societal and provider perspectives. The main model outcomes included the probability of unintended conception, costs, and incremental cost-effectiveness ratio (ICER) in terms of cost per unwanted pregnancy averted. Both deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the modelling results. All costs were reported in 2022 US dollars, and analyses were conducted in Microsoft Excel. Results In the base case analysis, the FPBC was superior to the SOC in outcomes. The probability of conception was lower in the FPBC than in the SOC (0.20 vs. 0.44). The average societal and provider costs were higher in the FPBC than in the SOC, i.e., $195 vs. $164 and $193 vs. $163, respectively. The ICER comparing the FPBC to the SOC was $125 per percentage reduction in the probability of unwanted conception from the societal perspective and $121 from the provider perspective. The results were robust to sensitivity analyses. Conclusion Given Uganda’s GDP per capita of $1046 in 2022, the FPBC is highly cost-effective compared to the SOC in reducing unintended pregnancies among young women in low-income settings. It can even get cheaper in the long run due to the low marginal costs of deploying additional FPBCs. Trial registration MUREC1/7 No. 10/05-17. Registered on July 19, 2017.

Myxomatous mitral valve disease (MMVD) is the most common acquired heart disease in dogs and its occurrence in small-and medium-sized dogs has been extensively investigated. MMVD has been described in large breed dogs as well, but substantial knowledge gaps remain. The aim of this study was to provide characteristics, survival times, and prognostic variables in large breed dogs with MMVD. Medical records of dogs diagnosed with MMVD, between 2012 and 2021, were retrospectively reviewed and 202 dogs were analyzed. Median survival time (MST) for all-cause mortality was 800 days for stage B1 dogs, 274 days for stage B2 dogs, and 184 days for stage C dogs. The MST for cardiac-related death for B1 dogs could not be calculated (because survival was greater than 50% at the last timepoint) and for stage B2 and C dogs the MST were 484 and 252 days, respectively. These findings suggest that the frequency of cardiac-related death is low in large breed dogs with stage B1 MMVD. In addition, increased left atrial and ventricular size, evidence of systolic dysfunction, a thrilling murmur, and increased early trans-mitral peak velocity are predictors of cardiac-related death. Data also suggest that the risk of a negative outcome increases profoundly when large breed dogs advance from ACVIM stage B1 into stage B2 or C.

Abstract As the sawmill industry is moving towards thinner bandsaws for higher yields, it is important to study the cutting force in more detail. The cutting force can be split into two zones. Zone I concerns the force on the major cutting edge as well as the friction force on the major first flank. Zone II considers the forces on the minor cutting edges as well as the friction forces on the minor first flanks. Zone II cutting can significantly affect the cutting force and has not been studied in great detail. Frozen, non-frozen and dry heartwood of Norway spruce and Scots pine were cut using different tooth geometries and the cutting force was measured. The major cutting edge, clearance, band thickness, minor cutting edge angle and minor cutting edge clearance angle were investigated. The y-intercept of the cutting force–width graph was used as the Zone II force (at this point the Zone I forces are assumed to be zero). The Zone II force contribution to the cutting force was studied. The results show that frozen wood has less elastic spring-back and therefore less Zone II cutting. Dried wood showed a significantly higher degree of Zone II cutting (55−75% contribution to the cutting force). Changing the major cutting edge from 2.87 mm to 1.6 mm resulted in 10–15% higher Zone II force contributions.

Abstract Background Adverse economic consequences of antibiotic resistance, both in health care systems and in society at large, have been estimated to emerge and significantly affect the global economy. To date, most studies of the societal costs of antibiotic resistance have had a macroeconomic perspective, using the number of attributable deaths as a quantifier for production loss. In contrast, there have been few studies of the consequences of antibiotic resistance in terms of the length of sick leave and hence the impact of morbidity on production loss. The aim of our study was to estimate the production loss from ill health caused by antibiotic resistance. Method To estimate additional production loss due to antibiotic resistance, we used Swedish register-based cohort data to determine days of long-term sick leave (LTSL) for episodes of infection caused by resistant and susceptible bacteria respectively. We collected patient data for four common infection types (bloodstream infection, urinary tract infection, skin and soft tissue infection, and pneumonia), as well as, antibiotic susceptibility test data, and total days of LTSL. We used a two-part model to estimate the number of LTSL days attributable to resistance, and controlled for comorbidities and demographic variables such as age and gender. Results The results show that antibiotic resistance adds an additional 8.19 days of LTSL compared with a similar infection caused by susceptible bacteria, independent of infection type and resistance type. Furthermore, the results suggest that production loss due to temporary sick leave caused by antibiotic resistance in a working-age population amounts to about 7% of total health care costs attributable to antibiotic resistance in Sweden. Conclusion Estimating the effect of antibiotic resistance in terms of temporary production loss is important to gain a better understanding of the economic consequences of antibiotic resistance in society and, by extension, enable more effective resource allocation to combat further emergence of resistance. Society’s economic costs of antibiotic resistance are, however, probably much greater than those of sick leave due to disease alone.

Abstract Background Over the next decade, the number of osteoarthritis consultations in health care is expected to increase. Physiotherapists may be considered equally qualified as primary assessors as physicians for patients with knee osteoarthritis. However, economic evaluations of this model of care have not yet been described. To determine whether physiotherapists as primary assessors for patients with suspected knee osteoarthritis in primary care are a cost-effective alternative compared with traditional physician-led care, we conducted a cost-effectiveness analysis alongside a randomized controlled pragmatic trial. Methods Patients were randomized to be assessed and treated by either a physiotherapist or physician first in primary care. A cost-effectiveness analysis compared costs and effects in quality adjusted life years (QALY) for the different care models. Analyses were applied with intention to treat, using complete case dataset, and missing data approaches included last observation carried forward and multiple imputation. Non-parametric bootstrapping was conducted to assess sampling uncertainty, presented with a cost-effectiveness plane and cost-effectiveness acceptability curve. Results 69 patients were randomized to a physiotherapist (n = 35) or physician first (n = 34). There were significantly higher costs for physician visits and radiography in the physician group (p

BackgroundPreterm birth is the leading cause of childhood mortality and morbidity. We aimed to provide a comprehensive systematic review on randomized controlled trials (RCTs) on progesterone, cerclage, pessary, and acetylsalicylic acid (ASA) to prevent preterm birth in asymptomatic women with singleton pregnancies defined as risk of preterm birth and multifetal pregnancies.MethodsSix databases (including PubMed, Embase, Medline, the Cochrane Library) were searched up to February 2022. RCTs published in English or Scandinavian languages were included through a consensus process. Abstracts and duplicates were excluded. The trials were critically appraised by pairs of reviewers. The Cochrane risk-of-bias tool was used for risk of bias assessment. Predefined outcomes including preterm birth, perinatal/neonatal/maternal mortality and morbidity, were pooled in meta-analyses using RevMan 5.4, stratified for high and low risk of bias trials. The certainty of evidence was assessed using the GRADE approach. The systematic review followed the PRISMA guideline.ResultsThe search identified 2,309 articles, of which 87 were included in the assessment: 71 original RCTs and 16 secondary publications with 23,886 women and 32,893 offspring. Conclusions were based solely on trials with low risk of bias (n = 50). Singleton pregnancies: Progesterone compared with placebo, reduced the risk of preterm birth

Introduction: A range of adverse events (AEs) may occur in patients with subarachnoid hemorrhage (SAH). Endovascular treatment is commonly used to prevent aneurysm re-rupture. Research question: The aim of this study was to identify AEs related to endovascular treatment, analyze risk factors for AEs and how AEs affect patient outcome. Material and methods: Patients with aneurysmal SAH admitted to all neurosurgical centers in Sweden during a 3.5-year period (2014–2018) were prospectively registered. AEs related to endovascular aneurysm treatment were thromboembolic events, aneurysm re-rupture, vessel dissection and puncture site hematoma. Potential risk factors for the AEs were analyzed using multivariate logistic regression. Functional outcome was assessed at one year using the extended Glasgow outcome scale. Results: In total, 1037 patients were treated for ruptured aneurysms. Of which, 715 patients were treated with endovascular occlusion. There were 115 AEs reported in 113 patients (16%). Thromboembolic events were noted in 78 patients (11%). Aneurysm re-rupture occurred in 28 (4%), vessel dissection in 4 (0.6%) and puncture site hematoma in 5 (0.7%). Blister type aneurysm, aneurysm smaller than 5 mm and endovascular techniques other than coiling were risk factors for treatment-related AEs. At follow-up, 230 (32%) of the patients had unfavorable outcome. Patients suffering intraprocedural aneurysm re-rupture were more likely to have unfavorable outcome (OR 6.9, 95% CI 2.3–20.9). Discussion and conclusion: Adverse events related to endovascular occlusion of a ruptured aneurysm were seen in 16% of patients. Aneurysm re-rupture during endovascular treatment was associated with increased risk of unfavorable functional outcome.

Abstract Background There is no consensus for when publicly funded breast reduction is indicated and recommendations in guidelines vary greatly, indicating a lack of evidence and unequal access. The primary aim of this review was to examine risks and benefits of breast reduction to treat breast hypertrophy. Secondary aims were to examine how the studies defined breast hypertrophy and indications for a breast reduction. Methods A systematic literature search was conducted in PubMed, MEDLINE All, Embase, the Cochrane Library, and PsycInfo. The included articles were critically appraised, and certainty of evidence was assessed using the GRADE approach. Meta-analyses were performed when possible. Results Fifteen articles were included; eight reporting findings from four randomised controlled trials, three non-randomised controlled studies, three case series, and one qualitative study. Most studies had serious study limitations and problems with directness. Few of the studies defined breast hypertrophy. The studies showed significantly improved health-related quality of life and sexuality-related outcomes in patients who had undergone breast reduction compared with controls, as well as reduced depressive symptoms, levels of anxiety and pain. Most effect sizes exceeded the reported minimal important difference for the scale. Certainty of evidence for the outcomes above is low (GRADE ⊕ ⊕). Although four studies reported significantly improved physical function, the effect is uncertain (very low certainty of evidence, GRADE ⊕). None of the included studies reported data regarding work ability or sick leave. Three case series reported a 30-day mortality of zero. Reported major complications after breast reduction ranged from 2.4 to 14% and minor complications from 2.4 to 69%. Conclusion There is a lack of high-quality studies evaluating the results of breast reduction. A breast reduction may have positive psychological and physical effects for women, but it is unclear which women benefit the most and which women should be offered a breast reduction in the public healthcare system. Several priorities for further research have been identified. Pre-registration The study is based on a Health Technology Assessment report, pre-registered and then published on the website of The Regional HTA Centre of Region Västra Götaland, Sweden.

Administration of the human papillomavirus (HPV) vaccine in early adolescence is effective in preventing cervical cancer, a common cancer in sub-Saharan Africa. Nigeria is in the pre-introduction era of the HPV vaccine. Understanding the preferences of the population for the vaccine can help design the HPV immunization program to ensure high uptake of the vaccine. This study explored the preferences for the HPV vaccine among stakeholders in selected communities in Ibadan, Nigeria. A discrete choice experiment survey based on six attributes of the HPV vaccine (which were the number of doses, the efficacy of the vaccine, cost of the vaccine, location of the service point, other benefits of the vaccine apart from prevention of cervical cancer and the odds of a side effect from the vaccine) was carried out in five communities. Data were analyzed using conditional and mixed logit models. Seven hundred community members were recruited, 144 (20.7%) were adolescents and 248 (35.4%) were males. In line with expectations, respondents preferred vaccines with higher efficacy, less severe side effects and lower costs. Preference heterogeneity was identified for adolescents that were less price-sensitive and other community members who were less likely to prefer using schools as the service point. The high socioeconomic class preferred a vaccine that also prevents genital warts. There were variabilities in the preferences for the attributes of the HPV vaccine in the study communities. These variabilities need to be considered in the introduction of the HPV vaccine to ensure high uptake of the vaccine.

Abstract Objectives To study the cost-effectiveness of a care manager organization for patients with mild to moderate depression in Swedish primary care in a 12-month perspective. Methods Cost-effectiveness analysis of the care manager organization compared to care as usual (CAU) in a pragmatic cluster randomised controlled trial including 192 individuals in the care manager group and 184 in the CAU group. Cost-effectiveness was assessed from a health care and societal perspectives. Costs were assessed in relation to two different health outcome measures: depression free days (DFDs) and quality adjusted life years (QALYs). Results At the 12-month follow-up, patients treated at the intervention Primary Care Centres (PCCs) with a care manager organization had larger health benefits than the group receiving usual care only at control PCCs. Mean QALY per patient was 0.73 (95% CI 0.7; 0.75) in the care manager group compared to 0.70 (95% CI 0.66; 0.73) in the CAU group. Mean DFDs was 203 (95% CI 178; 229) in the care manager group and 155 (95% CI 131; 179) in the CAU group. Further, from a societal perspective, care manager care was associated with a lower cost than care as usual, resulting in a dominant incremental cost-effectiveness ratio (ICER) for both QALYs and DFDs. From a health care perspective care manager care was related to a low cost per QALY (36,500 SEK / €3,379) and DFD (31 SEK/€3). Limitations A limitation is the fact that QALY data was impaired by insufficient EQ-5D data for some patients. Conclusions A care manager organization at the PCC to increase quality of care for patients with mild-moderate depression shows high health benefits, with no decay over time, and high cost-effectiveness both from a health care and a societal perspective. Trial registration details: The trial was registered in ClinicalTrials.com ( https://clinicaltrials.gov/ct2/show/NCT02378272 ) in 02/02/2015 with the registration number NCT02378272. The first patient was enrolled in 11/20/2014.

Abstract Background Severe traumatic brain injury (TBI) is associated with blood–brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. Methods We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6–12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (Q A), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. Results TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with Q A, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR 2 = 7.4%) and complement factor B in serum (p = 0.003, ΔR 2 = 9.2%) were independent outcome predictors also following step-down modelling. Conclusions This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.

Purpose: To investigate contemporary results of percutaneous transluminal renal angioplasty (PTRA). Materials and Methods: A multicentre retrospective study analysing all patients treated with PTRA for primary symptomatic renal artery stenosis (RAS) between 2010 and 2013 at four tertiary centres. Procedures during the preceding four years were counted to evaluate for change in PTRA frequency. Results: The number of PTRA procedures decreased by approximately 50% from 2006 to 2013. Patients treated in the post-ASTRAL period (n = 224) had a significant reduction in mean systolic pressure (168 to 146 mmHg, p

Abstract Purpose While most Achilles tendon ruptures are dramatic and diagnosed quickly, some are missed, with a risk of becoming chronic. A chronic Achilles tendon rupture is defined as a rupture that has been left untreated for more than 4 weeks. By mapping the health economic cost of chronic Achilles tendon ruptures the health-care system might be able to better distribute resources to detect these ruptures at an earlier time. Method All patients with a chronic Achilles tendon rupture who were treated surgically at Sahlgrenska University Hospital or Kungsbacka Hospital between 2013 and 2018 were invited to participate in the study. The patients were evaluated postoperatively using the validated Achilles tendon Total Rupture Score (ATRS). The health-care costs were assessed using clinical records. The production-loss costs were extracted from the Swedish Social Insurance Agency. The cost of chronic Achilles tendon ruptures was then compared with the cost of acute ruptures in a previous study by Westin et.al. Results Forty patients with a median (range) age of 66 (28–86) were included in the study. The mean total cost (± SD) for the patients with a chronic Achilles tendon rupture was 6494 EUR ± 6508, which is 1276 EUR higher than the mean total cost of acute ruptures. Patients with chronic Achilles tendon ruptures reported a mean (min-max) postoperative ATRS of 73 (14–100). Conclusion Missing an Achilles tendon rupture will entail higher health-care costs compared with acute ruptures. Health-care resources can be saved if Achilles tendon ruptures are detected at an early stage.

Peripheral nerves have a propensity for axon growth and regeneration that the central nervous system lacks (CNS). However, CNS axons can also grow long distances if introduced to a graft harvested from a peripheral nerve (PNGs), which is the rationale for using PNGs as repair strategy for injuries of the spinal cord. From a clinical perspective, PNGs provide interesting possibilities with potential to repair the injured spinal cord. First, there are numerous options to harvest autologous grafts associated with low risk for the patient. Second, a PNG allow axons to grow considerable distances and can, by the surgical procedure, be navigated to specific target sites in the CNS. Furthermore, a PNG provides all necessary biological substrates for myelination of elongating axons. A PNG can thus be suited to bridge axons long distances across an injury site and restore long tracts in incomplete SCI. Experimentally, locomotor functions have been improved transplanting a PNG after incomplete injury. However, we still know little with regard to the formation of new circuitries and functional outcome in association to when, where, and how grafts are inserted into the injured spinal cord, especially for sensory functions. In this perspective, we discuss the advantages of PNG from a clinical and surgical perspective, the need for adding/repairing long tracts, how PNGs are best applied for incomplete injuries, and the unexplored areas we believe are in need of answers.

Abstract Background Ethiopia was among the 15 countries that, together accounted for 64% of the world’s severe episodes of pneumonia among children below the age of 5 in 2011. To reduce this burden, the 10-valent pneumococcal conjugate vaccine (PCV 10) was introduced into the general childhood national immunization program in Ethiopia in 2011. However, there is little evidence on its cost-effectiveness, and the aim of this study was to estimate the cost-effectiveness of the introduction of PCV 10 vaccination in the Ethiopian setting. Methods The cost-effectiveness analysis was carried out based on a quasi-experimental evaluation of implementing PCV 10 at the Butajira rural health program site in Ethiopia. The intervention and the control groups consisted 876 and 1010 children, respectively. Using data from program site’s surveillance system database as a framework, health outcome and vaccination data were collected from medical records, immunization registration books and reports. Disability- Adjusted Life Year (DALY) was a main health outcome metric complimented by incidence of acute lower respiratory infection/1000-person years. Vaccination and treatment costs were collected by document review and cross-sectional household survey. Results In the intervention cohort, 626 of 876 (71.5%) children received PCV 10 vaccination. Until the first year of life, the incidence of acute lower respiratory infection was higher in the intervention group. After the first year of life, the incidence rate was 35.2 per 1000-person years in the intervention group compared to 60.4 per 1000-person years in the control group. The incremental cost-effectiveness ratio (ICER) per averted DALY for the intervention group during the total follow-up period was (2013 US$) 394.3 (undiscounted) and 413.8 (discounted). The ICER per averted DALY excluding the first year of life was (2013 US$) 225 (undiscounted) and 292.7 (discounted). Conclusion Compared to the WHO’s suggested cost-effectiveness threshold value, the results indicate that the general childhood PCV 10 vaccination was a cost-effective intervention in the Butajira rural health program site.

Summary: Long-term survival and integration of neural progenitor cells (NPCs) transplanted following spinal cord injury (SCI) have been observed. However, questions concerning the differentiation choice, the mechanism of action, and the contribution of NPCs to functional recovery remains unanswered. Therefore, we investigated the differentiation of NPCs, global transcriptomal changes in transplanted NPCs, the effect of NPCs on neuroinflammation, and the causality between NPC transplantation and functional recovery. We found that NPCs transplanted following SCI differentiate mainly into oligodendrocytes and enhance myelination, upregulate genes related to synaptic signaling and mitochondrial activity, and downregulate genes related to cytokine production and immune system response. NPCs suppress the expression of pro-inflammatory cytokines/chemokines; moreover, NPC ablation confirm that NPCs were responsible for enhanced recovery in hindlimb locomotor function. Understanding the reaction of transplanted NPCs is important for exploiting their full potential. Existence of causality implies that NPCs are useful in the treatment of SCI. : In this article, Brundin and colleagues show that NPCs transplanted following SCI differentiated mainly into oligodendrocytes and enhanced myelination, upregulated genes related to synaptic signaling and mitochondrial activity, suppressed pro-inflammation, and were responsible for enhanced recovery in hindlimb function. Understanding the reaction of transplanted NPCs is important for exploiting their full potential. Existence of causality implies that NPCs are useful in the treatment of SCI. Keywords: spinal cord injury, neural progenitor cells, global transcriptomal changes, neuroinflammation, oligodendrocyte, myelination, regeneration, hindlimb locomotor function, transplantation

Abstract Background A model for triaging patients in primary care to provide immediate contact with the most appropriate profession to treat the condition in question has been developed and implemented in parts of Sweden. Direct triaging of patients with musculoskeletal disorders (MSD) to physiotherapists at primary healthcare centres has been proposed as an alternative to initial assessment by general practitioners (GPs) and has been shown to have many positive effects. The aim of this study was to evaluate the cost-effectiveness from the societal perspective of this new care-pathway through primary care regarding triaging patients with MSD to initial assessment by physiotherapists compared to standard practice with initial GP assessment. Methods Nurse-assessed patients with MSD (N = 55) were randomised to initial assessment and treatment with either physiotherapists or GPs and were followed for 1 year regarding health-related quality of life, utilization of healthcare resources and absence from work for MSD. Quality-adjusted life-years (QALYs) were calculated based on EQ5D measured at 5 time-points. Costs for healthcare resources and production loss were compiled. Incremental cost-effectiveness ratios (ICERS) were calculated. Multiple imputation was used to compensate for missing values and bootstrapping to handle uncertainty. A cost-effectiveness plane and a cost-effectiveness acceptability curve were construed to describe the results. Results The group who were allocated to initial assessment by physiotherapists had slightly larger gains in QALYs at lower total costs. At a willingness-to-pay threshold of 20,000 €, the likelihood that the intervention was cost-effective from a societal perspective including production loss due to MSD was 85% increasing to 93% at higher thresholds. When only healthcare costs were considered, triaging to physiotherapists was still less costly in relation to health improvements than standard praxis. Conclusion From the societal perspective, this small study indicated that triaging directly to physiotherapists in primary care has a high likelihood of being cost-effective. However, further larger randomised trials will be necessary to corroborate these findings. Trial registration ClinicalTrials.gov NCT02218749. Registered August 18, 2014.

Abstract Background Mesenchymal stem cells (MSCs) and their cellular response to various stimuli have been characterized in great detail in culture conditions. In contrast, the cellular response of MSCs in an in vivo setting is still uncharted territory. In this study, we investigated the cellular response of MSCs following transplantation into spinal cord injury (SCI). Methods Mouse bone marrow-derived MSCs were transplanted 24 h following severe contusion SCI in mice. As controls, MSCs transplanted to the uninjured spinal cord and non-transplanted MSCs were used. At 7 days post transplantation, the MSCs were isolated from the SCI, and their global transcriptional changes, survival, differentiation, proliferation, apoptosis, and phenotypes were investigated using RNA sequencing, immunohistochemistry, and flow cytometry. Results MSCs transplanted into SCI downregulated genes related to cell-cycle regulation/progression, DNA metabolic/biosynthetic process, and DNA repair and upregulated genes related to immune system response, cytokine production/response, response to stress/stimuli, signal transduction and signaling pathways, apoptosis, and phagocytosis/endocytosis. MSCs maintained their surface expression of Sca1 and CD29 but upregulated expression of CD45 following transplantation. Transplanted MSCs maintained their surface expression of MHC-I but upregulated surface expression of MHC-II. Transplanted MSCs survived and proliferated to a low extent, did not express Caspase-3, and did not differentiate into neurons or astrocytes. Conclusion MSCs transplanted into SCI upregulate expression of CD45 and MHC-II and expression of genes related to cytokine production, phagocytosis/endocytosis, and immune cells/response and thereby adopt immune cell-like characteristics within the recipient.

BackgroundHypertension is one of the largest contributors to the disease burden and a major economic challenge for health-care systems. Early detection of persons with high blood pressure can be achieved through screening and has the potential to reduce morbidity and mortality. We evaluate the cost-effectiveness of an opportunistic hypertension screening programme in a dental-care facility for individuals aged 40-75 in comparison to care as usual (the no-screening baseline scenario).MethodsA cost-effectiveness analysis (CEA) was carried out from the payer and societal perspectives, and the short-term (from screening until diagnosis has been established) cost per identified case of hypertension and long-term (20 years) cost per quality-adjusted life year (QALY) were reported. Data on the short-term cost were based on a real-world screening programme in which 2025 healthy individuals were screened for hypertension. Data on the long-term cost were based on the short-term outcomes combined with modelling in a Markov cohort model. Deterministic and probabilistic sensitivity analyses were carried out to assess uncertainty.ResultsThe short-term analysis showed an additional cost of 4,800 SEK (€470) per identified case of hypertension from the payer perspective and from the societal perspective 12,800 SEK (€1,240). The long-term analysis showed a payer cost per QALY of 2.2 million SEK (€210,000) and from the societal perspective 2.8 million SEK per QALY (€270,000).ConclusionThe long-term model results showed that the screening model is unlikely to be cost-effective in a country with a well-developed health-care system and a relatively low prevalence of hypertension.

BackgroundProtecting people from financial hardship and impoverishment due to health care costs is one of the fundamental purposes of the Mongolian health system. However, the inefficient, oversized hospital sector is considered one of the main shortcomings of the system. The aim of this study is to contribute to policy discussions by estimating the extent of catastrophic health expenditure and impoverishment due to inpatient care at secondary-level and tertiary-level public hospitals and private hospitals.MethodsData were derived from a nationally representative survey, the Household Socio-Economic Survey 2012, conducted by the National Statistical Office of Mongolia. A total of 12,685 households were involved in the study. "Catastrophic health expenditure" is defined as out-of-pocket payments for inpatient care that exceed a threshold of 40% of households' non-discretionary expenditure. The "impoverishment" effect of out-of-pocket payments for inpatient care was estimated as the difference between the poverty level before health care payments and the poverty level after these payments.ResultsAt the threshold of 40% of capacity to pay, 0.31%, 0.07%, and 0.02% of Mongolian households suffered financially as a result of their member(s) staying in tertiary-level and secondary-level public hospitals and private hospitals respectively. About 0.13% of the total Mongolian population was impoverished owing to out-of-pocket payments for inpatient care at tertiary-level hospitals. Out-of-pocket payments for inpatient care at secondary-level hospitals and private hospitals were responsible for 0.10% and 0.09% respectively of the total population being pushed into poverty.ConclusionsAlthough most inpatient care at public hospitals is covered by the social health insurance benefit package, patients who utilized inpatient care at tertiary-level public hospitals were more likely to push their households into financial hardship and poverty than the inpatients at private hospitals. Improving the hospital sector's efficiency and financial protection for inpatients would be a crucial means of attaining universal health coverage in Mongolia.

Background: Secondary transports of patients suffering from traumatic brain injury (TBI) may result in a delayed management and neurosurgical intervention, which is potentially detrimental. The aim of this study was to study the effect of triaging and delayed transfers on outcome, specifically studying time to diagnostics and neurosurgical management.Methods: This was a retrospective observational cohort study of TBI patients in need of neurosurgical care, 15 years and older, in the Stockholm Region, Sweden, from 2008 throughout 2014. Data were collected from pre-hospital and in-hospital charts. Known TBI outcome predictors, including the protein biomarker of brain injury S100B, were used to assess injury severity. Characteristics and outcomes of direct trauma center (TC) and those of secondary transfers were evaluated and compared. Functional outcome, using the Glasgow Outcome Scale, was assessed in survivors at 6–12 months after trauma. Regression models, including propensity score balanced models, were used for endpoint assessment.Results: A total of n = 457 TBI patients were included; n = 320 (70%) patients were direct TC transfers, whereas n = 137 (30%) were secondary referrals. In all, n = 295 required neurosurgery for the first 24 h after trauma (about 75% of each subgroup). Direct TC transfers were more severely injured (median Glasgow Coma Scale 8 vs. 13) and more often suffered a high energy trauma (31 vs. 2.9%) than secondary referrals. Admission S100B was higher in the TC transfer group, though S100B levels 12–36 h after trauma were similar between cohorts. Direct or indirect TC transfer could be predicted using propensity scoring. The secondary referrals had a shorter distance to the primary hospital, but had later radiology and surgery than the TC group (all p < 0.001). In adjusted multivariable analyses with and without propensity matching, direct or secondary transfers were not found to be significantly related to outcome. Time from trauma to surgery did not affect outcome.Conclusions: TBI patients secondary transported to a TC had surgical intervention performed hours later, though this did not affect outcome, presumably demonstrating that accurate pre-hospital triaging was performed. This indicates that for selected patients, a wait-and-see approach with delayed neurosurgical intervention is not necessarily detrimental, but warrants further research.

Abstract Background Differences in health care utilization across geographical areas are well documented within several countries. If the variation across areas cannot be explained by differences in medical need, it can be a sign of inefficiency or misallocation of public health care resources. Methods In this observational, longitudinal panel study we use regional level data covering the 21 Swedish regions (county councils) over 13 years and a random effects model to assess to what degree regional variation in outpatient physician visits is explained by observed demand factors such as health, demography and socio-economic factors. Results The results show that regional mortality, as a proxy for population health, and demography do not explain regional variation in visits to primary care physicians, but explain about 50% of regional variation in visits to outpatient specialists. Adjusting for socio-economic and basic supply-side factors explains 33% of the regional variation in primary physician visits, but adds nothing to explaining the variation in specialist visits. Conclusion 50–67% of regional variation remains unexplained by a large number of observable regional characteristics, indicating that omitted and possibly unobserved factors contribute substantially to the regional variation. We conclude that variations in health care utilization across regions is not very well explained by underlying medical need and demand, measured by mortality, demographic and socio-economic factors.

Abstract Background The entire population of Mongolia has free access to primary health care, which is fully funded by the government. It is provided by family health centers in urban settings. In rural areas, it is included in outpatient and inpatient services offered by rural soum (district) health centers. However, primary health care utilization differs across population groups. The aim of this study was to evaluate income-related inequality in primary health care utilization in the urban and rural areas of Mongolia. Methods Data from the Household Socio-Economic Survey 2012 were used in this study. The Erreygers concentration index was employed to assess inequality in primary health care utilization in both urban and rural areas. The indirect standardization method was applied to measure the degree of horizontal inequity. Results The concentration index for primary health care at family health centers in urban areas was significantly negative (−0.0069), indicating that utilization was concentrated among the poor. The concentration index for inpatient care utilization at the soum health centers was significantly positive (0.0127), indicating that, in rural areas, higher income groups were more likely to use inpatient services at the soum health centers. Conclusions Income-related inequality in primary health care utilization exists in Mongolia and the pattern differs across geographical areas. Significant pro-poor inequality observed in urban family health centers indicates that their more effective gatekeeping role is necessary. Eliminating financial and non-financial access barriers for the poor and higher need groups in rural areas would make a key contribution to reducing pro-rich inequality in inpatient care utilization at soum health centers.

Abstract Background Post-traumatic stress disorder (PTSD) is debilitating for patients and society. There are a number of treatment methods albeit not all patients respond to these and an interesting method using electroencephalography-based neurofeedback (EEG-NF) has become more prominent in recent years. This systematic review aimed to assess whether EEG-NF, compared with sham NF, other treatment, or no treatment, is effective for PTSD. Primary outcomes were self-harm, PTSD symptoms, level of functioning and health-related quality of life. Methods Systematic literature searches for randomized controlled trials (RCTs) were conducted in six databases. Random effects meta-analysis was performed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Results Four RCTs were included (123 participants). Suicidal thoughts were significantly reduced after EEG-NF compared with a waiting list in a small study. PTSD symptoms were assessed in all studies with different instruments. Results were consistently in favor of EEG-NF with large effect sizes (standardized mean difference −2.30 (95% confidence interval: −4.37 to −0.24). One study reported significantly improved level of executive functioning and one study a reduction in use of psychotropic medication. Complications were scarcely reported. Certainty of evidence was assessed as very low for the four assessed outcomes. Conclusions Based on four RCTs, with several study limitations and imprecision, it is uncertain whether EEG-NF reduces suicidal thoughts, PTSD symptoms, medication use, or improves function. Although all studies showed promising results, further studies are needed to increase the certainty of evidence.

Priority setting criteria in health care are commonly set by politicians on behalf of the public. It is desirable that these criteria are in line with societal preferences in order to gain acceptance for decisions on what health services to provide and reimburse. We study public preferences for the allocation of the health care budget based on age, disease severity and treatment cost. We use data from a web survey where 1,160 respondents provided their views on priority setting criteria in health care. The data was analyzed using multinomial logistic regression analyses and one-sample proportion tests. Between 13 to 25 percent of the respondents agree that age, disease severity and treatment cost are valid criteria for priority setting, whereas 56 to 80 percent support weaker versions of the statements. We also find significant differences within the population; young men are for example more prone to support explicit priority setting criteria. Our results imply a need for trade-offs in health care priority setting if balancing differing preferences among population groups. To achieve a greater understanding for priority setting in general, and for using economic reasoning in particular, there may be a need for more public transparency to make clear that priority setting is inevitable. Published: Online December 2019

Introduction: Intracranial lesion development is a recognized complication in adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased mortality. As neurological assessment during ECMO treatment remains challenging, protein biomarkers of cerebral injury could provide an opportunity to detect intracranial lesion development at an early stage. The aim of this study was to determine if serially sampled S100B could be used to detect intracranial lesion development during ECMO treatment.Methods: We conducted an observational cohort study of all patients treated with ECMO at ECMO Center Karolinska (Karolinska University Hospital, Stockholm, Sweden) between January and August 2018, excluding patients who did not undergo a computerized tomography scan (CT) during treatment. S100B was prospectively collected at hospital admission and then once daily. The primary end-point was any type of CT verified intracranial lesion. Receiver operating characteristics (ROC) curves and Cox proportional hazards models were employed.Results: Twenty-nine patients were included, of which 15 (52%) developed an intracranial lesion and exhibited higher levels of S100B overall. S100B had a robust association with intracranial lesion development, especially during the first 200 hours following admission. The best area-under-curve (AUC) to predict intracranial lesion development was 40 and 140 hours following ECMO initiation, were a S100B level of 0.69μg/L had an AUC of 0.81 (0.628-0.997). S100B levels were markedly increased following the development of intracranial hemorrhage.Conclusions: Serial serum S100B samples in ECMO patients were both significantly elevated and had an increasing trajectory in patients developing intracranial lesions. Larger prospective trials are warranted to validate these findings and to ascertain their clinical utility.

Abstract Background The aim of the study was to address the lack of evaluations of school-based substance use prevention programs and to conduct a quasi-experimental evaluation of the alcohol use part of the Triad intervention. Methods Eleven Swedish intervention schools (285 pupils) and three control schools (159 pupils) participated in the evaluation. Baseline measurements were conducted in 2011 before the alcohol part in the prevention program was implemented in the intervention schools (school year 6, ages 12–13). We estimated an Intention-To-Treat (ITT) Difference-in-Difference (DD) model to analyze the effectiveness of the intervention on subsequent alcohol use measured in grades 7, 8 and 9. Results The main results show no effect on the likelihood of drinking alcohol or drinking to intoxication. Conclusions The lack of positive effects highlights the need for policy-makers and public health officials need to carefully consider and evaluate prevention programs in order to ensure that they are worthwhile from school, health, and societal perspectives.

BackgroundIn an effort to translate preclinical success in achieving spinal cord regeneration through peripheral nerve grafts, this study details the design and sizing of a guiding device for precision grafting of peripheral nerves for use in a clinical trial in complete (AIS-A) thoracic spinal cord injury (SCI). The device’s design and sizing are compared to a simulation of human spinal cord sizes based on the best available data.MethodsSpinal cord segmental sizes were generated by computer simulation based on data from a meta-analysis recently published by our group. Thoracic segments T2–T12 were plotted, and seven elliptical shapes were positioned across the center of the distribution of sizes. Geometrical measures of error-of-fit were calculated. CAD modeling was used to create cranial and caudal interfaces for the human spinal cord, aiming to guide descending white matter tracts to gray matter at the caudal end of the device and ascending white matter tracts to gray matter at the cranial end of the device. The interfaces were compared qualitatively to the simulated spinal cord sizes and gray-to-white matter delineations.ResultsThe mean error-of-fit comparing simulated spinal cord segments T2–T12 to the best elliptical shape was 0.41 and 0.36 mm, and the 95th percentile was found at 1.3 and 0.98 mm for transverse and anteroposterior diameter, respectively. A guiding device design was reached for capturing the majority of corticospinal axons at the cranial end of the device and guiding them obliquely to gray matter at the caudal end of the device. Based on qualitative comparison, the vast majority of spinal cord sizes generated indicate an excellent fit to the device’s interfaces.ConclusionA set of SCI guiding devices of seven sizes can cover the variability of human thoracic spinal cord segments T2–T12 with an acceptable error-of-fit for the elliptical shape as well as guiding channels. The computational framework developed can be used with other medical technologies involving the human spinal cord where exact sizes and positioning are of importance.

BackgroundPrehospital intubation in traumatic brain injury (TBI) focuses on limiting the effects of secondary insults such as hypoxia, but no indisputable evidence has been presented that it is beneficial for outcome. The aim of this study was to explore the characteristics of patients who undergo prehospital intubation and, in turn, if these parameters affect outcome.Material and methodsPatients ≥15 years admitted to the Department of Neurosurgery, Stockholm, Sweden with TBI from 2008 through 2014 were included. Data were extracted from prehospital and hospital charts, including prospectively collected Glasgow Outcome Score (GOS) after 12 months. Univariate and multivariable logistic regression models were employed to examine parameters independently correlated to prehospital intubation and outcome.ResultsA total of 458 patients were included (n = 178 unconscious, among them, n = 61 intubated). Multivariable analyses indicated that high energy trauma, prehospital hypotension, pupil unresponsiveness, mode of transportation, and distance to the hospital were independently correlated with intubation, and among them, only pupil responsiveness was independently associated with outcome. Prehospital intubation did not add independent information in a step-up model versus GOS (p = 0.154). Prehospital reports revealed that hypoxia was not the primary cause of prehospital intubation, and that the procedure did not improve oxygen saturation during transport, while an increasing distance from the hospital increased the intubation frequency.ConclusionIn this modern trauma cohort, prehospital intubation was not independently associated with outcome; however, hypoxia was not a common reason for prehospital intubation. Prospective trials to assess efficacy of prehospital airway intubation will be difficult due to logistical and ethical considerations.

BackgroundDespite seemingly functional coagulation, hemorrhagic lesion progression is a common and devastating condition following traumatic brain injury (TBI), stressing the need for new diagnostic techniques. Multiple electrode aggregometry (MEA) measures platelet function and could aid in coagulopathy assessment following TBI. The aims of this study were to evaluate MEA temporal dynamics, influence of concomitant therapy, and its capabilities to predict lesion progression and clinical outcome in a TBI cohort.Material and methodsAdult TBI patients in a neurointensive care unit that underwent MEA sampling were retrospectively included. MEA was sampled if the patient was treated with antiplatelet therapy, bled heavily during surgery, or had abnormal baseline coagulation values. We assessed platelet activation pathways involving the arachidonic acid receptor (ASPI), P2Y12 receptor, and thrombin receptor (TRAP). ASPI was the primary focus of analysis. If several samples were obtained, they were included. Retrospective data were extracted from hospital charts. Outcome variables were radiologic hemorrhagic progression and Glasgow Outcome Scale assessed prospectively at 12 months posttrauma. MEA levels were compared between patients on antiplatelet therapy. Linear mixed effect models and uni-/multivariable regression models were used to study longitudinal dynamics, hemorrhagic progression and outcome, respectively.ResultsIn total, 178 patients were included (48% unfavorable outcome). ASPI levels increased from initially low values in a time-dependent fashion (p

OBJECTIVE:The objective of this study was to evaluate the cost effectiveness of tissue engineered bovine tissue pericardium scaffold (CardioCel) for the repair of congenital heart defects in comparison with surgery using xenogeneic, autologous, and synthetic patches over a 40-year time horizon from the perspective of the UK National Health Service. METHODS:A six-state Markov state-transition model to model natural history of disease and difference in the interventional effect of surgeries depending on patch type implanted. Patches differed regarding their probability of re-operation due to patch calcification, based on a systematic literature review. Transition probabilities were based on the published literature, other clinical inputs were based on UK registry data, and cost data were based on UK sources and the published literature. Incremental cost-effectiveness ratio (ICER) was determined as incremental costs per quality adjusted life years (QALY) gained. We used a 40-year analytic time-horizon and adopted the payer perspective. Comprehensive sensitivity analyses were performed. RESULTS:According to the model predictions, CardioCel was associated with reduced incidence of re-operation, increased QALY, and costs savings compared to all other patches. Cost savings were greatest compared to synthetic patches. Estimated cost savings associated with CardioCel were greatest within atrioventricular septal defect repair and lowest for ventricular septal defect repair. Based on our model, CardioCel relative risk for re-operations is 0.938, 0.956and 0.902 relative to xenogeneic, autologous, and synthetic patches, respectively. CONCLUSION:CardioCel was estimated to increase health benefits and save cost when used during surgery for congenital heart defects instead of other patches.

BackgroundTraumatic brain injury (TBI) is a major contributor to morbidity and mortality. Computerized tomography (CT) scanning of the brain is essential for diagnostic screening of intracranial injuries in need of neurosurgical intervention, but may also provide information concerning patient prognosis and enable baseline risk stratification in clinical trials. Novel CT scoring systems have been developed to improve current prognostic models, including the Stockholm and Helsinki CT scores, but so far have not been extensively validated. The primary aim of this study was to evaluate the Stockholm and Helsinki CT scores for predicting functional outcome, in comparison with the Rotterdam CT score and Marshall CT classification. The secondary aims were to assess which individual components of the CT scores best predict outcome and what additional prognostic value the CT scoring systems contribute to a clinical prognostic model.Methods and findingsTBI patients requiring neuro-intensive care and not included in the initial creation of the Stockholm and Helsinki CT scoring systems were retrospectively included from prospectively collected data at the Karolinska University Hospital (n = 720 from 1 January 2005 to 31 December 2014) and Helsinki University Hospital (n = 395 from 1 January 2013 to 31 December 2014), totaling 1,115 patients. The Marshall CT classification and the Rotterdam, Stockholm, and Helsinki CT scores were assessed using the admission CT scans. Known outcome predictors at admission were acquired (age, pupil responsiveness, admission Glasgow Coma Scale, glucose level, and hemoglobin level) and used in univariate, and multivariable, regression models to predict long-term functional outcome (dichotomizations of the Glasgow Outcome Scale [GOS]). In total, 478 patients (43%) had an unfavorable outcome (GOS 1-3). In the combined cohort, overall prognostic performance was more accurate for the Stockholm CT score (Nagelkerke's pseudo-R2 range 0.24-0.28) and the Helsinki CT score (0.18-0.22) than for the Rotterdam CT score (0.13-0.15) and Marshall CT classification (0.03-0.05). Moreover, the Stockholm and Helsinki CT scores added the most independent prognostic value in the presence of other known clinical outcome predictors in TBI (6% and 4%, respectively). The aggregate traumatic subarachnoid hemorrhage (tSAH) component of the Stockholm CT score was the strongest predictor of unfavorable outcome. The main limitations were the retrospective nature of the study, missing patient information, and the varying follow-up time between the centers.ConclusionsThe Stockholm and Helsinki CT scores provide more information on the damage sustained, and give a more accurate outcome prediction, than earlier classification systems. The strong independent predictive value of tSAH may reflect an underrated component of TBI pathophysiology. A change to these newer CT scoring systems may be warranted.

This paper compares the implementation of the two economic evaluation methods Cost-Effectiveness/Utility (CEA/CUA) and Cost-Benefit Analysis (CBA) as tools for allocation of national public funds in the health and transport sector in Sweden, respectively. We compare the recommended values for important economic parameters such as the social discount rate, the marginal cost of public funds, and the explicit and implicit valuation of health, and document a number of substantial and unexplained differences in implementation. Such differences are problematic considering that the increasing use of economic evaluations to guide policy decisions also has implied an overlap of application areas. We conclude with a discussion on the need of a harmonized procedure for economic evaluations in the public sector in order to reduce the risk of inefficient allocations purely due to different applications of the methods. Published: Online February 2017. In print December 2017.

Transplantation of neural stem cells and the mobilization of endogenous neuronal precursors in the adult brain have been proposed as therapeutic strategies for central nervous system disorders and injuries. The aim of the present study was to investigate the possible survival and integration of grafted neural progenitor cells (NPCs) from the subventricular zone (SVZ) in a hypoglossal nerve avulsion model with substantial neuronal loss. Adult neural progenitor cells (NPCs) from the subventricular zone (SVZ) were cultured from inbred transgenic eGFP Lewis rats and transplanted to the hypoglossal nucleus of inbred Lewis rat from the same family but that were not carrying the eGFP strain after avulsion of the hypoglossal nerve. Grafted cells survived in the host more than 3 months and differentiated into neurons [βIII tubulin (Tuj-1 staining)] with fine axon- and dendrite-like processes as well as astrocytes (GFAP) and oligodendrocytes (O4) with typical morphology. Staining for synaptic structures (synaptophysin and bassoon) indicated integration of differentiated cells from the graft with the host CNS. Furthermore, transplantation of NPCs increased the number of surviving motoneurons in the hypoglossal nucleus after nerve avulsion that, if untreated, result in substantial neuronal death. The NPCs used in this study expressed VEGF in vitro as well as in vivo following transplantation that may mediate the rescue effect of the axotomized motoneurons.

Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.

BackgroundFilum terminale (FT) is a structure that is intimately associated with conus medullaris, the most caudal part of the spinal cord. It is well documented that certain regions of the adult human central nervous system contains undifferentiated, progenitor cells or multipotent precursors. The primary objective of this study was to describe the distribution and progenitor features of this cell population in humans, and to confirm their ability to differentiate within the neuroectodermal lineage.Methodology/principal findingsWe demonstrate that neural stem/progenitor cells are present in FT obtained from patients treated for tethered cord. When human or rat FT-derived cells were cultured in defined medium, they proliferated and formed neurospheres in 13 out of 21 individuals. Cells expressing Sox2 and Musashi-1 were found to outline the central canal, and also to be distributed in islets throughout the whole FT. Following plating, the cells developed antigen profiles characteristic of astrocytes (GFAP) and neurons (β-III-tubulin). Addition of PDGF-BB directed the cells towards a neuronal fate. Moreover, the cells obtained from young donors shows higher capacity for proliferation and are easier to expand than cells derived from older donors.Conclusion/significanceThe identification of bona fide neural progenitor cells in FT suggests a possible role for progenitor cells in this extension of conus medullaris and may provide an additional source of such cells for possible therapeutic purposes. Filum terminale, human, progenitor cells, neuron, astrocytes, spinal cord.