Myxomatous Mitral Valve Disease in Large Breed Dogs: Survival Characteristics and Prognostic Variables.

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.

Analyses of quality of life in cancer drug trials - a review of measurements and analytical choices in post-reimbursement studies.

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.

Systematic review of cost-effectiveness in breast reconstruction: deep inferior epigastric perforator flap vs. implant-based breast reconstruction.

BACKGROUND: There are several techniques for reconstructing breasts after mastectomy, but little scientific evidence for which technique is superior. The aim of this systematic review was to compare the cost-effectiveness of implant-based and autologous reconstruction and to evaluate the overall certainty of evidence, as well as the quality of reporting of the included studies. METHODS: Studies investigating the cost-effectiveness of breast reconstruction with a deep inferior epigastric perforator (DIEP) flap compared to implant-based reconstruction, meeting criteria defined in a PICO (population, intervention, comparison, and outcome), were included. Medline, PubMed, Embase, Cochrane library, CinahL, EconLit, and NHS EED databases were searched. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence, and the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) 2022 was used to evaluate the quality of reporting. RESULTS AND CONCLUSIONS: A total of 256 abstracts were retrieved from the search, and after scrutiny, seven studies were included. The findings of this present systematic review should be interpreted with caution as the overall certainty of evidence is low (GRADE ƟƟОО). The included studies suggest that DIEP-flaps are cost-effective compared with implant-based breast reconstruction when the applied cost-effectiveness thresholds of $50,000 to $100,000 per quality-adjusted life years are used. It is noteworthy that no high level evidence exists regarding cost-effeciency, to support recommendations and decision in breast reconstruction. Methodological issues that can be improved in future studies are presented.

Cancer Drugs Reimbursed with Limited Evidence on Overall Survival and Quality of Life: Do Follow-Up Studies Confirm Patient Benefits?

BACKGROUND AND OBJECTIVE: Cancer drug costs have increased considerably within healthcare systems, but many drugs lack quality-of-life (QoL) and overall survival (OS) data at the time of reimbursement approval. This study aimed to review the extent of subsequent literature documenting improvements in OS and QoL for cancer drug indications where no such evidence existed at the time of reimbursement approval. METHODS: Drug indications with claims of added therapeutical value but a lack of evidence on OS and QoL that were reimbursed between 2010 and 2020 in Sweden were included for review. Searches were conducted in PubMed and ClinicalTrial.gov for randomized controlled trials examining OS and QoL. RESULTS: Of the 22 included drug indications, seven were found to have at least one trial with conclusive evidence of improvements in OS or QoL after a mean follow-up of 6.6 years. The remaining 15 drug indications either lacked subsequent randomized controlled trial data on OS or QoL (n = 6) or showed no statistically significant improvements (n = 9). Only one drug demonstrated evidence of improvement in both OS and QoL for its indication. CONCLUSIONS: A considerable share of reimbursed cancer drug indications continue to lack evidence of improvement in both OS and QoL. With limited healthcare resources and an increasing cancer burden, third-party payers have strong incentives to require additional post-reimbursement data to confirm any improvements in OS and QoL.

Stem cell-derived brainstem mouse astrocytes obtain a neurotoxic phenotype in vitro upon neuroinflammation.

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-1ß 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.

Healthcare cost and survival in patients with non-functioning pituitary adenoma.

OBJECTIVE: Pituitary adenomas and their consequences impact mortality and morbidity. We studied the healthcare costs, survival, and cost-effectiveness of growth hormone (GH) vs no GH replacement in patients with non-functioning pituitary adenoma (NFPA). DESIGN AND METHODS: A cohort study including all NFPA patients followed from 1987 or the date of diagnosis until the time of death or December 31, 2019, in the Västra Götaland region, Sweden. Data to assess resource use, costs, survival, and cost-effectiveness were collected from patient records and regional/national healthcare registries. RESULTS: A total of 426 patients with NFPA (274 men) with a follow-up of 13.6 ± 6.8 years (mean ± SD) were included. The total annual healthcare cost was higher in patients receiving GH (€9287) than those without GH (€6770), mainly driven by a higher pharmaceutical cost. Glucocorticoid replacement therapy (P = .02), diabetes insipidus (P = .04), body mass index (BMI) (P < .01), and hypertension (P < .01) were all individually associated with a higher total annual cost. The survival rate was higher in the GH group (HR [hazard ratio] 0.60; P = .01) and reduced in patients with glucocorticoid replacement (HR 2.02; P < .01) or diabetes insipidus (HR 1.67; P = .04). The cost per gained life-year for GH vs no GH replacement was about €37 000. CONCLUSIONS: This healthcare utilization study identified several factors driving the cost of care in NFPA patients, such as GH replacement, adrenal insufficiency, and diabetes insipidus. Life expectancy was increased in those with GH replacement and reduced in patients with adrenal insufficiency and diabetes insipidus.

Disease Specific Health Related Quality of Life in Patients With Chronic Limb Threatening Ischaemia Undergoing Revascularisation of Femoropopliteal Lesions.

OBJECTIVE: Patients with chronic limb threatening ischaemia (CLTI) suffer from pain and non-healing ulcers, which impact negatively on both their physical and mental health. While maintaining and improving quality of life is a principal aim with all treatments, little is known about the health related quality of life (HRQoL) of CLTI patients and how revascularisation procedures impact on HRQoL endpoints. The aim of this study was to investigate disease specific HRQoL before and after revascularisation in patients with CLTI undergoing femoropopliteal revascularisation. METHODS: HRQoL was prospectively analysed in 190 CLTI patients with main atherosclerotic target lesions in the femoropopliteal segment, who were planned for endovascular or open revascularisation. The choice of revascularisation method was made by the vascular team, represented by both open and endovascular expertise. The Vascular Quality of Life (VascuQoL) questionnaire was used to assess disease specific HRQoL before revascularisation and one month, one year, and two years after the procedure. Main endpoints were mean VascuQoL score changes, effect sizes of observed changes and the proportion reaching a minimally important difference (half a standard deviation change from baseline) during two years after revascularisation. RESULTS: Patient reported VascuQoL scores were low at baseline (mean 2.68, 95% CI 1.18 - 4.17). After revascularisation, the mean VascuQoL score improved statistically significantly over time, with the largest improvement observed after one year (difference from baseline 2.02, 95% CI 1.75 - 2.29; p < .001). No differences in HRQoL change over time were observed between patients treated with endovascular approaches compared with bypass surgery. Approximately half the patients reached the minimally important threshold at one year (53%), which was largely maintained also at two years (41%). CONCLUSION: While CLTI profoundly affected HRQoL, a large and clinically meaningful HRQoL increase was observed after revascularisation. This confirms the value of CLTI revascularisation on HRQoL and underlines the importance of including patient reported outcomes when evaluating revascularisation procedures in CLTI patients.

The impact of previous health on the mortality after aneurysmal subarachnoid hemorrhage: analysis of a prospective Swedish multicenter study.

PURPOSE: There is an an increasing awareness of the importance of health and lifestyle for stroke diseases like spontaneous subarachnoid hemorrhage (SAH). However, the importance of pre-existing medical conditions for clinical course and mortality after SAH has not been studied. The aim of the present study was to identify pre-existing conditions contributing to mortality after SAH. METHODS: Data were extracted from a Swedish national prospective study on patients with SAH. Variables were defined for age, sex, body mass index (BMI), clinical condition at admission, and for 10 pre-existing medical conditions. Models predicting mortality in three time intervals with all possible subsets of these variables were generated, compared and selected using Akaike's information criterion. RESULTS: 1155 patients with ruptured aneurysms were included. The mortality within 1 week was 7.6%, 1 month 14.3%, and 1 year 18.7%. The most common pre-existing medical conditions were smoking (57.6%) and hypertension (38.7%). The model's best predicting mortality within 1 week and from 1 week to 1 month included only the level of consciousness at admission and age, and these two variables were present in all the models among the top 200 in Akaike score for each time period. The most predictive model for mortality between 1 month and 1 year added previous stroke, diabetes, psychiatric disease, and BMI as predictors. CONCLUSION: Mortality within the first month was best predicted simply by initial level of consciousness and age, while mortality within from 1 month to 1 year was significantly influenced by pre-existing medical conditions.

Time Course and Clinical Significance of Hematoma Expansion in Moderate-to-Severe Traumatic Brain Injury: An Observational Cohort Study.

BACKGROUND: Preventing intracranial hematoma expansion has been advertised as a possible treatment opportunity in traumatic brain injury (TBI). However, the time course of hematoma expansion, and whether the expansion affects outcome, remains poorly understood. In light of this, the aim of this study was to use 3D volume rendering to determine how traumatic intracranial hematomas expand over time and evaluate its impact on outcome. METHODS: Single-center, population-based, observational cohort study of adults with moderate-to-severe TBI. Hematoma expansion was defined as the change in hematoma volume from the baseline computed tomography scan until the lesion had stopped progressing. Volumes were calculated by using semiautomated volumetric segmentation. Functional outcome was measured by using the 12 month Glasgow outcome scale (GOS). RESULTS: In total, 643 patients were included. The mean baseline hematoma volume was 4.2 ml, and the subsequent mean hematoma expansion was 3.8 ml. Overall, 33% of hematomas had stopped progressing within 3 h, and 94% of hematomas had stopped progressing within 24 h of injury. Contusions expanded significantly more, and for a longer period of time, than extra-axial hematomas. There was a significant dose-response relationship between hematoma expansion and 12 month GOS, even after adjusting for known outcome predictors, with every 1-ml increase in hematoma volume associated with a 6% increased risk of 1-point GOS deduction. CONCLUSIONS: Hematoma expansion is a driver of unfavorable outcome in TBI, with small changes in hematoma volume also impacting functional outcome. This study also proposes a wider window of opportunity to prevent lesion progression than what has previously been suggested.

Stated preferences for human papillomavirus vaccination for adolescents in selected communities in Ibadan, Southwest Nigeria: A discrete choice experiment.

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.

Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages.

Glioblastoma is believed to originate from nervous system cells; however, a putative origin from vessel-associated progenitor cells has not been considered. We deeply single-cell RNA-sequenced glioblastoma progenitor cells of 18 patients and integrated 710 bulk tumors and 73,495 glioma single cells of 100 patients to determine the relation of glioblastoma cells to normal brain cell types. A novel neural network-based projection of the developmental trajectory of normal brain cells uncovered two principal cell-lineage features of glioblastoma, neural crest perivascular and radial glia, carrying defining methylation patterns and survival differences. Consistently, introducing tumorigenic alterations in naïve human brain perivascular cells resulted in brain tumors. Thus, our results suggest that glioblastoma can arise from the brains' vasculature, and patients with such glioblastoma have a significantly poorer outcome.

A systematic review and meta-analysis of risks and benefits with breast reduction in the public healthcare system: priorities for further research.

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.

Editor's Choice - Cost Effectiveness of Primary Stenting in the Superficial Femoral Artery for Intermittent Claudication: Two Year Results of a Randomised Multicentre Trial.

OBJECTIVE: Invasive treatment of intermittent claudication (IC) is commonly performed, despite limited evidence of its cost effectiveness. IC symptoms are mainly caused by atherosclerotic lesions in the superficial femoral artery (SFA), and endovascular treatment is performed frequently. The aim of this study was to investigate its cost effectiveness vs. non-invasive treatment. METHODS: One hundred patients with IC due to lesions in the SFA were randomised to treatment with primary stenting, best medical treatment (BMT) and exercise advice (stent group), or to BMT and exercise advice alone (control group). Patients were recruited at seven hospitals in Sweden. For this analysis of cost effectiveness after 24 months, 84 patients with data on quality adjusted life years (QALY; based on the EuroQol Five Dimensions EQ-5D 3L™ questionnaire) were analysed. Patient registry and imputed cost data were used for accumulated costs regarding hospitalisation and outpatient visits. RESULTS: The mean cost per patient was €11 060 in the stent group and €4 787 in the control group, resulting in a difference of €6 273 per patient between the groups. The difference in mean QALYs between the groups was 0.26, in favour of the stent group, which resulted in an incremental cost effectiveness ratio (ICER) of € 23 785 per QALY. CONCLUSION: The costs associated with primary stenting in the SFA for the treatment of IC were higher than for exercise advice and BMT alone. With concurrent improvement in health related quality of life, primary stenting was a cost effective treatment option according to the Swedish national guidelines (ICER < €50 000 - €70 000) and approaching the UK's National Institute for Health and Care Excellence threshold for willingness to pay (ICER < £20 000 - £30 000). From a cost effectiveness standpoint, primary stenting of the SFA can, in many countries, be used as an adjunct to exercise training advice, but it must be considered that successful implementation of structured exercise programmes and longer follow up may alter these findings.

The cost-effectiveness of a two-step blood pressure screening programme in a dental health-care setting.

BACKGROUND: Hypertension 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). METHODS: A 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. RESULTS: The 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). CONCLUSION: The 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.

Transient hyperammonaemia following epileptic seizures in cats.

OBJECTIVES: The aim of this study was to determine whether transient postictal hyperammonaemia exists in cats. METHODS: The medical records of all feline patients that presented at a Swedish veterinary hospital between 2008 and 2018 were retrospectively reviewed to find those that had a recent or ongoing epileptic seizure. To qualify for inclusion, the medical record had to include information on at least one ammonia value taken in close proximity to, or during, an active seizure, the cat must have exceeded the normal upper limit of blood ammonia concentration on initial testing (reference interval 0-95 µmol/l), and there needed to be a follow-up ammonia value available within a maximum of 3 days. RESULTS: Five cats were included in the study, and they had blood ammonia concentrations on initial testing ranging from 146 to 195 µmol/l. They were all retested within a period of 2 h to 3 days of the original reading. All five cats had a spontaneous decrease in ammonia levels without any specific treatment for hyperammonaemia. CONCLUSIONS AND RELEVANCE: Pursuant to the findings of this retrospective study, transient hyperammonaemia may be noted after epileptic seizure in cats. Consequently, a differential diagnostic list in feline patients with hyperammonaemia could, depending on the context, include non-hepatic-related pathologies, such as epileptic seizures.

Amputation-free survival, limb symptom alleviation, and reintervention rates after open and endovascular revascularization of femoropopliteal lesions in patients with chronic limb-threatening ischemia.

BACKGROUND: The optimal strategy for revascularization in chronic limb-threatening ischemia (CLTI) is not yet completely known and is still under debate. Endovascular treatment methods predominate despite limited evidence for their advantage. In this concurrent, prospective observational cohort study, we investigated outcomes after open and endovascular revascularization in the femoropopliteal segment for CLTI. METHODS: Between March 2011 and January 2015, there were 190 patients presenting with CLTI with the principal target lesion in the superficial femoral or popliteal segment who underwent endovascular intervention (n = 117) or bypass surgery (n = 73) and were observed prospectively. The choice of revascularization technique was based on international and local guidelines. All patients were observed for 2 years. The primary end point was amputation-free survival (AFS) assessed with Kaplan-Meier estimates; secondary end points included CLTI symptom alleviation rates and reintervention rates. A Cox proportional hazards regression model was used to investigate risk factors for amputation and death. RESULTS: AFS at 2 years was 59% in the endovascular group and 76% in the bypass group (P = .020). Kaplan-Meier survival analysis confirmed a significant difference in AFS, with mortality rate as the main driver for the observed intergroup AFS difference. In sequential multivariable regression analysis, the observed difference in AFS between the groups favored bypass surgery and remained significant after controlling for covariates of known prognostic importance (hazard ratio, 2.38; 95% confidence interval, 1.14-4.96). At 2 years, a higher proportion of patients subjected to bypass surgery remained free from ischemic rest pain, wounds, and gangrene (65% vs 45%; P = .009). The proportions of patients who underwent reintervention within 2 years were similar in the two groups (38% vs 39%; P = .90), but repeated reinterventions were more frequent in the bypass group. CONCLUSIONS: At 2 years, bypass surgery was associated with higher AFS than endovascular intervention, a finding that could not be explained only by differences in case mix. More patients who had bypass surgery were free from CLTI symptoms at both 1 year and 2 years after revascularization. Reinterventions to maintain patency were equally common after bypass and endovascular intervention.

Absence of Long-Term Benefit of Revascularization in Patients With Intermittent Claudication: Five-Year Results From the IRONIC Randomized Controlled Trial.

BACKGROUND: The long-term benefit of revascularization for intermittent claudication is poorly understood. The aim of this study was to investigate the long-term effectiveness and cost-effectiveness compared with a noninvasive approach. METHODS: The IRONIC trial (Invasive Revascularization or Not in Intermittent Claudication) randomized patients with mild-to-severe intermittent claudication to either revascularization + best medical therapy + structured exercise therapy (the revascularization group) or best medical therapy + structured exercise therapy (the nonrevascularization group). The health-related quality of life short form 36 questionnaire was primary outcome and disease-specific health-related quality of life (vascular quality of life questionnaire) and treadmill walking distances were secondary end points. Health-related quality of life has previously been reported superior in the revascularization group at 1- and 2-year follow-up. In this study, the 5-year results were determined. The cost-effectiveness of the treatment options was analyzed from a payer/healthcare standpoint. RESULTS: Altogether, 158 patients were randomized in a 1:1 ratio. Regarding the primary end point, no intergroup differences were observed for the short form 36 sum or domain scores from baseline to 5 years, except for the short form 36 role emotional domain score, with greater improvement in the nonrevascularization group (n=116, P=0.007). No intergroup differences were observed in the vascular quality of life questionnaire total and domain scores (n=116, NS) or in treadmill walking distances (n=91, NS). A revascularization strategy resulted in almost twice the cost per patient compared with a noninvasive treatment approach ($13 098 versus $6965, P=0.02). CONCLUSIONS: After 5 years of follow-up, a revascularization strategy had lost its early benefit and did not result in any long-term improvement in health-related quality of life or walking capacity compared to a noninvasive treatment strategy. Revascularization was not a cost-effective treatment option from a payer/healthcare point of view. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01219842.

Delayed Neurosurgical Intervention in Traumatic Brain Injury Patients Referred From Primary Hospitals Is Not Associated With an Unfavorable Outcome.

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.

Mesenchymal stem cells transplanted into spinal cord injury adopt immune cell-like characteristics.

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.