Risk of Staphylococcus aureus bacteraemia in patients with rheumatoid arthritis and the effect of orthopaedic implants on the risk: a nationwide observational cohort study.

OBJECTIVE: It remains disputed how much the risk of Staphylococcus aureus bacteraemia (SAB) is increased in patients with rheumatoid arthritis (RA), and the extent to which orthopaedic implants explain the risk. We assessed SAB incidence rates (IRs) and incidence rate ratios (IRRs), comparing RA patients with a general population cohort (GPC) and individuals with versus without orthopaedic implants. METHOD: Danish residents aged ≥ 18 years without prior RA or SAB (=GPC) were followed up for RA and microbiologically verified SAB events (1996-2017). IRRs were calculated by age- and sex-stratified Poisson regression adjusted for age, comorbidities, calendar year, and socioeconomic status. RESULTS: The GPC comprised 5 398 690 individuals. We identified 33 567 incident RA patients (=RA cohort) (median follow-up 7.3 years, IQR 3.6-12.3). We observed 25 023 SAB events (n = 224 in the RA cohort). IRs per 100 000 person-years were 81.0 (RA cohort) and 29.9 (GPC). IRs increased with age. Adjusted IRRs in 18-59-year-old RA patients were 2.6 (95% confidence interval 1.8-3.7) for women and 1.8 (1.1-3.1) for men, compared with same sex and age group GPC. IRRs declined with age. Compared with the GPC without implants, IRRs for RA patients with implants ranged from 1.9 (1.3-2.8) (women ≥ 70 years) to 5.3 (2.2-12.8) (18-59-year-old men). CONCLUSION: In this nationwide registry-based cohort study RA was a risk factor for SAB, and orthopaedic implants further increased the risk. Clinicians should be aware of potential SAB in patients with RA and orthopaedic implants.

Impact of comorbidity on renal cell carcinoma prognosis: a nationwide cohort study.

BACKGROUND: Presence of comorbid diseases at time of cancer diagnosis may affect prognosis. We evaluated the impact of comorbidity on survival of patients diagnosed with renal cell carcinoma (RCC), overall and among younger (<70 years) and older (≥70 years) patients. METHODS: We established a nationwide register-based cohort of 7894 patients aged ≥18 years diagnosed with RCC in Denmark between 2006 and 2017. We computed 1- and 5-year overall survival and hazard ratios (HRs) for death according to the Charlson Comorbidity Index (CCI) score. RESULTS: Survival decreased with increasing CCI score despite an overall increase in survival over time. The 5-year survival rate of patients with no comorbidity increased from 57% among those diagnosed in 2006-2008 to 69% among those diagnosed in 2012-2014. During the same periods, the survival rate increased from 46% to 62% among patients with a CCI score of 1-2 and from 39% to 44% for those with a CCI score of ≥3. Patients with CCI scores of 1-2 and ≥3 had higher mortality rates than patients with no registered comorbidity (HR 1.15, 95% CI 1.06-1.24 and HR 1.56, 95% CI 1.40-1.73). Patterns were similar for older and younger patients. Particularly, diagnoses of liver disease (HR 2.09, 95% CI 1.53-2.84 and HR 4.01, 95% CI 2.44-6.56) and dementia (HR 2.16, 95% CI 1.34-3.48) increased mortality. CONCLUSION: Comorbidity decreased the survival of patients with RCC, irrespective of age, despite an overall increasing survival over time. These results highlight the importance of focusing on comorbidity in this group of patients.

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Considerations for understanding protein measurements: Identification of formation, degradation and more pathological relevant epitopes.

OBJECTIVES: There is a need for precision medicine and an unspoken promise of an optimal approach for identification of the right patients for value-based medicine based on big data. However, there may be a misconception that measurement of proteins is more valuable than measurement of fewer selected biomarkers. In population-based research, variation may be somewhat eliminated by quantity. However, this fascination of numbers may limit the attention to and understanding of the single. This review highlights that protein measurements (with collagens as examples) may mean different things depending on the targeted epitope - formation or degradation of tissues, and even signaling potential of proteins. DESIGN AND METHODS: PubMed was searched for collagen, neo-epitope, biomarkers. RESULTS: Ample examples of assays with specific epitopes, either pathological such as HbA1c, or domain specific such as pro-peptides, which total protein arrays would not have identified were evident. CONCLUSIONS: We suggest that big data may be considered as the funnel of data points, in which most important parameters will be selected. If the technical precision is low or the biological accuracy is limited, and we include suboptimal quality of biomarkers, disguised as big data, we may not be able to fulfill the promise of helping patients searching for the optimal treatment. Alternatively, if the technical precision of the total protein quantification is high, but we miss the functional domains with the most considerable biological meaning, we miss the most important and valuable information of a given protein. This review highlights that measurements of the same protein in different ways may provide completely different meanings. We need to understand the pathological importance of each epitope quantified to maximize protein measurements.

Pre-clinical evaluation of the effect of co-medication with antibiotics and oral steroids in Göttingen Minipigs on the biological activity of the probiotic medicinal product TSO (Trichuris suis ova).

The probiotic medicinal product TSO (Trichuris suis ova) is administered to patients with active ulcerative colitis in an ongoing clinical phase IIb trial where the typical co-medications are steroids (prednisolone or budesonide) and antibiotics (e.g., phenoxymethylpenicillin). The present pre-clinical study evaluates the effects of these co-medications on the biological activity of TSO in Göttingen Minipigs. This translationally relevant pre-clinical model allows administration of TSO with and without oral steroids or antibiotics in a manner similar to the administration to patients, followed by quantification of the biological activity of TSO. The biological activity of TSO was not affected by oral steroids but was reduced by oral antibiotics. Fecal calprotectin, the common marker of intestinal inflammation in patients with UC, did not differ between groups.

SunSmart Accreditation and Use of a Professional Policy Drafting Service: Both Positively and Independently Associated with High Sun Protective Hat Scores Derived from Primary School Policies.

BACKGROUND: The head and neck are exposed to the highest solar ultraviolet radiation levels and experience a disproportionate skin cancer burden. Sun protective hats can provide an effective barrier. Since early life exposure contributes to skin cancer risk, the World Health Organisation recommends prevention programmes in schools. The New Zealand SunSmart Schools programme is one example. Two criteria concern wearing hat outdoors: students are required to wear a hat providing protection for the face, neck, and ears; if a suitable hat is not worn, students must play in shaded areas. OBJECTIVES: To investigate two internationally relevant interventions as plausible statistical predictors of hat policy strength: (1) skin cancer primary prevention programme membership, (2) use of a professional policy drafting service. METHODS: Of 1,242 (62%) eligible schools participating in a 2017 national survey, 1,137 reported a sun protection policy and 842 were available for categorising and allocating protective scores (0-3). RESULTS: In multinomial (polytomous) logistic regression models of cross-sectional association, adjusted for school characteristics, SunSmart accredited schools and those utilising a policy drafting service were independently significantly more likely than their counterparts to obtain the most protective compared to the least protective hat score (respectively, RRR 6.48: 95% CI 3.66, 11.47; 7.47: 3.67, and 15.20). For the dichotomous shade measure, similar associations were found using adjusted logistic regression (OR 3.28: 95% CI 2.11, 5.09; 2.70: 1.54, 4.74). CONCLUSIONS: Our findings provide support for two plausible interventions that could potentially be implemented beneficially in primary schools via established infrastructure in any jurisdiction, internationally.

Diabetes and COVID-19: psychosocial consequences of the COVID-19 pandemic in people with diabetes in Denmark-what characterizes people with high levels of COVID-19-related worries?

AIM: To map COVID-19-specific worries and overall psychosocial health among people with diabetes in the initial phase of the COVID-19 pandemic in Denmark, and to explore characteristics of people with diabetes and high levels of worries related to the COVID-19 pandemic. METHODS: A cross-sectional survey was conducted by distributing online questionnaires to 2430 adult members (> 18 years) of two user panels consisting of people with diabetes who have volunteered to share information about their life with diabetes. The questionnaire included items on COVID-19-specific worries as well as such worries related to diabetes, sociodemographic and health status, social relations, diabetes-specific social support, diabetes distress and changes in diabetes-specific behaviours. Responses were analysed with descriptive statistics and logistic regressions. RESULTS: People with diabetes have COVID-19-specific worries related to their diabetes. More than half were worried about being overly affected due to diabetes if infected with COVID-19, about one-third about being characterized as a risk group due to diabetes and not being able to manage diabetes if infected. Logistic regressions showed that being female, having type 1 diabetes, diabetes complications and diabetes distress, feeling isolated and lonely, and having changed diabetes behaviours were associated with being more worried about COVID-19 and diabetes. CONCLUSION: People with diabetes have COVID-19-specific worries related to their diabetes which is associated with poorer psychosocial health. These worries should be addressed through support targeting specific questions and needs of individuals with diabetes as well as frequent updates on new knowledge regarding COVID-19 and diabetes.

Increased risk of incident primary cancer after Staphylococcus aureus bacteremia: A matched cohort study.

Susceptibility to infectious disease may be a marker of immunodeficiency caused by unrecognized cancer. To test the hypothesis, the risk of incident primary cancer was estimated among survivors of Staphylococcus aureus bacteremia (SAB) and compared to a random population cohort.Nation-wide population-based matched cohort study. Cases of SAB were identified from a national database and incident primary cancers were ascertained by record linkage. Incidence rate (IR) and ratio (IRR) with 95% confidence interval (CI) of 27 cancers was calculated by Poisson regression.During the first year of follow-up, 165 and 943 incident cases of cancer occurred in the case cohort (n = 12,918 (1.3%)) and the population cohort (n = 117,465 (0.8%)) for an IR of 3.78 (3.22-4.40) and 2.28 (2.14-2.43) per 100,000 person-years. The IRR was 1.65 (1.40-1.95). Of 27 cancers, 7 cancers occurred more frequently amongst cases than controls: cervical cancer (IRR 37.83 (4.23-338.47)), multiple myeloma (IRR 6.31 (2.58-15.44)), leukemia (IRR 4.73 (2.21-10.10)), sarcoma (IRR 4.73 (1.18-18.91)), liver cancer (IRR 3.64 (1.30-10.21)), pancreatic cancer (IRR 2.8 (1.27-6.16)), and urinary tract cancer (IRR 2.58 (1.23-5.39)). Compared to the control population, the risk of cancer was higher for those without comorbidity and with younger age. The overall risk of cancer during 2 to 5 years of follow-up was not increased (IRR 0.99 (95% CI: 0.89-1.11). However, the risk of pharyngeal cancer was increased (IRR 1.88 (1.04-3.39)) and the risk of liver cancer remained increased (IRR 3.93 (2.36-6.55)).The risk of primary incident cancer was 65% higher in the SAB cohort compared to the population cohort during the first year of follow-up and included 7 specific cancers. The risk was higher for those without comorbidity and with younger age. Screening for these specific cancers in selected populations may allow for earlier detection.

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome.

Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.

Increased abundance of proteobacteria in aggressive Crohn's disease seven years after diagnosis.

Intestinal dysbiosis in inflammatory bowel disease (IBD) patients depend on disease activity. We aimed to characterize the microbiota after 7 years of follow-up in an unselected cohort of IBD patients according to disease activity and disease severity. Fifty eight Crohn's disease (CD) and 82 ulcerative colitis (UC) patients were included. Disease activity was assessed by the Harvey-Bradshaw Index for CD and Simple Clinical Colitis Activity Index for UC. Microbiota diversity was assessed by 16S rDNA MiSeq sequencing. In UC patients with active disease and in CD patients with aggressive disease the richness (number of OTUs, p = 0.018 and p = 0.013, respectively) and diversity (Shannons index, p = 0.017 and p = 0.023, respectively) were significantly decreased. In the active UC group there was a significant decrease in abundance of the phylum Firmicutes (p = 0.018). The same was found in CD patients with aggressive disease (p = 0.05) while the abundance of Proteobacteria phylum showed a significant increase (p = 0.03) in CD patients. We found a change in the microbial abundance in UC patients with active disease and in CD patients with aggressive disease. These results suggest that dysbiosis of the gut in IBD patients is not only related to current activity but also to the course of the disease.

Surface tension determines tissue shape and growth kinetics.

The collective self-organization of cells into three-dimensional structures can give rise to emergent physical properties such as fluid behavior. Here, we demonstrate that tissues growing on curved surfaces develop shapes with outer boundaries of constant mean curvature, similar to the energy minimizing forms of liquids wetting a surface. The amount of tissue formed depends on the shape of the substrate, with more tissue being deposited on highly concave surfaces, indicating a mechano-biological feedback mechanism. Inhibiting cell-contractility further revealed that active cellular forces are essential for generating sufficient surface stresses for the liquid-like behavior and growth of the tissue. This suggests that the mechanical signaling between cells and their physical environment, along with the continuous reorganization of cells and matrix is a key principle for the emergence of tissue shape.

From macroscopic mechanics to cell-effective stiffness within highly aligned macroporous collagen scaffolds.

In the design of macroporous biomaterial scaffolds, attention is payed predominantly to the readily accessible macroscopic mechanical properties rather than to the mechanical properties experienced by the cells adhering to the material. However, the direct cell mechanical environment has been shown to be of special relevance for biological processes such as proliferation, differentiation and extracellular matrix formation both in vitro and in vivo. In this study we investigated how individual architectural features of highly aligned macroporous collagen scaffolds contribute to its mechanical properties on the macroscopic vs. the microscopic scale. Scaffolds were produced by controlled freezing and freeze-drying, a method frequently used for manufacturing of macroporous biomaterials. The individual architectural features of the biomaterial were carefully characterized to develop a finite element model (FE-model) that finally provided insights in the relation between the biomaterial's mechanical properties on the macro-scale and the properties on the micro-scale, as experienced by adhering cells. FE-models were validated by experimental characterization of the scaffolds, both on the macroscopic and the microscopic level, using mechanical compression testing and atomic force microscopy. As a result, a so-called cell-effective stiffness of these non-trivial scaffold architectures could be predicted for the first time. A linear dependency between the macroscopic scaffold stiffness and the cell-effective stiffness was found, with the latter being consistently higher by a factor of 6.4 ±â€¯0.6. The relevance of the cell-effective stiffness in controlling progenitor cell differentiation was confirmed in vitro. The obtained information about the cell-effective stiffness is of particular relevance for the early stages of tissue regeneration, when the cells first populate and interact with the biomaterial. Beyond the specific biomaterial investigated here, the introduced method is transferable to other complex biomaterial architectures. Design-optimization in 3D macroporous scaffolds that are based on a deeper understanding of the mechanical environment provided to the cells will help to enhance biomaterial-based tissue regeneration approaches.

Multidonor FMT capsules improve symptoms and decrease fecal calprotectin in ulcerative colitis patients while treated - an open-label pilot study.

Background: Growing evidence indicates that gut dysbiosis is a factor in the pathogenesis of ulcerative colitis (UC). Fecal microbiota transplantation (FMT) appears to be promising in inducing UC remission, but there are no reports regarding administration using capsules. Methods: Seven patients with active UC, aged 27-50 years, were treated with 25 multidonor FMT capsules daily for 50 days as a supplement to their standard treatment in an open-label pilot study. The primary objective was to follow symptoms through the Simple Clinical Colitis Activity Index (SCCAI). Secondary objectives were to follow changes in fecal calprotectin and microbial diversity through fecal samples and quality of life through the Inflammatory Bowel Disease Questionnaire (IBDQ). Participants were followed through regular visits for six months. Results: From a median of 6 at baseline, the SCCAI of all participants decreased, with median decreases of 5 (p = .001) and 6 (p = .001) after 4 and 8 weeks, respectively. Three of the seven patients had flare-up/relapse of symptoms after the active treatment period. The median F-calprotectin of ≥1800 mg/kg at baseline decreased significantly during the treatment period, but increased again in the follow-up period. The median IBDQ improved at all visits compared to baseline. The fecal microbiota α-diversity did not increase in the study period compared to baseline. All participants completed the treatment and no serious adverse events were reported. Conclusion: Fifty days of daily multidonor FMT capsules temporarily improved symptoms and health-related life quality and decreased F-calprotectin in patients with active UC.

Safety and feasibility of preoperative exercise training during neoadjuvant treatment before surgery for adenocarcinoma of the gastro-oesophageal junction.

Background: Neoadjuvant chemotherapy or chemoradiotherapy is used widely before tumour resection in cancer of the gastro-oesophageal junction (GOJ). Strategies to improve treatment tolerability are warranted. This study examined the safety and feasibility of preoperative exercise training during neoadjuvant treatment in these patients. Methods: Patients were allocated to a standard-care control group or an exercise group, who were prescribed standard care plus twice-weekly high-intensity aerobic exercise and resistance training sessions. The primary endpoint was the incidence of serious adverse events (SAEs) that prevented surgery, including death, disease progression or physical deterioration. Preoperative hospital admission, postoperative complications, changes in patient-reported quality of life and pathological treatment response were also recorded. In the exercise group, adherence to exercise and changes in aerobic fitness, muscle strength and body composition were measured. Results: The incidence of SAEs was not increased in the exercise group. The risk of failure to reach surgery was 5 versus 21 per cent in the control group (risk ratio (RR) 0·23, 95 per cent c.i. 0·04 to 1·29), the risk of preoperative hospital admission was 15 versus 38 per cent respectively (RR 0·39, 0·12 to 1·23) and the risk of postoperative complications was 58 versus 57 per cent (RR 1·06, 0·61 to 1·73). The exercise group attended a mean of 17·5 sessions, and improved fitness, muscle strength and Functional Assessment of Cancer Therapy - Esophageal (FACT-E) total score compared with the baseline level. Conclusion: Preoperative exercise training during neoadjuvant treatment in patients with GOJ cancer is safe and feasible, with improvements in fitness, strength and quality of life. Preoperative exercise training may be associated with a lower risk of critical SAEs that preclude surgery or result in hospitalization.

Disturbed sleep in cluster headache is not the result of transient processes associated with the cluster period.

BACKGROUND AND PURPOSE: Cluster headache (CH) is characterized by severe, unilateral attacks of pain and a high nocturnal attack burden. It remains unknown whether perturbations of sleep are solely present during the CH bout. Therefore, we aimed to investigate differences in sleep between the bout and remission period in patients with episodic CH and, secondly, to compare patients in the two phases with controls. METHODS: Patients with episodic CH (aged 18-65 years), diagnosed according to the International Classification of Headache Disorders 2nd edition, were admitted for polysomnography at the Danish Center for Sleep Medicine in bout and in remission. The macrostructure of sleep, including arousals, breathing parameters, limb movements and periodic limb movements, was compared with 25 age-, sex- and body mass index-matched healthy controls. RESULTS: There were no differences in any of the sleep parameters for patients in bout (n = 32) compared with patients in remission (n = 23). Attacks were unrelated to sleep stages, presence of apnea episodes, periodic limb movements, limb movements and arousals. In bout, patients had longer sleep latency (18.8 vs. 11.7 min, P < 0.05) and rapid eye movement sleep latency (1.7 vs. 1.2 h, P < 0.05) than controls and sleep efficiency was lower (82.5% vs. 86.5%, P < 0.05). Patients in remission only had a longer sleep latency compared with controls (17.5 vs. 11.7 min, P < 0.01). CONCLUSIONS: The results support the presence of a continuing or slowly recovering disturbance of sleep outside the bout rather than a disturbance occurring secondary to attacks. Further, we confirm that there is no relation between CH attacks and specific sleep stages or between CH and breathing parameters.

Detailed assessment of hypothalamic damage in craniopharyngioma patients with obesity.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. SUBJECTS/METHODS: A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17-56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. RESULTS: Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35-1168) mm3 vs. 879 (775-1086) mm3; P < 0.001. HT volume correlated negatively with fat mass and leptin among CP patients (rs = -0.67; P < .001; rs = -0.53; P = 0.001), and explained 39% of the variation in fat mass. For every 100 mm3 increase in HT volume fat mass decreased by 2.7 kg (95% CI: 1.5-3.9; P < 0.001). Qualitative assessments revealed HT damage in three out of six patients with normal volumetry, but HT damage according to operation records. CONCLUSIONS: A decrease in HT volume was associated with an increase in fat mass and leptin. We present a method with a high inter-rater reliability (0.94) that can be applied by nonradiologists for the assessment of HT damage. The method may be valuable in the risk assessment of diseases involving the HT.

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease.

AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

A biomaterial with a channel-like pore architecture induces endochondral healing of bone defects.

Biomaterials developed to treat bone defects have classically focused on bone healing via direct, intramembranous ossification. In contrast, most bones in our body develop from a cartilage template via a second pathway called endochondral ossification. The unsolved clinical challenge to regenerate large bone defects has brought endochondral ossification into discussion as an alternative approach for bone healing. However, a biomaterial strategy for the regeneration of large bone defects via endochondral ossification is missing. Here we report on a biomaterial with a channel-like pore architecture to control cell recruitment and tissue patterning in the early phase of healing. In consequence of extracellular matrix alignment, CD146+ progenitor cell accumulation and restrained vascularization, a highly organized endochondral ossification process is induced in rats. Our findings demonstrate that a pure biomaterial approach has the potential to recapitulate a developmental bone growth process for bone healing. This might motivate future strategies for biomaterial-based tissue regeneration.

Intensive care doctors' preferences for arterial oxygen tension levels in mechanically ventilated patients.

BACKGROUND: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors' preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors' preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. METHODS: In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. RESULTS: The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO2 ) the most important parameter; 24% a combination of PaO2 and arterial oxygen saturation (SaO2 ); and 23% preferred SaO2 . Increasing, decreasing or not changing a default fraction of inspired oxygen of 0.50 showed preferences for a PaO2 around 8 kPa in patients with chronic obstructive pulmonary disease, a PaO2 around 10 kPa in patients with healthy lungs, acute respiratory distress syndrome or sepsis, and a PaO2 around 12 kPa in patients with cardiac or cerebral ischaemia. Eighty per cent would accept a PaO2 of 8 kPa or lower and 77% would accept a PaO2 of 12 kPa or higher in a clinical trial of oxygenation targets. CONCLUSION: Intensive care unit doctors preferred PaO2 to SaO2 in monitoring oxygen treatment when peripheral oxygen saturation was not included in the question. The identification of PaO2 as the preferred target and the thorough clarification of preferences are important when ascertaining optimal oxygenation targets. In particular when designing future clinical trials of higher vs lower oxygenation targets in ICU patients.

The organisation of critical care for burn patients in the UK: epidemiology and comparison of mortality prediction models.

In the UK, a network of specialist centres has been set up to provide critical care for burn patients. However, some burn patients are admitted to general intensive care units. Little is known about the casemix of these patients and how it compares with patients in specialist burn centres. It is not known whether burn-specific or generic risk prediction models perform better when applied to patients managed in intensive care units. We examined admissions for burns in the Case Mix Programme Database from April 2010 to March 2016. The casemix, activity and outcome in general and specialist burn intensive care units were compared and the fit of two burn-specific risk prediction models (revised Baux and Belgian Outcome in Burn Injury models) and one generic model (Intensive Care National Audit and Research Centre model) were compared. Patients in burn intensive care units had more extensive injuries compared with patients in general intensive care units (median (IQR [range]) burn surface area 16 (7-32 [0-98])% vs. 8 (1-18 [0-100])%, respectively) but in-hospital mortality was similar (22.8% vs. 19.0%, respectively). The discrimination and calibration of the generic Intensive Care National Audit and Research Centre model was superior to the revised Baux and Belgian Outcome in Burn Injury burn-specific models for patients managed on both specialist burn and general intensive care units.