Excitonic Insulators and Superfluidity in Two-Dimensional Bilayers without External Fields.

We explore a new platform for realizing excitonic insulators, namely van der Waals (vdW) bilayers comprising two-dimensional Janus materials. In previous studies, type II heterobilayers have been brought to the excitonic insulating regime by tuning the band alignment using external gates. In contrast, the Janus bilayers presented here represent intrinsic excitonic insulators. We first conduct ab initio calculations to obtain the quasiparticle band structures, screened Coulomb interaction, and interlayer exciton binding energies of the bilayers. These ab initio-derived quantities are then used to construct a BCS-like Hamiltonian of the exciton condensate. By solving the mean-field gap equation, we identify 16 vdW Janus bilayers with insulating ground states and superfluid properties. Our calculations expose a new class of advanced materials that are likely to exhibit novel excitonic phases at low temperatures and highlight the subtle competition between interlayer hybridization, spin-orbit coupling, and dielectric screening that governs their properties.

Clinical predictors of incident somatic morbidity in a sample of depressed patients: A 16–30 years follow-up study

Background and objectives: We investigated the independent associations between various characteristics at trial entrance and subsequent development of somatic morbidity in patients participating trials on antidepressants.Methods338 in-patients diagnosed with major depression who had participated in trials on antidepressants conducted between 1983 and 1994 were followed for up to 30 years in Danish registers. By applying a Cox regression model with incident diagnoses of somatic disease as outcome, explanatory variables such as age at first episode, duration of index episode, bipolarity and scores on the Hamilton Depression Scale and subscales hereof, were investigated.ResultsCardiovascular diseases were associated with increasing number of previous depressive episodes at baseline (HR 1.06, 95% CI (1.00–1.11)). The risk of diabetes was associated with increasing duration of index episode (HR 1.01, 95% CI (1.00–1.01) as was respiratory disease (HR 1.00, 95% CI (1.00–1.01)). Diagnoses of infection were associated with increasing score on HAM-D6 (HR 1.11, CI 95 % (1.01–1.22)).ConclusionsThe association between number of previous depressive episodes and CVD is in line with previous results. The findings of associations between the psychometric measures and specific diseases should be interpreted with caution, as well as the associations between duration of episodes, higher severity and higher number of previous episodes, and increased risks of somatic morbidity, albeit these are in line with previous evidence. (AU)

The supramammillary nucleus controls anxiety-like behavior; key role of GLP-1R.

Anxiety disorders are among the most prevalent categories of mental illnesses. The gut-brain axis, along with gastrointestinally-derived neuropeptides, like glucagon-like peptide-1 (GLP-1), are emerging as potential key regulators of emotionality, including anxiety behavior. However, the neuroanatomical substrates from which GLP-1 exerts its anxiogenic effect remain poorly characterized. Here we focus on a relatively new candidate nucleus, the supramammillary nucleus (SuM), located just caudal to the lateral hypothalamus and ventral to the ventral tegmental area. Our focus on the SuM is supported by previous data showing expression of GLP-1R mRNA throughout the SuM and activation of the SuM during anxiety-inducing behaviors in rodents. Data show that chemogenetic activation of neurons in the SuM results in an anxiolytic response in male and female rats. In contrast, selective activation of SuM GLP-1R, by microinjection of a GLP-1R agonist exendin-4 into the SuM resulted in potent anxiety-like behavior, measured in both open field and elevated plus maze tests in male and female rats. This anxiogenic effect of GLP-1R activation persisted after high-fat diet exposure. Importantly, reduction of GLP-1R expression in the SuM, by AAV-shRNA GLP-1R knockdown, resulted in a clear anxiolytic response; an effect only observed in female rats. Our data identify a new neural substrate for GLP-1 control of anxiety-like behavior and indicate that the SuM GLP-1R are sufficient for anxiogenesis in both sexes, but necessary only in females.

Surgical treatment of basal cell carcinoma: a case series on factors influencing the risk of an incomplete primary excision.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer form, and one first-line treatment is surgical excision. Complete excision is vital to minimize risk of recurrence. Studies on occurrence of incomplete excisions have given diverse results and seldom include large populations from a dermatological setting. OBJECTIVES: The rate of positive surgical margins in primary surgery of BCC at a tertiary dermatology clinic is studied. Factors associated with an incomplete primary excision are analysed. METHODS: Patients scheduled for standard excision, without perioperative margin control, of BCC during the years 2008-2015 were prospectively enrolled in the study. Tumour-specific factors, including histopathologic subtype, as well as postoperative outcome were registered. Incomplete excisions were analysed in relation to patient- and tumour-related factors. RESULTS: In total, 4.6% of 3911 BCC tumours were incompletely excised. The rate of incomplete excisions was higher for facial tumours and among tumours with an aggressive histological subtype. Morpheiform BCC on the nose or ear had the highest rate of an incomplete excision, 61.5% and 50%, respectively. CONCLUSIONS: Most BCCs, irrespective of subtype, were completely excised during the primary excision. Tumour sites nose and ears were associated with the highest rate of positive primary surgical margins, especially for infiltrative or morpheiform BCCs. Surgery with perioperative examination of margins is strongly recommended for these tumours.

Is dissolved COD a suitable design parameter for ozone oxidation of organic micropollutants in wastewater?

Ozone oxidation of organic micropollutants in biologically treated wastewater was investigated in pilot-scale after a high- and a low loaded activated sludge process. Higher ozone doses were required to remove organic micropollutants in the effluent wastewater from the high loaded activated sludge process. Further comparison of the micropollutant removal was based on normalized ozone doses, expressed as g O3/g DOC and g O3/g soluble COD (sCOD). A clear difference was noted for the two effluents when the micropollutant removal was normalized by DOC. This difference disappeared almost completely when the removal was linked to ozone doses normalized by sCOD. The dose-response curves for the organic micropollutants were practically linear in the removal range up to 95%. A linear prediction model was developed and compared with literature values to test the transferability of the obtained results. Results from this comparison indicated that the slope of the dose-response functions could be used to predict the removal efficiency of organic micropollutants at a third plant with an average uncertainty of 10%. The modeled ozone requirements were then set in relation to the COD concentrations in the discharged water from approximately 90 Swedish activated sludge treatment plants with and without nitrogen removal. This comparison highlighted the need for a well-functioning biological treatment for an effective ozone oxidation of organic micropollutants. The results in this study suggest that soluble COD should be further explored for design and modeling of ozone oxidation of organic micropollutants in biologically treated wastewater.

First-principle simulations of electronic structure in semicrystalline polyethylene.

In order to increase our fundamental knowledge about high-voltage cable insulation materials, realistic polyethylene (PE) structures, generated with a novel molecular modeling strategy, have been analyzed using first principle electronic structure simulations. The PE structures were constructed by first generating atomistic PE configurations with an off-lattice Monte Carlo method and then equilibrating the structures at the desired temperature and pressure using molecular dynamics simulations. Semicrystalline, fully crystalline and fully amorphous PE, in some cases including crosslinks and short-chain branches, were analyzed. The modeled PE had a structure in agreement with established experimental data. Linear-scaling density functional theory (LS-DFT) was used to examine the electronic structure (e.g., spatial distribution of molecular orbitals, bandgaps and mobility edges) on all the materials, whereas conventional DFT was used to validate the LS-DFT results on small systems. When hybrid functionals were used, the simulated bandgaps were close to the experimental values. The localization of valence and conduction band states was demonstrated. The localized states in the conduction band were primarily found in the free volume (result of gauche conformations) present in the amorphous regions. For branched and crosslinked structures, the localized electronic states closest to the valence band edge were positioned at branches and crosslinks, respectively. At 0 K, the activation energy for transport was lower for holes than for electrons. However, at room temperature, the effective activation energy was very low (∼0.1 eV) for both holes and electrons, which indicates that the mobility will be relatively high even below the mobility edges and suggests that charge carriers can be hot carriers above the mobility edges in the presence of a high electrical field.

Diagnostic conversion to bipolar disorder in unipolar depressed patients participating in trials on antidepressants.

OBJECTIVE: In unipolar depressed patients participating in trials on antidepressants, we investigated if illness characteristics at baseline could predict conversion to bipolar disorder. METHOD: A long-term register-based follow-up study of 290 unipolar depressed patients with a mean age of 50.8 years (SD=11.9) participating in three randomized trials on antidepressants conducted in the period 1985-1994. The independent effects of explanatory variables were examined by applying Cox regression analyses. RESULTS: The overall risk of conversion was 20.7%, with a mean follow-up time of 15.2 years per patient. The risk of conversion was associated with an increasing number of previous depressive episodes at baseline, [HR 1.18, 95% CI (1.10-1.26)]. No association with gender, age, age at first depressive episode, duration of baseline episode, subtype of depression or any of the investigated HAM-D subscales included was found. LIMITATIONS: The patients were followed-up through the Danish Psychiatric Central Research Register, which resulted in inherent limitations such as possible misclassification of outcome. CONCLUSION: In a sample of middle-aged hospitalized unipolar depressed patients participating in trials on antidepressants, the risk of conversion was associated with the number of previous depressive episodes. Therefore, this study emphasizes that unipolar depressed patients experiencing a relatively high number of recurrences should be followed more closely, or at least be informed about the possible increased risk of conversion.

Preoperative prediction of histopathological outcome in basal cell carcinoma: flat surface and multiple small erosions predict superficial basal cell carcinoma in lighter skin types.

BACKGROUND: Prediction of the histopathological subtype of basal cell carcinoma (BCC) is important for tailoring optimal treatment, especially in patients with suspected superficial BCC (sBCC). OBJECTIVES: To assess the accuracy of the preoperative prediction of subtypes of BCC in clinical practice, to evaluate whether dermoscopic examination enhances accuracy and to find dermoscopic criteria for discriminating sBCC from other subtypes. MATERIALS AND METHODS: The main presurgical diagnosis was compared with the histopathological, postoperative diagnosis of routinely excised skin tumours in a predominantly fair-skinned patient cohort of northern Europe during a study period of 3 years (2011-13). The study period was split in two: during period 1, dermoscopy was optional (850 cases with a pre- or postoperative diagnosis of BCC), while during period 2 (after an educational dermoscopic update) dermoscopy was mandatory (651 cases). A classification tree based on clinical and dermoscopic features for prediction of sBCC was applied. RESULTS: For a total of 3544 excised skin tumours, the sensitivity for the diagnosis of BCC (any subtype) was 93·3%, specificity 91·8%, and the positive predictive value (PPV) 89·0%. The diagnostic accuracy as well as the PPV and the positive likelihood ratio for sBCC were significantly higher when dermoscopy was mandatory. A flat surface and multiple small erosions predicted sBCC. CONCLUSIONS: The study shows a high accuracy for an overall diagnosis of BCC and increased accuracy in prediction of sBCC for the period when dermoscopy was applied in all cases. The most discriminating findings for sBCC, based on clinical and dermoscopic features in this fair-skinned population, were a flat surface and multiple small erosions.

Liquid-core nanocellulose-shell capsules with tunable oxygen permeability.

Encapsulation of oxygen sensitive components is important in several areas, including those in the food and pharmaceutical sectors, in order to improve shelf-life (oxidation resistance). Neat nanocellulose films demonstrate outstanding oxygen barrier properties, and thus nanocellulose-based capsules are interesting from the perspective of enhanced protection from oxygen. Herein, two types of nanocellulose-based capsules with liquid hexadecane cores were successfully prepared; a primary nanocellulose polyurea-urethane capsule (diameter: 1.66 µm) and a bigger aggregate capsule (diameter: 8.3 µm) containing several primary capsules in a nanocellulose matrix. To quantify oxygen permeation through the capsule walls, an oxygen-sensitive spin probe was dissolved within the liquid hexadecane core, allowing non-invasive measurements (spin-probe oximetry, electron spin resonance, ESR) of the oxygen concentration within the core. It was observed that the oxygen uptake rate was significantly reduced for both capsule types compared to a neat hexadecane solution containing the spin-probe, i.e. the slope of the non-steady state part of the ESR-curve was approximately one-third and one-ninth for the primary nanocellulose capsule and aggregated capsule, respectively, compared to that for the hexadecane sample. The transport of oxygen was modeled mathematically and by fitting to the experimental data, the oxygen diffusion coefficients of the capsule wall was determined. These values were, however, lower than expected and one plausible reason for this was that the ESR-technique underestimate the true oxygen uptake rate in the present systems at non-steady conditions, when the overall diffusion of oxygen was very slow.

Budesonide inhaler device switch patterns in an asthma population in Swedish clinical practice (ASSURE).

BACKGROUND: Dry powder inhaler (DPI) device switch in asthma treatment could potentially increase with the entrance of new devices. We examined the switch patterns of budesonide (BUD) DPI analogues available in Sweden. METHODS: This observational real-life study linked primary healthcare medical records data from the Västra Götaland region to national Swedish registries, and included asthma patients (ICD-10-CM J45) prescribed BUD in a multidose DPI. Index date: first dispense of BUD DPI. Switch date: prescription of another BUD DPI device. Study outcomes (switch vs. non-switch) were exacerbations and prescription of short-acting ß2 -agonists. Study period was 1 July 2005 to 31 October 2013. RESULTS: Overall, 15,169 asthma patients were on treatment with BUD DPI; 1178 (7.35%) switched to another BUD DPI during the study. Pair-wise 1:1 matching of switchers vs. non-switchers resulted in two groups of 463 patients each (mean age 36 years, 55% female patients). A 25% higher exacerbation rate was seen postswitch (0.40 vs. 0.32; p = 0.047). Switchers were 4.5 year younger and had lower medication possession rate than non-switchers. Switch without primary healthcare visit did not differ between groups regarding consultations and exacerbations (no visit 4.96 and 0.90; visit 4.29 and 0.77, respectively). However, patients without primary healthcare visit at switch had significantly more outpatient hospital visits (2.01 vs. 0.81; p < 0.001). CONCLUSIONS: Considering the low switch rate, asthma patients and physicians in Swedish general practice seem reluctant to switch to another BUD DPI device. Switch, especially without primary healthcare visit, was associated with decreased asthma control resulting in higher exacerbation rate and more outpatient hospital visits.

Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study.

OBJECTIVE: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, or nonselective NSAIDs or totally unexposed to NSAIDs. METHODS: We performed a national register-based cohort study on patients with AS or SpA (n = 21,872) identified in the Swedish national patient register from 1987-2009. Treatment exposure was assessed time dependently based on the prescription drug register from 2006-2009, adjusting for sociodemographics and comorbidities derived from national population-based registers. RESULTS: Exposure to etoricoxib, celecoxib, and nonselective NSAIDs was 7.6%, 3.9%, and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal, or renal adverse events were seen among the 3 exposure groups. Patients unexposed to NSAIDs had more baseline comorbidities and an increased relative risk for congestive heart failure events during the study period (2.0, 95% confidence interval [95% CI] 1.3-3.2). The relative risk for atherosclerotic events was nonsignificant when compared to the nonselective NSAID group (1.0, 95% CI 0.7-1.5), while the relative risk for gastrointestinal events was lower for unexposed patients (0.5, 95% CI 0.4-0.7). CONCLUSION: Overall, serious adverse events related to nonselective NSAIDs, etoricoxib, and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerably more baseline comorbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAIDs in clinical practice.

A prospective, multicenter validation study of a prognostic index composed of S-phase fraction, progesterone receptor status, and tumour size predicts survival in node-negative breast cancer patients: NNBC, the node-negative breast cancer trial.

BACKGROUND: In a retrospective study on node-negative breast cancer, a prognostic index consisting of a proliferation factor, S-phase fraction (SPF), progesterone receptor status (PR), and tumour size identified one-third of patients as high risk, with a sixfold increased risk of breast cancer death. This prospective multicenter cohort study was set up to validate the index. PATIENTS AND METHODS: In 576 T1-2N0 patients <60 years, prospective analyses of PR and SPF were carried out. High risk was defined as ≥2 of the following: size >20 mm, PR-negativity, and high SPF (in the absence of SPF, Bloom-Richardson grade 3). Median follow-up was 17.8 years. RESULTS: Thirty-one percent were high risk. In univariate analysis, the index was prognostic for breast cancer-specific survival after 5 years [hazard ratio (HR) = 4.7, 95% confidence interval (95% CI) 2.5-8.9], 10 years (HR = 2.2, 95% CI 1.5-3.3), and 15 years (HR = 1.7, 95% CI 1.2-2.5), and remained significant after adjustment for adjuvant medical treatment and age. In the 37% of patients with no risk factors, only one patient died of breast cancer the first 5 years. CONCLUSIONS: This prospective study validates a prognostic index consisting of a proliferation factor, PR-status, and tumour size. The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy.

Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest.

BACKGROUND: Therapeutic hypothermia (TH) after cardiac arrest protects from neurological sequels and death and is recommended in guidelines. The Hypothermia Registry was founded to the monitor outcome, performance and complications of TH. METHODS: Data on out-of-hospital cardiac arrest (OHCA) patients admitted to intensive care for TH were registered. Hospital survival and long-term outcome (6-12 months) were documented using the Cerebral Performance Category (CPC) scale, CPC 1-2 representing a good outcome and 3-5 a bad outcome. RESULTS: From October 2004 to October 2008, 986 TH-treated OHCA patients of all causes were included in the registry. Long-term outcome was reported in 975 patients. The median time from arrest to initiation of TH was 90 min (interquartile range, 60-165 min) and time to achieving the target temperature (< or =34 degrees C) was 260 min (178-400 min). Half of the patients underwent coronary angiography and one-third underwent percutaneous coronary intervention (PCI). Higher age, longer time to return of spontaneous circulation, lower Glasgow Coma Scale at admission, unwitnessed arrest and initial rhythm asystole were all predictors of bad outcome, whereas time to initiation of TH and time to reach the goal temperature had no significant association. Bleeding requiring transfusion occurred in 4% of patients, with a significantly higher risk if angiography/PCI was performed (2.8% vs. 6.2%P=0.02). CONCLUSIONS: Half of the patients survived, with >90% having a good neurological function at long-term follow-up. Factors related to the timing of TH had no apparent association to outcome. The incidence of adverse events was acceptable but the risk of bleeding was increased if angiography/PCI was performed.

Is contact allergy to disperse dyes and related substances associated with textile dermatitis?

BACKGROUND: Disperse dyes (DDs) are the most common sensitizers among textile dyes, but there is little knowledge of the clinical relevance of positive patch test reactions. OBJECTIVE: To investigate if patient-reported textile-related skin problems can be explained by contact allergy to eight different DDs and/or to chemically related substances, by occupation or by atopic constitution, and if the skin problems are influenced by age or sex. METHODS: A questionnaire on textile-related skin problems was answered by 858 of 982 consecutively patch tested patients in Malmö, Sweden and in Leuven, Belgium. The baseline series used for patch testing was supplemented with a textile dye mix (TDM) consisting of the eight DDs and with the separate dyes. The association between textile-related skin problems and contact allergy to the DDs and other risk factors was investigated using multiple logistic regression analysis. RESULTS: Eighteen per cent of the patients suspected textiles as a cause of their skin problems. Atopic constitution and female sex were risk factors for skin reactions. Synthetic materials were the most common textiles to give skin problems. A significant association was found between self-reported textile-related skin problems and contact allergy to para-phenylenediamine (PPD) [adjusted odds ratio (OR) 2.1; 95% confidence interval (CI) 1.0-4.3]. A similar, but more imprecise, adjusted OR was found for TDM (OR 1.9; 95% CI 0.57-5.6). Contact allergy to black rubber mix was too rare to be evaluated. CONCLUSIONS: Contact allergy to PPD was a more prevalent indicator for skin reactions to textiles than the TDM used in this study.

In vivo and in vitro uptake of 111In, delivered with the affibody molecule (ZEGFR:955)2, in EGFR expressing tumour cells.

The epidermal growth factor receptor, EGFR, is overexpressed in many carcinomas. Targeting this receptor with radionuclides is important for imaging and therapy applications in nuclear medicine. We investigated the in vitro and in vivo properties of a new high affinity EGFR binding affibody molecule, (ZEGFR:955)2, when conjugated with CHX-A''-DTPA and labelled with 111In. The binding time patterns and retention studies were performed using cultured squamous carcinoma A431 cells that overexpress EGFR. In the in vivo studies, female BALB/c nu/nu mice carrying tumours from xenografted A431 cells were used. The in vitro studies showed EGFR specific binding, high uptake and good retention of 111In when delivered as [111In](ZEGFR:955)2. The retention after 72 h of incubation was 38.0+/-1.15% of the initial level. The biodistribution study showed a tumour specific 111In uptake of 3.8+/-1.4% of injected dose per gram tumour tissue 4 h post-injection. The tumour to blood ratio was 9.1 and the tumours could easily be visualized with a gamma camera at this time-point. 111In delivered with [111In](ZEGFR:955)2 gave an EGFR specific uptake and the results indicated that the (ZEGFR:955)2 affibody molecule is a candidate for radionuclide-based tumour imaging. Potential therapy applications are discussed.

Depressive disorders and anti-parkinson drug treatment: a case register study.

OBJECTIVE: To estimate the rate of treatment with anti-parkinson drugs (APD) among patients with depression. METHOD: In a nationwide case register linkage study, all persons with a main diagnosis of depression during 5 years were identified. A control group of persons with diagnoses of osteoarthritis was included. The subsequent risk of getting treatment with APD was estimated for the two groups. Statistical analyses involved Poisson's regression and competing risk models. RESULTS: A total of 14 991 persons were included. The rate of getting APD was 2.57 (95% CI: 1.46-4.52) times higher for persons with depression than for persons with osteoarthritis. Overall, the rate was highest for men. However, women with depression had a 3.89 (95% CI: 1.98-7.62) times higher rate of APD treatment as women with osteoarthritis while no significant difference was found among men. CONCLUSION: Provided that prescription of APD reflects the presence of Parkinson's disease, results support a positive statistical association between depressive disorders and Parkinson's disease.

Body mass index and outcome after coronary artery bypass surgery.

AIM: Morbidity and mortality after surgical interventions are influenced by different preoperative factors. We investigated the impact of body mass index (BMI) on outcome after coronary artery bypass grafting (CABG). METHODS: A total of 4 749 CABG patients were divided into 4 groups: low BMI (or=35 kg/m(2), n=146). The incidence of severe perioperative complications (heart failure, renal failure or perioperative stroke), 30-day mortality, length of stay (LOS) and long-term survival were compared. A multivariate analysis with BMI, age, gender and Cleveland Clinic risk score as independent variables and 30-day mortality as dependent variable was performed. RESULTS: Compared to patients with normal BMI, low BMI patients had higher incidence of severe complications (12.5 vs 7.0%, P=0.039), higher 30-day mortality (6.2 vs 1.7 %, P=0.001) and inferior cumulative long-term survival (P=0.04). Patients with moderately increased BMI had longer LOS (10.8 vs 9.0 days, P=0.003) but no difference in incidence of severe complications or mortality. Patients with severely increased BMI had a higher incidence of severe complications (12.3 vs 7.0%, P=0.015, longer LOS (13.0 vs 9.0 days, P<0.001), but no significant difference in early or long-term mortality. Low but not high BMI was an independent predictor for 30-day mortality. CONCLUSIONS: The results suggest that low BMI is associated with increased morbidity and mortality after CABG. Overweight is associated with more postoperative complications and longer hospitalisation but not with an increased early or long-term mortality.

Phage display selection of Affibody molecules with specific binding to the extracellular domain of the epidermal growth factor receptor.

Affibody molecules specific for the epidermal growth factor receptor (EGFR) have been selected by phage display technology from a combinatorial protein library based on the 58-residue, protein A-derived Z domain. EGFR is overexpressed in various malignancies and is frequently associated with poor patient prognosis, and the information provided by targeting this receptor could facilitate both patient diagnostics and treatment. Three selected Affibody variants were shown to selectively bind to the extracellular domain of EGFR (EGFR-ECD). Kinetic biosensor analysis revealed that the three monomeric Affibody molecules bound with similar affinity, ranging from 130 to 185 nM. Head-to-tail dimers of the Affibody molecules were compared for their binding to recombinant EGFR-ECD in biosensor analysis and in human epithelial cancer A431 cells. Although the dimeric Affibody variants were found to bind in a range of 25-50 nM affinities in biosensor analysis, they were found to be low nanomolar binders in the cellular assays. Competition assays using radiolabeled Affibody dimers confirmed specific EGFR-binding and demonstrated that the three Affibody molecules competed for the same epitope. Immunofluorescence microscopy demonstrated that the selected Affibody dimers were initially binding to EGFR at the cell surface of A431, and confocal microscopy analysis showed that the Affibody dimers could thereafter be internalized. The potential use of the described Affibody molecules as targeting agents for radionuclide based imaging applications in various carcinomas is discussed.

Long-term outcome in heart failure patients evaluated for heart transplantation but considered too well.

Patients referred for heart transplantation evaluation may be accepted for transplantation, or denied due to existing contraindications or judged to be too well. There is little knowledge about long-term outcome in patients considered too well for transplantation. Ninety-five patients (mean age 47 +/- 12 years, 73% men) judged "too well" at evaluation were included in this study. Acceptance for transplantation followed international guidelines. The follow-up (mean 4.5 years) was complete. Twenty of the 95 patients (21%) were eventually accepted for transplantation during the follow-up period. Twenty-one patients (22%) died, 13 without preceding acceptance for transplantation, 4 on the waiting list for transplantation, and 4 after transplantation. Cumulative and transplant-free survival at 1, 5, and 10 years were 91%, 82%, and 65%, and 90%, 70%, and 50%, respectively. In conclusion, long-term survival in patients considered too well for transplantation is better than in most contemporary series of heart transplant recipients, which suggests that the guidelines for acceptance are appropriate. However, almost one fifth of the patients die without preceding acceptance for transplantation or while on the waiting list, which illustrates the need for frequent reevaluation and tools to identify heart failure patients with an increased risk for sudden death.