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Objective: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. Design, Participants, Measurements: Thirty‐seven individuals with CAH and 33 age‐ and sex‐matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24‐h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. Results: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA‐IR): 2.7 vs. 1.9, p = 0.018), prolonged E‐wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self‐reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. Conclusion: A sex‐specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self‐reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits. [ABSTRACT FROM AUTHOR]

Objective: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high‐risk TS and reduce screening in TS participants with low cardiovascular risk. Design, Patients, Participants and Measurements: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re‐examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFβ), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease. Results: TS participants had lower TGFβ1 and TGFβ2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFβ1 were correlated with the aortic diameter at several measuring positions. During follow‐up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFβ1 and TGFβ2 levels in TS. Conclusion: TGFβ and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants. [ABSTRACT FROM AUTHOR]

Histidine–M2+ coordination bonds are a recognized bond motif in biogenic materials with high hardness and extensibility, which has led to growing interest in their use in soft materials for mechanical function. However, the effect of different metal ions on the stability of the coordination complex remains poorly understood, complicating their implementation in metal‐coordinated polymer materials. Herein, rheology experiments and density functional theory calculations are used to characterize the stability of coordination complexes and establish the binding hierarchy of histamine and imidazole with Ni2+, Cu2+, and Zn2+. It is found that the binding hierarchy is driven by the specific affinity of the metal ions to different coordination states, which can be macroscopically tuned by changing the metal‐to‐ligand stoichiometry of the metal‐coordinated network. These findings facilitate the rational selection of metal ions for optimizing the mechanical properties of metal‐coordinated materials. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of the study was to assess the validity of the hematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) and of pulmonary comorbidity prior to HCT in terms of predicting non‐relapse mortality (NRM) and overall survival (OS). Methods: In this retrospective single‐center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low‐risk, intermediate‐risk, and high‐risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT‐CI. Results: In univariate analysis, the HCT‐CI and the PCS were associated with OS after transplantation when comparing patients in high‐risk groups with patients in low‐risk groups. Using the PCS, the hazard ratios (HRs) of the 2‐year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (p <.001) and 3.27 (p <.001), respectively, whereas the HRs using the HCT‐CI were 1.83 (p <.001) and 2.57 (p =.002). The 2‐year NRM incidence in the three risk‐groups in the entire population was significant using both indexes. In the MAC group, the 2‐year NRM was significant using the PCS (p =.003), but not using the HCT‐CI (p =.23). Conclusions: Our study suggest that pulmonary function alone is a strong predictor of 2‐year OS and NRM after HCT. [ABSTRACT FROM AUTHOR]

Objective: We investigated the efficacy and safety of carfilzomib‐containing induction before salvage high‐dose melphalan with autologous stem‐cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma. Methods: This randomised, open‐label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re‐induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 → 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86). Results: Median time to progression (TTP) after randomisation was 25.1 months (22.5‐NR) in the carfilzomib‐dexamethasone maintenance group and 16.7 months (14.4–21.8) in the control group (HR 0.46, 95% CI 0.30–0.71; P =.0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections. Conclusion: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well‐tolerated with manageable toxicity. [ABSTRACT FROM AUTHOR]

The evolution of hemoglobin function in the transition from water‐ to air‐breathing has been highly debated but remains unresolved. Here, we characterized the hemoglobin function in five closely related water‐ and air‐breathing catfishes. We identify distinct directions of hemoglobin evolution in the clades that evolved air‐breathing, and we show strong selection on hemoglobin function within the catfishes. These findings show that the lack of a general direction in hemoglobin function in the transition from water‐ to air‐breathing may have resulted from divergent selection on hemoglobin function in independent clades of air‐breathing fishes. Research highlights: 1.We show that the evolution of air‐breathing resulted in distinct changes in hemoglobin function.2.This illustrates that the adaptations to air‐breathing cannot be generalized across independent groups of air‐breathing fishes. [ABSTRACT FROM AUTHOR]

In fully transient, mussel‐inspired hydrogels, metal‐coordinate complexes form supramolecular crosslinks, which offer tunable viscoelastic properties and mechanical reversibility. The metal‐coordination complexation that comprises the crosslinks can take on tris‐, bis‐, mono‐, and free‐state modalities (3, 2, 1, or 0 ligands per ion, respectively). Although prior work has established relationships between network crosslinking and mechanical properties, the effect of crosslink and ligand modalities on gel‐surface adhesion is not well understood for fully transient hydrogels. Using glass and nickel‐coated spherical probes, the effect of network crosslinking modalities on the adhesive strength of hydrogels based on histidine‐Ni2+ and nitrodopamine‐Fe3+ ion crosslinks is investigated. Since crosslink modalities have a strong impact on the mechanical properties of the bulk network, it is first determined how adhesion relates to the mechanical properties, regardless of the distribution of crosslinking modalities and ligand type. It is ultimately found that the peak adhesive stress increases with decreasing percentage of ligands in tris‐crosslinks. [ABSTRACT FROM AUTHOR]

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype‐tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10−7 either in EBV‐transformed B‐lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression‐free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4‐rs1992292, TBRG4‐rs2287535 and ENTPD1‐rs2153913) showed associations with OS at P <.05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta‐analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4‐rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04‐1.26, P =.007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients. What's new? Multiple myeloma (MM) remains incurable for most patients, although recent therapeutic advances have extended survival. MM is highly heterogeneous, but gene expression profiling can identify patients with poor outcomes and classify patients by how they will respond to drugs. Here, the authors evaluate certain genetic loci that influence the amount of RNA transcript produced, called expression quantitative trait loci (eQTLs). They found two eQTLs of genes associated with MM prognosis that were directly associated with adverse outcomes. These results provide a proof‐of‐concept that eQTLs can serve as a surrogate for gene expression profile as a predictor of survival, and they are much easier to measure. [ABSTRACT FROM AUTHOR]

We aimed to use a novel standardized whole‐blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day −21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat‐killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra‐ and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon‐γ, interleukin (IL)‐12p40, IL‐10, IL‐1β, IL‐6, IL‐8, IL‐10, IL‐12p40, IL‐17A and tumour necrosis factor‐α using a multiplex Luminex assay. Pre‐HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post‐HCT cytokine responses were higher and less intercorrelated than pre‐HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat‐killed Candida albicans stimuli, we identified a cluster of patients in whom post‐HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections. [ABSTRACT FROM AUTHOR]

In Marfan syndrome (MFS), pregnancy is considered as high risk due to the deficiency of fibrillin in the connective tissue and increased risk of aortic dissection. The objective was to demonstrate the consequences on maternal health, in women with diagnosed and undiagnosed MFS at the time of pregnancy and childbirth. By using national health care registries, we identified all pregnancy related outcomes, from women with MFS (n = 183) and an age‐matched background population (n = 18,300). We found 91 pregnancies during follow‐up. Significantly fewer women with MFS gave birth, compared to the background population. No women with known MFS had a pregnancy related aortic dissection but complications related to the cervix were increased (HR:19.8 [95% CI:2.2–177.5]). Fifty women with MFS were undiagnosed at the time of their first pregnancy and/or childbirth. Among these, there were more birth canal related complications HR:27.2 (95% CI: 2.3–315.0), preeclampsia (HR:2.25 [95% CI: 1.11–4.60]), fetal deaths (HR:12.3 [95% CI: 1.51–99.8]), and all delivery‐related dissections came from this subgroup. In conclusion, undiagnosed women with MFS experienced more pregnancy and childbirth related complications including fetal death, birth canal issues, preeclampsia, and aortic disease, which emphasizes the need for an early MFS diagnosis and special care during pregnancy and childbirth. [ABSTRACT FROM AUTHOR]

Rapid damping of interfaces experiencing vibrations is critical to the performance of many complex mechanical systems ranging from airplanes to human bodies. Current synthetic materials utilized in vibration damping are limited by either their damping frequency range, tunability, or environmental stability. Here, it is shown how single metal ion cross‐linked hydrogels exhibit tunable damping across a large frequency range and multiple metal ion hydrogels exhibit broadband damping within a single material. Additionally, an enhanced resistance to freezing and dehydration is shown with the use of glycerol as a cosolvent. It is expected that material design principles presented here will help advance the development of programmable damping materials better able to meet the demands of sustained operation under broad environmental conditions. [ABSTRACT FROM AUTHOR]

Summary: In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population‐based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk‐groups with an observed hazard ratio of 2.91 for early death in high‐risk versus low‐risk patients. [ABSTRACT FROM AUTHOR]

Objectives: Vitamin E has antioxidant and immunomodulatory effects that might influence the development of acute graft‐versus‐host disease (GvHD). We investigated the association between plasma vitamin E levels and acute GvHD. Methods: We studied 115 adults who underwent myeloablative allogeneic hematopoietic cell transplantation between July 2015 and August 2018. Vitamin E was measured by high‐performance liquid chromatography in stored plasma samples obtained pre‐transplantation at day –23 (±15 days) and post‐transplantation at day +28 (±3 days). Results: Pre‐transplantation vitamin E levels were inversely associated with grade II–IV acute GvHD (hazard ratio 0.68 per 10 µmol/L increase, 95% confidence interval [CI]: 0.47‐0.98). The association remained after adjustment for known prognostic factors for acute GvHD. Patients with levels below the median had a cumulative incidence of grade II–IV acute GvHD of 46% (CI: 33‐59%) versus 21% (CI: 10‐32%) in patients with levels above the median. No clear association with non‐relapse mortality, relapse, or chronic GvHD was found. Post‐transplantation vitamin E levels (measured in 72 [63%] patients) were correlated with pre‐transplantation levels (ρ =.31) but were not associated with subsequent grade II–IV acute GvHD. Conclusions: High pre‐transplantation vitamin E levels were associated with less acute GvHD. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the presence and characterization of chemotherapy‐induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty‐one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess chemotherapy‐induced polyneuropathy (CIPN) 5 years after adjuvant chemotherapy in patients with breast and colorectal cancer. The association of CIPN with quality of life, anxiety, and depression was analyzed. Methods: Of a set of 100 patients with breast cancer and of 74 with colorectal cancer who had undergone surgery and adjuvant chemotherapy in 2011‐2012, 80 and 52 patients alive, respectively, were included together with two reference groups of 249 breast cancer patients and 83 colorectal cancer patients who had undergone surgery only. All patients were sent a questionnaire on alcohol consumption, smoking habits, comorbidity, medicine consumption, and oxaliplatin‐specific questions, as well as the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), the Douleur Neuropathique 4 Questions (DN4q), the EQ‐5D, and the Hospital Anxiety and Depression Scale. Possible polyneuropathy was defined as the presence of numbness and/or tingling in the feet, secondly as a score of ≥4 on the MNSIq. Possible painful polyneuropathy was defined as pain in both feet and a score ≥3 on the DN4q. Results: The prevalence of possible polyneuropathy defined by numbness and/or tingling in the feet was 38.8% (28.1‐50.3) after adjuvant docetaxel and 57.7% (43.2‐71.3) after adjuvant oxaliplatin, with no significant difference from a previous 1‐year follow‐up (P >.35). Fewer had possible polyneuropathy as defined by the MNSIq. Patients with possible polyneuropathy after adjuvant chemotherapy reported significantly lower quality of life than patients treated with surgery only. Conclusion: Symptoms of polyneuropathy following adjuvant docetaxel and oxaliplatin persist 5 years after treatment and affect quality of life negatively. [ABSTRACT FROM AUTHOR]

Objectives: Extracellular vesicles (EVs) are important for intercellular signalling in cancer. Tumour‐associated macrophages, expressing the haemoglobin‐haptoglobin and mannose receptors CD163 and CD206, are crucial for cancer progression. We recently identified CD163 on EVs in the circulation as a fraction of total soluble CD163 (sCD163). Here, we investigated the presence of CD163 and CD206‐positive EVs (EV‐CD163, EV‐CD206) in patients with multiple myeloma (MM). Methods: We enrolled patients with MM (n = 32), monoclonal gammopathy of undetermined significance (MGUS) (n = 8) and healthy donors (n = 16). Plasma protein levels were determined by ELISA before and after vesicle precipitation. Monocytes were examined by flow cytometry, and leucocyte CD163 mRNA by qPCR. Results: Fractions of EV‐CD163 and EV‐CD206 were significantly elevated in patients with newly diagnosed MM (median = 39.8%, 76.5%, respectively) compared to patients with relapse (15.6%, P =.02, 42.5%, P =.003), remission (16.9%, P <.0001, 25.2%, P <.0001), MGUS (17.8%, P <.01, 33.1%, P =.0005) and healthy donors (14.8%, P <.0001, 35.5%, P <.0001). Whole blood CD163 mRNA did not vary between the groups. The intermediate monocyte subset showed a higher CD163 expression in newly diagnosed patients. Conclusions: Our results indicate that macrophage‐derived EVs may play a role in the late phase of malignant progression of MM, and encourage further EV investigations in functional experiments. [ABSTRACT FROM AUTHOR]

Max Weber excluded the phenomenon of emotions from the idea of rational bureaucracy. Modern European organizational theories are on the other hand almost obsessed by emotions and especially affect. Emotion re‐entered organizational theory around the limited topic of 'emotional labour', but today, passion is generally praised as a driver in successful organizations. An important element here is the demand upon passionate employees to install the organization as their significant other. To the extent that they rely on this new concept of themselves and their employees, organizations become dependent upon the authenticity of the 'self‐enrolment' expected of each employee. In the discursive field of organization, we therefore see a number of new communicative media, which centre upon emotion and upon helping the organization to attribute authenticity and inauthenticity to employees. This paper also makes the case that these media are liminal in nature and extend beyond the use of discursive symbolism in a Sisyphean effort to reach the authentic emotional 'heart' of each employee. [ABSTRACT FROM AUTHOR]

Lytic polysaccharide monooxygenases (LPMOs) are copper‐containing enzymes capable of oxidizing crystalline cellulose which have large practical application in the process of refining biomass. The catalytic mechanism of LPMOs still remains debated despite several proposed reaction mechanisms. Here, we report a long‐lived intermediate (t1/2=6–8 minutes) observed in an LPMO from Thermoascus aurantiacus (TaLPMO9A). The intermediate with a strong absorption around 420 nm is formed when reduced LPMO‐CuI reacts with sub‐equimolar amounts of H2O2. UV/Vis absorption spectroscopy, electron paramagnetic resonance, resonance Raman and stopped‐flow spectroscopy suggest that the observed long‐lived intermediate involves the copper center and a nearby tyrosine (Tyr175). Additionally, activity assays in the presence of sub‐equimolar amounts of H2O2 showed an increase in the LPMO oxidation of phosphoric acid swollen cellulose. Accordingly, this suggests that the long‐lived copper‐dependent intermediate could be part of the catalytic mechanism for LPMOs. The observed intermediate offers a new perspective into the oxidative reaction mechanism of TaLPMO9A and hence for the biomass oxidation and the reactivity of copper in biological systems. [ABSTRACT FROM AUTHOR]

Purpose: To compare mean global cerebral blood flow (CBF) measured by phase-contrast mapping magnetic resonance imaging (PCM MRI) and by 15 O-H2 O positron emission tomography (PET) in healthy subjects. PCM MRI is increasingly being used to measure mean global CBF, but has not been validated in vivo against an accepted reference technique.Materials and Methods: Same-day measurements of CBF by 15 O-H2 O PET and subsequently by PCM MRI were performed on 22 healthy young male volunteers. Global CBF by PET was determined by applying a one-tissue compartment model with measurement of the arterial input function. Flow was measured in the internal carotid and vertebral arteries by a noncardiac triggered PCM MRI sequence at 3T. The measured flow was normalized to total brain weight determined from a volume-segmented 3D T1 -weighted anatomical MR-scan.Results: Mean CBF was 34.9 ± 3.4 mL/100 g/min measured by 15 O-H2 O PET and 57.0 ± 6.8 mL/100 g/min measured by PCM MRI. The measurements were highly correlated (P = 0.0008, R2  = 0.44), although values obtained by PCM MRI were higher compared to 15 O-H2 O PET (absolute and relative differences were 22.0 ± 5.2 mL/100 g/min and 63.4 ± 14.8%, respectively).Conclusion: This study confirms the use of PCM MRI for quantification of global CBF, but also that PCM MRI systematically yields higher values relative to 15 O-H2 O PET, probably related to methodological bias.Level Of Evidence: 3 J. Magn. Reson. Imaging 2017;45:692-699. [ABSTRACT FROM AUTHOR]

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review. [ABSTRACT FROM AUTHOR]

Traditionally sustained monomorphic ventricular tachycardia (SMVT) is associated with areas of myocardial scar such as that of chronic coronary artery disease. We present a case of SMVT in the initial setting of an acute myocardial infarction in a previously healthy individual suggesting that acute ischemia can give rise to SMVT. [ABSTRACT FROM AUTHOR]

The authors discuss how funding agencies will seek to identify how their research contributes to measurable impacts for non-academic stakeholders in industry, government, and society at large. Topics mentioned include the use of Google Scholar web search engine as a source for ranking academics, response of funding agencies to the strong relationship between the number of citations and the extent of societal impact, and the need for evaluating a stronger societal impact value orientation.

Objectives: We studied cardiac autonomic changes in relation to metabolic factors, body composition and 24‐hour ambulatory blood pressure measurements in Turner syndrome patients without known hypertension. Design: Cross sectional. Patients: Participants were 48 TS women and 24 healthy female controls aged over 18 years. Methods: Short‐term power spectral analysis was obtained in supine‐standing‐supine position. Bedside tests included three conventional cardiovascular reflex tests of heart rate response to standing up, heart rate response to deep breathing and blood pressure response to standing up. Mean heart rate during the last 2 minutes of work was used to calculate the maximal aerobic power (VO2max). Results: We found a significantly higher mean reciprocal of the heart rate per second (RR) in TS. Testing for interaction between position and status (TS or control), there were highly significant differences between TS and controls in high‐frequency (HF) power, the coefficient of component variation (square root of HF power/mean RR) and low‐frequency (LF): HF ratio, with a dampened decline in vagal activity among TS during standing. Bedside test showed TS had a significantly higher diastolic BP in the supine position compared to controls, and the adaptive rise in BP, when changing to upright position was reduced. VO2max and self‐reported level of physical activity were significantly correlated to systolic ambulatory blood pressure both 24‐hour and night diastolic ambulatory blood pressure. Conclusion: Vagal tone and modulation of the sympathovagal balance during alteration in body position are impaired in TS. These changes can be risk factors for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Introduction: Rapid and accessible methods for diagnosing diabetic polyneuropathy (DPN) have been developed, but not validated, in large cohorts of people with diabetes.Methods: The performance of a point-of-care device (POCD) was studied in 168 patients with type 2 diabetes, estimating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) compared with conventional sural nerve conduction studies (NCS).Results: A POCD amplitude limit of 6 µV increased the sensitivity (96%) and NPV (98%), but decreased the specificity (71%) and PPV (54%) compared with the 4-µV limit, which had values of 78%, 92%, 89%, and 71%, respectively. POCD on both legs showed better performance than on 1 leg. POCD amplitudes and conduction velocities correlated significantly with conventional sural NCS, but POCD values were underestimated compared with NCS.Discussion: The POCD may be used as a suitable screening tool for detection of DPN. Patients with abnormal and borderline results should undergo conventional NCS. Muscle Nerve 59:187-193, 2019. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We document leukostasis leading to acute fatal right‐sided heart failure. In patients presenting with leukostasis and cardiopulmonary symptoms, clinicians should aim to assess for cardiac involvement, that is, by ECG and acute echocardiogram, since early recognition of right ventricular disease may provide an opportunity to treat this potentially reversible condition. We document leukostasis leading to acute fatal right‐sided heart failure. In patients presenting with leukostasis and cardiopulmonary symptoms, clinicians should aim to assess for cardiac involvement, that is, by ECG and acute echocardiogram, since early recognition of right ventricular disease may provide an opportunity to treat this potentially reversible condition. [ABSTRACT FROM AUTHOR]

In the western Baltic Sea (WBS), whiting Merlangius merlangus is the main piscivorous fish together with cod Gadus morhua. In the present study, we investigate the growth and food consumption rates of WBS M. merlangus and compare the growth rates of males and females with those of M. merlangus in the North Sea (NS). Food consumption rates are estimated directly from sampled stomach contents in the WBS using a gastric evacuation rate model and indirectly by using a static energy‐budget model together with the growth rates. The results indicate that male and female M. merlangus in the WBS have similar feeding and growth strategies, while in the NS M. merlangus show more pronounced differences in food consumption and growth dynamics between the sexes. Female WBS M. merlangus grow significantly slower than their conspecifics in the NS, but there is no significant difference for males. Sexual size dimorphism is seen in both areas, but for M. merlangus in the WBS the difference is less pronounced. Food consumption rates in the WBS differ between seasons, with the lowest food intake in the first 2 quarters of the year and the highest in the 3rd quarter. No differences in consumption rates were seen between males and females, which could be related to the more similar growth pattern seen for M. merlangus in the WBS. [ABSTRACT FROM AUTHOR]

Abstract: This paper investigates the case of shipments of containers with avocados from farmers in Africa to grocery store shelves in the European Union. We find 3 predominant challenges to containerized shipping that effectively become trade barriers: international trade cost, lead time uncertainty, and security risks. We use activity theory to describe, understand, and analyze the shipping activity in the international trade ecosystem with focus on physical objects and their related information. We find that the shipment becomes problematic and can be characterized as a runaway object in the heterogeneous and multiple organizational setting of international trade. Our analysis of shipping reveals (1) inefficient collaboration across loosely coupled activity systems and (2) fragmented information infrastructures. We propose the solution of Shipping Information Pipeline, a shared information infrastructure, thus facilitating collaboration in containerized shipping and contributing to lowering trade barriers. Shipping Information Pipeline can significantly improve containerized shipping resulting in estimated potential benefits of up to 4.7% growth in global GDP. [ABSTRACT FROM AUTHOR]

Designing new antimicrobial peptides (AMPs) focuses heavily on the activity of the peptide and less on the elements that stabilize the secondary structure of these peptides. Studies have shown that improving the structure of naturally occurring AMPs can affect activity and so here we explore the relationship between structure and activity of two non-naturally occurring AMPs. We have used a backbone-cyclized peptide as a template and designed an uncyclized analogue of this peptide that has antimicrobial activity. We focused on beta-hairpin-like structuring features. Improvements to the structure of this peptide reduced the activity of the peptide against gram-negative, Escherichia coli but improved the activity against gram-positive, Corynebacterium glutamicum. Distinctions in structuring effects on gram-negative versus gram-positive activity were also seen in a second peptide system. Structural improvements resulted in a peptide that was more active than the native against gram-positive bacterium but less active against gram-negative bacterium. Our results show that there is not always a correlation between improved hairpin-structuring and activity. Other factors such as the type of bacteria being targeted as well as net positive charge can play a role in the potency of AMPs. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We read with interest the article by Cauldwell et al., which concluded that pregnancy in women with Turner syndrome is associated with major maternal cardiovascular risks, and that cardiovascular assessment and counselling prior to assisted or spontaneous pregnancy should be managed by a specialist team. Details on pregnancies per centre are not presented but there must have been many centres where a Turners syndrome pregnancy was a rarity, not even happening once a year. If such pre-pregnancy assessment is in place and caretaking is centralised, cardiovascular risk during pregnancy is very low in women with Turner syndrome.1-4 DISCLOSURE OF INTERESTS None declared. [Extracted from the article]

Aims: This study aimed to characterize invasive haemodynamics during exercise in subjects with cardiac amyloidosis (CA).Methods and Results: The study population numbered 44 subjects. Group A (CA-positive, n = 24) comprised wild-type transthyretin patients (n = 10), familial transthyretin amyloidosis mutation carriers (ATTRm) with cardiac involvement (n = 5), and light-chain amyloidosis patients with cardiac involvement (n = 9). Group B (CA-negative, n = 20) comprised four healthy ATTRm subjects without cardiac involvement documented by 11 C-PIB positron emission tomography and 16 healthy controls. All subjects underwent a symptom-limited, semi-supine exercise test with expired gas analysis and simultaneous right heart catheterization. CA patients had lower peak oxygen consumption [15 ± 6 mL/min/kg bodyweight (bwt) vs. 33 ± 7 mL/min/kg bwt; P < 0.0001] than controls. Myocardial reserve during exercise was significantly reduced in CA patients as reflected in a small increase in stroke volume index (SVI) and cardiac index (CI) compared with controls [ΔSVI: 4 mL/m2 (range: -1 to 8) vs. 14 mL/m2 (range: 5-25); P < 0.0001; ΔCI: 2 ± 2 L/min vs. 7 ± 2 L/min; P < 0.0001]. During exercise, CA patients had significantly higher left and right ventricular filling pressures than controls. Furthermore, CA patients had severely impaired pulmonary arterial compliance (PAC) compared with controls [2.9 mL/mmHg (range: 2.1-4.5) vs. 7.5 mL/mmHg (range: 5.7-10.4); P < 0.0001].Conclusions: Cardiac amyloid deposits are associated with severely reduced inotropic myocardial reserve and increased left and right ventricular filling pressures during exercise. Furthermore, CA subjects have severely reduced PAC, which may contribute to right heart failure and reduced exercise capacity. [ABSTRACT FROM AUTHOR]

Stomach content composition and prey-specific consumption rates of juvenile and adult harbor porpoises ( Phocoena phocoena) were estimated from a data set including 339 stomachs collected over a 32 yr period (1980-2011) in the western Baltic Sea. The stomach contents were mainly hard parts of fish prey and in particular otoliths. The bias originating from differential residence time of otoliths in the stomachs was addressed by use of a recently developed approach. Atlantic cod and herring were the main prey of adults, constituting on average 70% of the diet mass. Juvenile porpoises also frequently consumed gobies. Here, the mass contribution by gobies was on average 25%, which was as much as cod. Other species such as whiting, sprat, eelpout, and sandeels were of minor importance for both juveniles and adults. The diet composition differed between years, quarters, and porpoise acquisition method. Yearly consumption rates for porpoises in the western Baltic Sea were obtained in three scenarios on the daily energy requirements of a porpoise in combination with an estimate including the 95% CLs of the porpoise population size. Cod of age groups 1 and 2 and intermediate-sized herring suffered the highest predation from porpoises. [ABSTRACT FROM AUTHOR]

The best approach for allogeneic haematopoietic stem cell transplantations (allo HCT) in patients with chronic lymphocytic leukaemia ( CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival ( EFS) in a large retrospective study. Data of 684 CLL patients who received a first allo HCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [ CI], 34-42%). Larger numbers of CLL allo HCTs (hazard ratio [ HR] 0·96, P = 0·002), certification of quality management ( HR 0·7, P = 0·045) and a higher gross national income per capita ( HR 0·4, P = 0·04) improved EFS. In vivo T-cell depletion ( TCD) with alemtuzumab compared to no TCD ( HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient ( HR 1·4, P = 0·02) had a negative impact on EFS, but not non-myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL. [ABSTRACT FROM AUTHOR]

Currently, diagnosis of colon cancer is based on manual examination of histopathological images by a pathologist. This can be time consuming and interpretation of the images is subject to inter- and intra-observer variability. This may be improved by introducing a computer-aided diagnosis (CAD) system for automatic detection of cancer tissue within whole slide hematoxylin and eosin (H&E) stains. Cancer disrupts the normal control mechanisms of cell proliferation and differentiation, affecting the structure and appearance of the cells. Therefore, extracting features from segmented cell nuclei structures may provide useful information to detect cancer tissue. A framework for automatic classification of regions of interest (ROI) containing either benign or cancerous colon tissue extracted from whole slide H&E stained images using cell nuclei features was proposed. A total of 1,596 ROI's were extracted from 87 whole slide H&E stains (44 benign and 43 cancer). A cell nuclei segmentation algorithm consisting of color deconvolution, k-means clustering, local adaptive thresholding, and cell separation was performed within the ROI's to extract cell nuclei features. From the segmented cell nuclei structures a total of 750 texture and intensity-based features were extracted for classification of the ROI's. The nine most discriminative cell nuclei features were used in a random forest classifier to determine if the ROI's contained benign or cancer tissue. The ROI classification obtained an area under the curve (AUC) of 0.96, sensitivity of 0.88, specificity of 0.92, and accuracy of 0.91 using an optimized threshold. The developed framework showed promising results in using cell nuclei features to classify ROIs into containing benign or cancer tissue in H&E stained tissue samples. © 2017 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma. [ABSTRACT FROM AUTHOR]

Protein design advancements have led to biotechnological strategies based on more stable and more specific structures. Herein we present a 6-residue sequence (HPATGK) that acts as a stable structure-nucleating turn at physiological and higher pH but is notably unfavorable for chain direction reversal at low pH. When placed into the turn of a β-sheet, this leads to a pH switch of folding. Using a standard 3-stranded β-sheet model, the WW domain, it was found that the pH switch sequence insertion caused minimal change at pH 8 but a ca. 50 °C drop in the melting temperature (Tm) was observed at pH 2.5: ΔΔGF ≥11.3 kJ mol−1. Using the strategies demonstrated in this article, the redesign of β-sheets to contain a global, or local, pH-dependent conformational switch should be possible. [ABSTRACT FROM AUTHOR]

Protein loops make up a large portion of the secondary structure in nature. But very little is known concerning loop closure dynamics and the effects of loop composition on fold stability. We have designed a small system with stable β-sheet structures, including features that allow us to probe these questions. Using paired Trp residues that form aromatic clusters on folding, we are able to stabilize two β-strands connected by varying loop lengths and composition (an example sequence: R WITVTI - loop - KKIRV WE). Using NMR and CD, both fold stability and folding dynamics can be investigated for these systems. With the 16 residue loop peptide (sequence: R WITVTI-(GGGGKK)2GGGG-KKIRV WE) remaining folded (ΔGU = 1.6 kJ/mol at 295K). To increase stability and extend the series to longer loops, we added an additional Trp/Trp pair in the loop flanking position. With this addition to the strands, the 16 residue loop (sequence: R WITVRI W-(GGGGKK)2GGGG- WKTIRV WE) supports a remarkably stable β-sheet (Δ GU = 6.3 kJ/mol at 295 K, Tm = ∼55°C). Given the abundance of loops in binding motifs and between secondary structures, these constructs can be powerful tools for peptide chemists to study loop effects; with the Trp/Trp pair providing spectroscopic probes for assessing both stability and dynamics by NMR. [ABSTRACT FROM AUTHOR]

Key Clinical Message Low-dose QT-prolonging drugs may have detrimental effects on women with Turner's syndrome. Preventive measures would be to use potential QT-prolonging drugs with precaution and ensure that both before and during treatment, ECGs are evaluated and drug treatment stopped if the QT interval increases. [ABSTRACT FROM AUTHOR]

Many naturally occurring antimicrobial peptides (AMPs) are amphipathic with a β-hairpin conformation stabilized by cross-strand disulfides across the associated β-strands. Here, we show that the disulfides are not essential. Other structuring means such as better β-turns and noncovalent cross-strand interactions can, with proper design, replace the disulfides with no loss in antimicrobial activity. Our results also demonstrate that the hairpin turn region may play a role in membrane recognition for at least one member of this class, since a homodimeric turnless β-sheet analog showed no antimicrobial activity. We also examined the effects of N-terminal fatty acid adducts on AMPs. Surprisingly, the large hydrophobic carboxylic moieties examined completely eliminated the antimicrobial activity of previously active β-hairpin peptides. [ABSTRACT FROM AUTHOR]

Since cardiotoxicity is a life threatening late effect, a reduction of cardiotoxicity in the treatment of acute myeloid leukaemia (AML) is essential. This review is a compilation of the current knowledge about cardiotoxicity after AML treatment and of how future directions in treatment may affect its incidence. A total of six studies concerning AML and cardiotoxicity were identified. The incidence of late subclinical cardiotoxicity varied between 1·3 and 15·3%, and late clinical cardiotoxicity varied between 1·3 and 9·3%. Cumulative dose of anthracyclines ( ACs) and history of relapse were the most common risk factors identified. No conclusions could be drawn about new, potentially less toxic ACs. Differences in treatment data and variations in study populations made comparisons uncertain. The echocardiographic techniques used in the majority of the studies are inferior to more modern echocardiographic methods. This decreases reproducibility and may increase the risk of overestimation of cardiotoxicity. In summary, AML cannot be cured today without ACs. However, some ACs may cause less cardiotoxicity than others. Furthermore there is currently no consensus on equipotent doses of ACs and risk factors for cardiotoxicity. Further research including randomized trials is needed to evaluate whether or not the potentially less cardiotoxic agents fulfil their promise. [ABSTRACT FROM AUTHOR]

In recent decades, the prognosis of Mantle Cell Lymphoma ( MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 11·4 years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 12·7 and 8·5 years, respectively. The MCL International Prognostic Index ( MIPI), biological MIPI, including Ki67 expression ( MIPI-B) and the MIPI-B including mIR-18b expression ( MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12 years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL. [ABSTRACT FROM AUTHOR]

The present case illustrates the diagnostic challenges in symptomatic patients with heart failure of unknown etiology. The patients were previously diagnosed with κ-light chain amyloidosis without cardiac involvement. Echocardiography showed heart failure with mildly reduced ejection fraction but no signs of amyloidosis. Coronary angiogram showed normal arteries and 11C- PIB positron emission tomography was negative for amyloid deposits. Exercise testing revealed severe heart failure and reduced coronary flow velocity reserve. Endomyocardial biopsies showed amyloid in the intramural coronary arteries without interstitial amyloid deposits. Hence, the patient was diagnosed with microvascular dysfunction-induced heart failure due to vessel wall amyloidosis. [ABSTRACT FROM AUTHOR]

An abstract of the article "An important step towards accurate estimation of diet composition and consumption rates for the harbor porpoise (Phocoena phocoena)" by Stine D. Ross and colleagues is presented.

The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received either 65 IU rHuEPO × kg-1 every second day for two weeks (normal-dose), 390 IU rHuEPO × kg-1 on three consecutive days (high-dose), or frequent placebo treatment for 13 days in a randomized, placebo-controlled, double-blind crossover design. Blood variables were measured 4, 11, and 25 days following treatment initiation. The ABP based on haemoglobin concentration ([Hb]) and OFF-hr score ([Hb] - 60 × √ret%) yielded atypical profiles following both normal-dose and high-dose treatment (0 %, 31 %, 13 % vs. 21 %, 33 %, 20 % at days 4, 11, and 25 after normal and high dose, respectively). Including ret% as a stand-alone marker for atypical blood profiles increased (P < 0.05) the sensitivity of the adaptive model at day 11 to 63 % and 67 % for normal-dose and high-dose rHuEPO administration, respectively. In conclusion, ~30 % of subjects injecting a normal-dose rHuEPO for two weeks or a high-dose rHuEPO for three days will present an atypical ABP profile. Including ret% as a stand-alone parameter improves the sensitivity two-fold. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Several risk scores for disease progression in patients with smoldering multiple myeloma ( SMM) have been proposed; however, all have been developed using single-center registries. To examine risk factors for time to progression ( TTP) to multiple myeloma ( MM) for SMM, we analyzed a nationwide population-based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥30 g/L and immunoparesis significantly influenced TTP ( HR 2.7, 95% CI (1.5;4.7), P = 0.001, and HR 3.3, 95% CI (1.4;7.8), P = 0.002, respectively). High free light chain ( FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high-risk of transformation to MM. Using only immunoparesis and M-protein ≥30 g/L, we created a scoring system to identify low-, intermediate-, and high-risk SMM. This first population-based study of patients with SMM confirms that an M-protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM. [ABSTRACT FROM AUTHOR]

Versions of a previously discovered β-hairpin peptide inhibitor of IAPP aggregation that are stabilized in that conformation, or even forced to remain in the hairpin conformation by a backbone cyclization constraint, display superior activity as inhibitors. The cyclized hairpin, cyclo- WW2, displays inhibitory activity at substoichiometric concentrations relative to this amyloidogenic peptide. The hairpin-binding hypothesis stands confirmed. [ABSTRACT FROM AUTHOR]

Objectives We report cardiac function of patients treated for Childhood acute myeloid leukemia with chemotherapy only according to three consecutive Nordic protocols. Methods Ninety-eight of 138 eligible patients accepted examination with standardized echocardiography. Results were compared with age- and sex-matched controls. Results The median age was 3 yr at diagnosis (range 0-15), and the median time from diagnosis to study was 11 yr (4-25). All but one patient had received doxorubicin and 90% had received mitoxantrone. The median cumulative dose of daunorubicin equivalents was 300 mg/m2 (210-525). Left ventricular fractional shortening ( LVFS) and ejection fraction ( LVEF) were lower in patients than in controls (32.6% ( SD 4.0) vs. 35.2% ( SD 3.4), P = 0.002 and 59.9% ( SD 5.5) vs. 64.2% ( SD 4.4), P = 0.001). The myocardial performance index ( MPI) was higher in patients than in controls (0.32 ( SD 0.081) vs. 0.26 ( SD 0.074), P < 0.0001). Cumulative dose of doxorubicin but not mitoxantrone was related to lower LVFS ( P = 0.037) and LVEF ( P = 0.016). Longer follow-up was associated with lower LVFS ( P = 0.034). Higher MPI was associated with young age at diagnosis ( P = 0.04) and longer follow-up ( P = 0.031). Conclusions In this study, most patients had cardiac function within normal limits and reported very few cardiac symptoms. However, compared with healthy controls, they had significantly reduced left ventricular function. [ABSTRACT FROM AUTHOR]

ABSTRACT We have extended our studies of Trp/Trp to other Aryl/Aryl through-space interactions that stabilize hairpins and other small polypeptide folds. Herein we detail the NMR and CD spectroscopic features of these types of interactions. NMR data remains the best diagnostic for characterizing the common T-shape orientation. Designated as an edge-to-face (EtF or FtE) interaction, large ring current shifts are produced at the edge aryl ring hydrogens and, in most cases, large exciton couplets appear in the far UV circular dichroic (CD) spectrum. The preference for the face aryl in FtE clusters is W ≫ Y ≥ F (there are some exceptions in the Y/F order); this sequence corresponds to the order of fold stability enhancement and always predicts the amplitude of the lower energy feature of the exciton couplet in the CD spectrum. The CD spectra for FtE W/W, W/Y, Y/W, and Y/Y pairs all include an intense feature at 225-232 nm. An additional couplet feature seen for W/Y, W/F, Y/Y, and F/Y clusters, is a negative feature at 197-200 nm. Tyr/Tyr (as well as F/Y and F/F) interactions produce much smaller exciton couplet amplitudes. The Trp-cage fold was employed to search for the CD effects of other Trp/Trp and Trp/Tyr cluster geometries: several were identified. In this account, we provide additional examples of the application of cross-strand aryl/aryl clusters for the design of stable β-sheet models and a scale of fold stability increments associated with all possible FtE Ar/Ar clusters in several structural contexts. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 337-356, 2016. [ABSTRACT FROM AUTHOR]

Purpose: Mild hyperthermia can be used as an adjuvant therapy to enhance radiation therapy or chemotherapy of cancer. However, administering mild hyperthermia is technically challenging due to the high accuracy required of the temperature control. MR guided high-intensity focused ultrasound (MR-HIFU) is a technology that can address this challenge. In this work, accurate and spatially uniform mild hyperthermia is demonstrated for deep-seated clinically relevant heating volumes using a HIFU system under MR guidance. Methods: Mild hyperthermia heating was evaluated for temperature accuracy and spatial uniformity in 11 in vivo porcine leg experiments. Hyperthermia was induced with a commercial Philips Sonalleve MR-HIFU system embedded in a 1.5T Ingenia MR scanner. The operating software was modified to allow extended duration mild hyperthermia. Heating time varied from 10 min up to 60 min and the assigned target temperature was 42.5 °C. Electronic focal point steering, mechanical transducer movement, and dynamic transducer element switch-off were exploited to enlarge the heated volume and obtain uniform heating throughout the acoustic beam path. Multiple temperature mapping images were used to control and monitor the heating. The magnetic field drift and transducer susceptibility artifacts were compensated to enable accurate volumetric MR thermometry. Results: The obtained mean temperature for the target area (the cross sectional area of the heated volume at focal depth primarily used to control the heating) was on average 42.0±0.6 °C. Temperature uniformity in the target area was evaluated using T10 and T90, which were 43.1±0.6 and 40.9±0.6 °C, respectively. For the near field, the corresponding temperatures were 39.3±0.8 °C (average), 40.6±1.0 °C (T10), and 38.0±0.9 °C (T90). The sonications resulted in a concise heating volume, typically in the shape of a truncated cone. The average depth reached from the skin was 86.9 mm. The results show that the heating algorithm was able to induce deep heating while keeping the near-field temperature uniform and at a safe level. Conclusions: The capability of MR-HIFU to induce accurate, spatially uniform, and robust mild hyperthermia in large deep-seated volumes was successfully demonstrated through a series of in vivo animal experiments. [ABSTRACT FROM AUTHOR]