Personalized circulating tumor DNA in patients with hepatocellular carcinoma: a pilot study.

BACKGROUND: Mutational analysis of circulating tumor DNA (ctDNA) can potentially be used for early detection of recurrence after resection for hepatocellular carcinoma (HCC). Mutations from tumor may be identified in plasma as an early sign of recurrence. We conducted a pilot study investigating if somatic mutations could be detected in plasma in patients undergoing liver resection for HCC and in patients with advanced non-resectable HCC. METHODS AND RESULTS: We prospectively included patients undergoing curative liver resection for HCC. Tumor tissue was investigated with whole exome sequencing and preoperative blood samples were evaluated for ctDNA using targeted next-generation sequencing (NGS) with TruSight Oncology 500 including 523 cancer-associated genes. Subsequently, the method was evaluated in patients with advanced HCC. We included eight patients curatively resected for HCC, where tumor tissue mutations were identified in seven patients. However, only in one patient tumor specific mutations were found in the preoperative blood sample. In all three patients with advanced HCC, tumor mutations were detected in the blood. CONCLUSIONS: In patients with resectable HCC, ctDNA could not be reliably detected using the applied targeted NGS method. In contrast, ctDNA was detected in all patients with advanced HCC. Small tumors, tumor heterogeneity and limited sequencing coverage may explain the lack of detectable ctDNA.

Managing upstream oil and gas emissions: A public health oriented approach.

Oil and natural gas are the largest primary global energy sources, and upstream gas emissions from these fuels can impact global climate change and local public health. This paper employs a public health-oriented perspective that reviews grey and academic literature, industry data, technical reports, and policy trends to highlight issues of emissions monitoring. We identify gaps in the existing landscape of emissions reduction strategies and highlight options for addressing them. Policy recommendations include the use of new digital monitoring technologies to better understand causes of emission events, to create data-driven oil and gas regulations, and to begin accurately measuring the volumes of gases released during oil and gas production. Areas for future research relating to emissions and public health impacts are outlined to further enable oil and gas policy discussions.

Salivary functions in mastication, taste and textural perception, swallowing and initial digestion.

Saliva exerts multiple functions in relation to the initial digestive processes taking place in the upper parts of the gastrointestinal tract. Ingestion of food and beverages, in turn, is a strong stimulus for secretion of saliva with a differential composition depending on the neuronal stimulation pattern. This review paper provides insight into the mechanisms by which saliva acts in relation to taste, mastication, bolus formation, enzymatic digestion and swallowing. Also, the protective functions of saliva including maintenance of dental and mucosal integrity will be discussed as they indirectly influence the digestive process. The final part of this study focuses on the implications of xerostomia and salivary gland dysfunction on gastrointestinal functions.

Salivary secretion in health and disease.

Saliva is a complex fluid produced by 3 pairs of major salivary glands and by hundreds of minor salivary glands. It comprises a large variety of constituents and physicochemical properties, which are important for the maintenance of oral health. Saliva not only protects the teeth and the oropharyngeal mucosa, it also facilitates articulation of speech, and is imperative for mastication and swallowing. Furthermore, saliva plays an important role in maintaining a balanced microbiota. Thus, the multiple functions provided by saliva are essential for proper protection and functioning of the body as a whole and for the general health. A large number of diseases and medications can affect salivary secretion through different mechanisms, leading to salivary gland dysfunction and associated oral problems, including xerostomia, dental caries and fungal infections. The first part of this review article provides an updated insight into our understanding of salivary gland structure, the neural regulation of salivary gland secretion, the mechanisms underlying the formation of saliva, the various functions of saliva and factors that influence salivary secretion under normal physiological conditions. The second part focuses on how various diseases and medical treatment including commonly prescribed medications and cancer therapies can affect salivary gland structure and function. We also provide a brief insight into how to diagnose salivary gland dysfunction.

Towards low-dimensional hole systems in Be-doped GaAs nanowires.

GaAs was central to the development of quantum devices but is rarely used for nanowire-based quantum devices with InAs, InSb and SiGe instead taking the leading role. p-type GaAs nanowires offer a path to studying strongly confined 0D and 1D hole systems with strong spin-orbit effects, motivating our development of nanowire transistors featuring Be-doped p-type GaAs nanowires, AuBe alloy contacts and patterned local gate electrodes towards making nanowire-based quantum hole devices. We report on nanowire transistors with traditional substrate back-gates and EBL-defined metal/oxide top-gates produced using GaAs nanowires with three different Be-doping densities and various AuBe contact processing recipes. We show that contact annealing only brings small improvements for the moderately doped devices under conditions of lower anneal temperature and short anneal time. We only obtain good transistor performance for moderate doping, with conduction freezing out at low temperature for lowly doped nanowires and inability to reach a clear off-state under gating for the highly doped nanowires. Our best devices give on-state conductivity 95 nS, off-state conductivity 2 pS, on-off ratio [Formula: see text], and sub-threshold slope 50 mV/dec at [Formula: see text] K. Lastly, we made a device featuring a moderately doped nanowire with annealed contacts and multiple top-gates. Top-gate sweeps show a plateau in the sub-threshold region that is reproducible in separate cool-downs and indicative of possible conductance quantisation highlighting the potential for future quantum device studies in this material system.

Large animal models of atherosclerosis--new tools for persistent problems in cardiovascular medicine.

Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk stratification and monitoring of drug effects in humans. Efficient large animal models of atherosclerosis may help tackle these problems. Recent years have seen tremendous advances in gene-editing tools for large animals. This has made it possible to create gene-modified minipigs that develop atherosclerosis with many similarities to humans in terms of predilection for lesion sites and histopathology. Together with existing porcine models of atherosclerosis that are based on spontaneous mutations or severe diabetes, such models open new avenues for translational research in atherosclerosis. In this review, we discuss the merits of different animal models of atherosclerosis and give examples of important research problems where porcine models could prove pivotal for progress.

Prognostic factors for survival after salvage total laryngectomy following radiotherapy or chemoradiation failure: a 10-year retrospective longitudinal study in eastern Denmark.

OBJECTIVE: The primary aims were to determine the rates of and prognostic factors for overall survival, disease-specific survival and disease-free survival following salvage total laryngectomy. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 142 patients in eastern Denmark undergoing salvage total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. MAIN OUTCOME MEASURES: 5-year overall survival, 5-year disease-specific survival, 5-year disease-free survival and prognostic factors for these outcomes. RESULTS: 5-year overall survival, disease-specific survival and disease-free survival were 37.7%, 54.9% and 55.3%, respectively. N classification at primary diagnosis, lymph node excision and postoperative complications within 1 year after salvage total laryngectomy were prognostic factors for shorter overall survival, disease-specific survival and disease-free survival. Residual tumour/recurrence was negatively associated with overall survival, close or involved resection margins with disease-specific survival, and second primary cancer was associated with longer disease-specific survival and disease-free survival. Nine per cent of all patients had residual tumour and 33.8% developed a recurrence. CONCLUSION: Our overall survival, disease-specific survival and disease-free survival findings are in accordance with previous studies. With the purpose of identifying recurrent tumour, we suggest extra attention being given to patients with higher N classification and need for lymph node excision during salvage total laryngectomy along with use of frozen sections. The high number of patients with recurrence within 1 year after salvage total laryngectomy occurred although thorough and regular follow-up visits were performed.

Low-grade inflammation is associated with lower haemoglobin levels in healthy individuals: results from the Danish blood donor study.

BACKGROUND AND OBJECTIVES: Chronic inflammation can lead to anaemia of chronic disease due to the sequestration of iron caused by inflammatory cytokines and the protein hepcidin. However, the effect of low-grade inflammation (LGI) on haemoglobin among healthy individuals is not known. This study examines the effect of LGI on haemoglobin among Danish blood donors. MATERIALS AND METHODS: We performed multivariable linear regression to assess the effect of LGI (i.e. high-sensitivity C-reactive protein above 3 mg/l but below 10 mg/l) on haemoglobin in 17 322 Danish blood donors. We also performed multivariable logistic regression to evaluate the effect of LGI on the risk of having low haemoglobin (below the 10th percentile among men and women, respectively). We adjusted for donation activity, age, sex, low ferritin, oral contraceptives and menopause. All analyses were stratified by current smoking status. RESULTS: LGI was associated with lower haemoglobin (0·08 mm lower [0·12 g/dl], 95% confidence interval (CI): -0·11-0·05) and increased risk of low haemoglobin (OR = 1·22, 95% CI: 1·05-1·43) in non-smokers. Conversely, LGI was associated with higher haemoglobin in smokers (0·12 mm [0·19 g/dl], 95% CI: 0·06-0·18). CONCLUSION: In this first study of LGI and haemoglobin in healthy individuals, there was a negative association between LGI and haemoglobin in non-smokers. The association was positive in smokers, probably because smoking leads to both increased inflammation and increased haemoglobin through CO exposure.

Large eccentric strength increase using the Copenhagen Adduction exercise in football: A randomized controlled trial.

Hip adductor injuries are frequent in football, and players with low adductor strength appear to be at increased risk of injury. High adductor muscle activity has been shown in the Copenhagen Adduction exercise (CA); however, an associated strength gain has not been investigated. This study aims to examine the eccentric hip adduction strength (EHAD) gain using the CA in-season. Two U-19 sub-elite football teams, including 24 football players, were randomized to either an 8-week supervised progressive training program in addition to the usual training (intervention) or to continue training as usual (control). EHAD, eccentric hip abduction strength (EHAB), and side-bridge endurance were measured using reliable test procedures at baseline and follow-up by a blinded tester. There was a significant interaction between group and time on EHAD, EHAB, and EHAD/EHAB ratio (P < 0.025). The intervention group demonstrated a 35.7% increase in EHAD (P < 0.001); a 20.3% increase in EHAB (P = 0.003), and 12.3% increase in EHAD/EHAB ratio (P = 0.019). No significant within-group differences were found in the control group (P > 0.335). Compliance was 91.25%, and median muscle soreness ranged from 0 to 2. The CA implemented in-season with an 8-week progressive training program elicited a large significant increase in EHAD, EHAB, and EHAD/EHAB ratio.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Risk factors for postoperative complications after total laryngectomy following radiotherapy or chemoradiation: a 10-year retrospective longitudinal study in Eastern Denmark.

OBJECTIVES: To determine the rates of and risk factors for postoperative complications following total laryngectomy in patients treated with radiotherapy or chemoradiation. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 143 patients undergoing total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. MAIN OUTCOME MEASURES: Overall postoperative complications and fistula formation. RESULTS: Overall postoperative complications, fistula formation, wound infection, bleeding and wound necrosis within one year after total laryngectomy occurred in 56.6%, 42.3%, 31.0%, 11.3% and 9.2% of patients, respectively. Stenosis of the pharynx/oesophagus and stoma shrinkage within five years after surgery were each seen in 18.2% of cases. In 66.7% of cases, conservative treatment of the fistulas was chosen. Rehospitalisations within five years occurred for 44.8% with a median rate of 1.5 (range 1-11). Smoking status (P = 0.005 and 0.013) and chronic obstructive pulmonary disease (COPD) (P = 0.013 and 0.011) were significant risk factors for both overall postoperative complications and fistula formation in uni- and multivariate analysis. Tumour localisation in the hypopharynx was associated with overall postoperative complications (P = 0.036). Residual tumour or cancer recurrence was associated with late-onset fistulas (P < 0.001). CONCLUSION: The frequencies of postoperative complications after total laryngectomy were comparable with similar international studies, although fistula formation rate is increasing in Denmark. We suggest optimising treatment of COPD and to further encourage to smoking cessation. We propose that development of fistulas >2 months after surgery prompts immediate biopsies. Additionally, we suggest standardised registration of surgical techniques to identify variables affecting the frequency of postoperative complications.

Graphene supported plasmonic photocatalyst for hydrogen evolution in photocatalytic water splitting.

It is well known that the noble metal nanoparticles show active absorption in the visible region because of the existence of the unique feature known as surface plasmon resonance (SPR). Here we report the effect of plasmonic Au nanoparticles on the enhancement of the renewable hydrogen (H2) evolution through photocatalytic water splitting. The plasmonic Au/graphene/TiO2 photocatalyst was synthesized in two steps: first the graphene/TiO2 nanocomposites were developed by the hydrothermal decomposition process; then the Au was loaded by photodeposition. The plasmonic Au and the graphene as co-catalyst effectively prolong the recombination of the photogenerated charges. This plasmonic photocatalyst displayed enhanced photocatalytic H2 evolution for water splitting in the presence of methanol as a sacrificial reagent. The H2 evolution rate from the Au/graphene co-catalyst was about 9 times higher than that of a pure graphene catalyst. The optimal graphene content was found to be 1.0 wt %, giving a H2 evolution of 1.34 mmol (i.e., 26 µmolh(-1)), which exceeded the value of 0.56 mmol (i.e., 112 µmolh(-1)) observed in pure TiO2. This high photocatalytic H2 evolution activity results from the deposition of TiO2 on graphene sheets, which act as an electron acceptors to efficiently separate the photogenerated charge carriers. However, the Au loading enhanced the H2 evolution dramatically and achieved a maximum value of 12 mmol (i.e., 2.4 mmolh(-1)) with optimal loading of 2.0 wt% Au on graphene/TiO2 composites. The enhancement of H2 evolution in the presence of Au results from the SPR effect induced by visible light irradiation, which boosts the energy intensity of the trapped electron as well as active sites for photocatalytic activity.

One-step synthesis of graphene via catalyst-free gas-phase hydrocarbon detonation.

A one-step, gas-phase, catalyst-free detonation of hydrocarbon (C2H2) method was developed to produce gram quantities of pristine graphene nanosheets (GNs). The detonation of C2H2 was carried out in the presence of O2. The molar ratios of O2/C2H2 were 0.4, 0.5, 0.6, 0.7 and 0.8. The obtained GNs were analyzed by XRD, TEM, XPS and Raman spectroscopy. The GNs are crystalline with a (002) peak centered at 26.05° (d = 0.341 nm). TEM shows that the GNs are stacked in two to three layers and sometimes single layers. An increase in the size of the GNs (35-250 nm) along with a reduction in defects (Raman I(D)/I(G) ~ 1.33-0.28) and specific surface area (187-23 m(2) g(-1)) was found with increasing O2 content. The high temperature of the detonation, ca. 4000 K, is proposed as the cause of graphene production rather than normal soot. The method allows for the control of the number of layers, shape and size of the graphene nanosheets. The process can be scaled up for industrial production.

Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males.

The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. METHODS: 30 young, healthy, sodium loaded, non-obese males were exposed to -15 mmHg LBNP, -30 mmHg LBNP, -15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. RESULTS: All intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; -15 mmHg: -3.1 ± 0.9 %, -30 mmHg: -2.9 ± 0.6 %, -15 mmHg + aslikiren: -1.8 ± 0.6 %). -15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. CONCLUSION: Sympathetic stimulation for 90 min via LBNP at -30 mmHg LBNP compared to -15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.

Computer simulations of nucleation of nanoparticle superclusters from solution.

This paper presents simulation studies of nanoparticle supercluster (NPSC) nucleation from a temperature quenched system. The nanoparticles are represented as 5 nm, spherical gold nanoparticles ligated with alkane thiols. The pair potential accounts for the van der Waals interaction between the metallic cores and ligand-ligand and ligand-solvent interactions. Phenomena well-known for molecular systems are observed including a prenucleation induction period, fluctuating prenucleation clusters that predominately add monomers one at a time, a critical nucleus size, and growth of NPSCs from solution in the presence of an equilibrium supernatant, all consistent with classical nucleation theory. However, only the largest prenucleating clusters are dense, and the cluster size can occasionally range greater than the critical size in the prenucleation regime until a cluster with low enough energy occurs, then nucleation ensues. Late in the nucleation process, the clusters display a crystalline structure that is a random mix of face-centered cubic (fcc) and hexagonal close-packed (hcp) lattices and indistinguishable from a randomized icosahedra structure.

Nucleation in short-range attractive colloids: ordering and symmetry of clusters.

Results from extensive Brownian dynamics simulations are presented for nucleation in a system of colloidal particles interacting via a short-range attractive potential. Our analysis shows that, even though the system is not in equilibrium, structures of small size clusters compare well with the theoretically predicted and experimentally observed ground state structures for short-range colloidal systems. In addition, the distribution of the symmetric structures in nucleation is comparable to the distribution seen in equilibrium. We also investigate how the shape and structure of fluctuating clusters in the prenucleation regime affect the formation of a stable nucleating cluster.

Exploring radiographers' experience with mobile X-ray of patients in their homes.

INTRODUCTION: To offer citizens with frailty or dementia living in nursing homes or other institutions a less stressful and anxious X-ray examination, a Danish hospital offers to perform the examination in the citizen's residence. This has changed the working procedure for the radiographers performing the examination. The aim of this study was to explore if the radiographers self-perceived competencies have changed whilst working in the mobile X-ray unit and if so, how these competencies are utilised within the department-based medical imaging team. METHOD: This study had a qualitative design following a hermeneutic approach. Individual semi structured interviews included nine radiographers, four radiographers working in the mobile X-ray unit and five radiographers working exclusively in the medical imaging team. RESULTS: Radiographers who worked in the mobile X-ray unit did acquire new competencies such as better communication and creative positioning skills. All nine participants recognised the advantage of sharing experiences and competencies with colleagues, and recommended a formal forum to do so. They sought opportunities for the use of the mobile X-ray unit to be more widespread within their own region, and within the profession. CONCLUSION: This study indicates that radiographers working with mobile X-ray unit gained new competencies in communication and positioning, but without spread of new knowledge to colleagues in the medical imaging team. IMPLICATION FOR PRACTICE: The use of home-based mobile X-ray is a new way to provide health care services and gain new competencies for the radiographers to focus on patient centred care.

Kinetics of nanochain formation in a simplified model of amelogenin biomacromolecules.

We show that the kinetics of nanochain formation of amelogenin molecules is well described by a combination of translational and rotational diffusion of a simplified anisotropic bipolar model consisting of hydrophobic spherical colloid particles and a point charge located on each particle surface. The colloid particles interact via a standard depletion attraction whereas the point charges interact through a screened Coulomb repulsion. We study the kinetics via a Brownian dynamics simulation of both translational and rotational motions and show that the anisotropy brought in by the charge dramatically affects the kinetic pathway of cluster formation and our simple model captures the main features of the experimental observations.

Antigen-specific suppression in genetic responder mice to L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). Characterization of conventional and hybridoma-derived factors produced by suppressor T cells from mice injected as neonates with syngeneic GAT macrophages.

Spleen cells from C57BL/10 mice injected with syngeneic B10 L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)-pulsed macrophages (GAT-M phi) within 18 h of birth were unable to respond to soluble GAT, GAT-methylated bovine serum albumin, or B10 GAT-M phi as adults. Spleen cells from these neonatally treated mice responded at control levels to GAT presented in allogeneic M phi and to sheep erythrocytes. Partially purified T cells from these neonatally treated mice suppressed responses by syngeneic virgin, but not primed, spleen cells in an antigen-specific manner and acted during the early phases of the response. These responder GAT-specific suppressor T cells (GAT-TSR) were sensitive to anti-Thy-1 + C and 500-rad irradiation and have the phenotype Ly-1-2+, I-J+; GAT-TSR cells can only suppress responses by spleen cells syngeneic with the GAT-TSR cells at the I-J subregion of H-2. Restimulation of these Ts cells with syngeneic GAT-M phi induces an antigen-specific suppressor factor within the supernatant fluid. The factor, GAT-TsFR, is a glycoprotein with a molecular weight between 48,000 and 63,000, as determined by gel filtration chromatography using isotonic buffers; it bears serologically detectable determinants encoded by the I-J subregion of the H-2 complex, has an antigen-binding site for GAT and L-glutamic acid50-L-tyrosine50, and shares idiotypic determinants with anti-GAT antibodies. The presence of GAT-TsFR in the first 36 h of in vitro culture is required for significant suppression. Furthermore, only responses by spleen cell syngeneic with the cells producing GAT-TsFR at the I-J subregion are suppressed. The fusion of GAT-TsFR-producing cells with BW5147 resulted in generation of two hybridomas with properties and characteristics identical to those of the conventional GAT-TsFR with one exception: conventional and hybridoma 372.D6.5 GAT-TsFR only suppress responses by spleen cells of the I-Jb haplotype, whereas suppression mediated by the second hybridoma GAT-TsFR (372.B3.5) is genetically unrestricted. These hybridoma GAT-TsFR are compared with nonresponder GAT-Ts factor (GAT-TsF) and these responder and nonresponder GAT-TsF are considered in the context of suppressor pathways.