Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer.

Background: Treatment of patients with locally advanced rectal cancer (LARC) is based on a combination of chemo-radiotherapy (CRT) and surgery. The rate of distant recurrences remains over 25%. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer-specific DNA segments and is a promising biomarker in patients with colorectal cancer. The aim of our study was to investigate plasma cfDNA as a prognostic marker for outcome in patients with LARC treated with neoadjuvant CRT and surgery. Patients and methods: In total, 123 patients with LARC were included in 2 biomarker studies. Patients were treated with neoadjuvant CRT before TME surgery. Fifty-two (42%) of the patients received induction chemotherapy with capecitabine + oxaliplatin. Total cfDNA was measured by direct fluorescent assay in EDTA plasma samples obtained at baseline, after induction chemotherapy, and after CRT. Serial samples 5 years after surgery were collected in 51 patients (41%). Results: Median follow-up was 55 months. Distant or local recurrence was seen in 30.9% of the patients. Patients with baseline cfDNA levels above the 75th quartile had a higher risk of local or distant recurrence and shorter time to recurrence compared with patients with plasma cfDNA below the 75th percentile (HR = 2.48, 95% CI: 1.3-4.8, P = 0.007). The same applied to disease-free survival (DFS) (HR = 2.43, 95% CI: 1.27-4.7, P = 0.015). In multivariate analysis, a high cfDNA level was significantly associated with time to progression and DFS. During follow-up, the association remained significant regardless of time point for sample analysis. Conclusion: We have demonstrated an association between a high baseline plasma level of cfDNA and increased risk of recurrence, shorter time to recurrence, and shorter DFS in patients with LARC. Consequently, cfDNA could potentially improve pre- and post-treatment risk assessment and facilitate individualized therapy for patients with LARC.

On-Orbit Performance of the Helioseismic and Magnetic Imager Instrument onboard the Solar Dynamics Observatory.

The Helioseismic and Magnetic Imager (HMI) instrument is a major component of NASA's Solar Dynamics Observatory (SDO) spacecraft. Since commencement of full regular science operations on 1 May 2010, HMI has operated with remarkable continuity, e.g. during the more than five years of the SDO prime mission that ended 30 September 2015, HMI collected 98.4% of all possible 45-second velocity maps; minimizing gaps in these full-disk Dopplergrams is crucial for helioseismology. HMI velocity, intensity, and magnetic-field measurements are used in numerous investigations, so understanding the quality of the data is important. This article describes the calibration measurements used to track the performance of the HMI instrument, and it details trends in important instrument parameters during the prime mission. Regular calibration sequences provide information used to improve and update the calibration of HMI data. The set-point temperature of the instrument front window and optical bench is adjusted regularly to maintain instrument focus, and changes in the temperature-control scheme have been made to improve stability in the observable quantities. The exposure time has been changed to compensate for a 20% decrease in instrument throughput. Measurements of the performance of the shutter and tuning mechanisms show that they are aging as expected and continue to perform according to specification. Parameters of the tunable optical-filter elements are regularly adjusted to account for drifts in the central wavelength. Frequent measurements of changing CCD-camera characteristics, such as gain and flat field, are used to calibrate the observations. Infrequent expected events such as eclipses, transits, and spacecraft off-points interrupt regular instrument operations and provide the opportunity to perform additional calibration. Onboard instrument anomalies are rare and seem to occur quite uniformly in time. The instrument continues to perform very well.

Synthesis of ligand-free CZTS nanoparticles via a facile hot injection route.

Single-phase, ligand-free Cu2ZnSnS4 (CZTS) nanoparticles that can be dispersed in polar solvents are desirable for thin film solar cell fabrication, since water can be used as the solvent for the nanoparticle ink. In this work, ligand-free nanoparticles were synthesized using a simple hot injection method and the precursor concentration in the reaction medium was tuned to control the final product. The as-synthesized nanoparticles were characterized using various techniques, and were found to have a near-stoichiometric composition and a phase-pure kesterite crystal structure. No secondary phases were detected with Raman spectroscopy or scanning transmission electron microscopy energy dispersive x-ray spectroscopy. Furthermore, high resolution transmission electron microscopy showed large-sized nanoparticles with an average diameter of 23 nm ± 11 nm. This approach avoids all organic materials and toxic solvents that otherwise could hinder grain growth and limit the deposition techniques. In addition the synthesis route presented here results in nanoparticles of a large size compared to other ligand-free CZTS nanoparticles, due to the high boiling point of the solvents selected. Large particle size in CZTS nanoparticle solar cells may lead to a promising device performance. The results obtained demonstrate the suitability of the synthesized nanoparticles for application in low cost thin film solar cells.

Femtosecond-laser ablation dynamics of dielectrics: basics and applications for thin films.

Laser ablation of dielectrics by ultrashort laser pulses is reviewed. The basic interaction between ultrashort light pulses and the dielectric material is described, and different approaches to the modeling of the femtosecond ablation dynamics are reviewed. Material excitation by ultrashort laser pulses is induced by a combination of strong-field excitation (multi-photon and tunnel excitation), collisional excitation (potentially leading to an avalanche process), and absorption in the plasma consisting of the electrons excited to the conduction band. It is discussed how these excitation processes can be described by various rate-equation models in combination with different descriptions of the excited electrons. The optical properties of the highly excited dielectric undergo a rapid change during the laser pulse, which must be included in a detailed modeling of the excitations. The material ejected from the dielectric following the femtosecond-laser excitation can potentially be used for thin-film deposition. The deposition rate is typically much smaller than that for nanosecond lasers, but film production by femtosecond lasers does possess several attractive features. First, the strong-field excitation makes it possible to produce films of materials that are transparent to the laser light. Second, the highly localized excitation reduces the emission of larger material particulates. Third, lasers with ultrashort pulses are shown to be particularly useful tools for the production of nanocluster films. The important question of the film stoichiometry relative to that of the target will be thoroughly discussed in relation to the films reported in the literature.

Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiation in patients with locally advanced rectal cancer has no impact on overall survival (OS) and distant recurrences. The aim of the study was to evaluate local downstaging, toxicity and long-term outcome in patients with locally advanced rectal cancer after induction therapy with capecitabine and oxaliplatin (CAPEOX) followed by radiotherapy concomitant with capecitabine [chemoradiotherapy (CRT)] before total mesorectal excision (TME). PATIENTS AND METHODS: Patients with T4 tumors, all T3N+ tumors or T3 tumors involving or with a distance ≤1 mm to the mesorectal fascia were included. Patients were planned for two cycles of CAPEOX followed by radiotherapy concomitant with capecitabine. TME was carried out 6 weeks after the completion of CRT. RESULTS: Of 84 consecutively admitted patients starting induction CAPEOX, 77 patients underwent surgery. R0 resection was seen in 94% and T downstaging in 69%. In the intention-to-treat group, pathological complete response was seen in 23%. Five-year disease-free survival (DFS) and OS were 63% [95% confidence interval (CI), 52.2% to 73.7%] and 67% (95% CI, 56.1% to 77.3%), respectively. Grade 3/4 toxicity was seen in 18%, and four deaths occurred within 2 months of therapy. CONCLUSION: Induction chemotherapy before CRT and surgery showed a high local control rate and promising long-term outcome as OS and DFS.

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men.

AIMS/HYPOTHESIS: We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. METHODS: We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. RESULTS: Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function. CONCLUSIONS/INTERPRETATION: Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.

Methodological development and biological observations of cell free DNA with a simple direct fluorescent assay in colorectal cancer.

BACKGROUND: Cell free DNA (cfDNA) has shown promising utility as prognostic biomarker for patients with colorectal cancer (CRC), with an ongoing need to optimize and validate the laboratory methodology. Here, we report our optimization and validation of a direct fluorescent assay and display the potential utility in patients with colorectal cancer. METHODS: Plasma cfDNA was analyzed by a direct fluorescent assay (DFA) and compared to quantification by droplet digital PCR (ddPCR). For clinical validation, baseline blood samples were available for a total of 273 patients from six different Nordic trials, covering patients with locally advanced rectal cancer (n = 176, cohorts A + B), liver limited metastatic CRC (n = 75C + D) and wide spread metastatic CRC (n = 22 E + F). RESULTS: Validating the DFA analysis with ddPCR revealed a strong correlation with an R2 of 0.81. For the clinical cohorts, the levels of cfDNA were: 0.8 ng/uL (95%CI 0.75-0.83) (A + B), 0.93 ng/uL (95%CI 0.86-1.02) (C + D) and 1.2 ng/uL (95%CI 0.85-1.47) (E + F), respectively (p < 0.01). All cohorts of colorectal cancer had higher levels of cell free DNA than healthy individuals (n = 94) (p < 0.01). CONCLUSION: Analysis of cell free DNA by a direct fluorescent assay could be an attractive laboratory option for a rapid inexpensive quantification of cell free DNA.

d-Propoxyphene kinetics after single oral and intravenous doses in man.

d-Propoxyphene kinetics was studied in 8 healthy male subjects after single oral doses of d-propoxyphene at 65, 130, and 190 mg and after slow intravenous infusion of 65 mg. Total urinary excretion (7 days) indicated complete oral absorption but systemic availability was reduced corresponding to fist-pass elimination of 30% to 70%. There was linearity between oral dose and the corresponding area under the plasma concentration/time curve of d-propoxyphene and the metabolite norpropoxyphene. The kinetic measurements showed 2- to 3-fold interindividual variations: oral clearance, 1.3 to 3.6 1/min; systemic clearance, 0.6 to 1.2 1/min; apparent volume of distribution, 700 to 1,800 1; d-propoxyphene half-life (t1/2), 8 to 24 hr; and norpropoxyphene t1/2, 18 to 29 hr. There were pronounced intraindividual dose-dependent variations in oral clearance in some subjects. The intravenous concentration curves indicated a 3-compartment distribution model.

Angular distribution of electron temperature and density in a laser-ablation plume

The angular distribution of electron temperature and density in a laser-ablation plume has been studied for the first time. The electron temperature ranges from 0.1 to 0.5 eV and is only weakly dependent on the angle in the low-intensity range studied here. In contrast, the typical ion energy is about 2 orders of magnitude larger, and its angular distribution is more peaked about the target normal. The derived values of the electron density are in agreement with the measured values of ion density.

Changes in sexual behavior after orthopedic replacement of hip or knee in elderly males--a prospective study.

The aim of this study was to investigate two questions: Does arthroplastic surgery affect the patient's status as being sexually active; and if patients are sexually active, does surgery affect their erectile function? The study was designed prospectively and the patients filled in a questionnaire concerning sexuality and erectile function before and 6 months after alloplastic hip-or knee surgery. Ninety-nine males were included, mean age 70.6 y. The results demonstrate that 17% of patients lost a sexual activity that they had preoperatively, and no one regained sexual activity after surgery. A correlation between increasing age and risk of losing sexual activity was demonstrated. 26.1% lost a normal erectile function they had preoperatively, while 6.7% regained normal erections. A similar correlation between increasing age and increased risk was demonstrated. From this study of elderly males undergoing orthopaedic alloplastic surgery it is concluded that the risk of losing sexual activity and erectile capability is increased after surgery, and especially in the group where sexual functions are already impaired.

Abdominal haemorrhage--a preventable cause of death after field stabilization?

The causes of preventable death vary in different operational settings, and the topic has not previously been explored in a fully developed central European rescue system. The factors associated with potentially preventable death were studied in a retrospective study of 430 fatal traffic accident victims (1980-96) in Lörrach County, Germany. Mission protocols could be retrieved for detailed analysis in 239 of the cases. These were studied in order to identify factors associated with preventable death. At the scene of the accident, 38% of the patients died without cardiopulmonary resuscitation (CPR) and 18% after CPR. Four patients died after a certain delay without CPR before reaching hospital. A total of 43% of the victims were admitted to hospital, 5% had received prehospital CPR and the remaining 38% had not. In a subgroup representing the experience of a single emergency physician 60 fatalities were studied. Of these, 27 (45%) patients died within the hospital; almost half of these cases (13/27) had been conscious at some time after the accident and of these, seven (7/13) died from intra-abdominal bleeding within 4 h after admission. The same cause of death was found in 3 of the 14 comatose patients. Pleural drainage was carried out in four patients and unrecognized pneumothoraces or spinal injuries did not occur. Tracheal intubation was employed in 24/27. Medical antishock trousers (MAST) were not available. The data indicate that intra-abdominal haemorrhage is an underestimated cause of death in a comprehensive rescue system, possibly as a consequence of field stabilization. The use of MAST may be a relevant therapeutic option to prevent these fatalities. The method offers the possibility of intra-abdominal compression and haemostasis after tracheal intubation has been performed. Previous controlled studies on MAST may have been biased by faulty methodology (e.g. absence of tracheal intubation) and inappropriate indications (e.g. other causes of shock). The value of MAST in comprehensive rescue systems should therefore be reassessed. The difficulties in identifying factors leading to preventable death in a retrospective analysis, are discussed and it is recommended that a permanent prospective quality control be performed in all cases of fatal accidents in order to ensure the continued improvement of prehospital emergency medical systems.

The effect of imipramine and lithium on "learned helplessness" and acetylcholinesterase in rat brain.

The effect of short- and long-term treatment with imipramine and lithium on shock stress-induced escape failures in a shuttlebox (the "learned helplessness" model of depression) was investigated in rats. Acetylcholinesterase (AChE) activity was measured in the frontal cortex, hippocampus and striatum after the shuttlebox test. Imipramine was found to normalize escape behavior, whereas lithium further aggravated escape behavior. No correlation was found between escape behavior and AChE activity in the three brain areas investigated. However, a significant decrease in AChE activity in striatum was found in rats exposed either to shock stress and no drug treatment or to drug treatment and no shock stress. In rats exposed to the combination of shock stress and drug (imipramine or lithium), a slight or no decrease of AChE activity occurred. Exposure to shock stress alone produced no changes in AChE activity in the hippocampus and frontal cortex. In conclusion, lithium did not have an antidepressant effect on "learned helplessness" and AChE activity was not correlated to escape behavior. However, both imipramine and lithium normalized the decreased level of AChE activity in striatum in rats exposed to shock stress.

Gastro-intestinal absorption and in vitro release of boric acid from water-emulsifying ointments.

Boric acid taken orally by six male volunteers in a cross-over study was absorbed to equal extents from a water solution and a 3% waterless, water-emulsifying ointment, though with a slight initial delay in the latter case. Virtually complete gastro-intestinal absorption and renal excretion were indicated by the 96-hr urinary recovery, amounting to 89.1-98.3% (mean 93.9%) and 89.2-97.5% (mean 92.4%) of the dose ingested as solution and ointment, respectively, normal daily boron excretion having been taken into account. The in vitro release of boric acid, measured for 24 hr by dialysis in water at 37 degrees C, reached 95% from a purely water-based jelly but only about 5% from the water-emulsifying ointment. The low boric acid release from the ointment was not significantly influenced when the ointment was dialysed against buffer solutions of pH 2.5 and 9.6 instead of water, or when the maximum possible amount of water (26.9% w/w) was incorporated into the ointment before dialysis. The 24-hr boric acid release from a number of other oil-based ointments, either hydrophobic or water-emulsifying and containing 1-3% boric acid and 0-28.5% water, was also low (0.9-18.3% of the boric acid content). This indicates that the formulation of the ointment is an important factor in determining the extent of release of boric acid when the ointment is applied externally, but that it does not alter the absorption of boric acid should the ointment be ingested.

The occurrence of negative middle ear pressure in children: an analysis of supposed associated factors.

This study analyzed the occurrence of negative middle ear pressure in various groups of children by comparing them with control groups. A screening procedure recording middle ear pressure and screening audiogram was performed several times throughout the year in an unselected group of 352 seven-year-old children. From about 4000 measurements of middle ear pressure an average value for each child was calculated. By applying thresholds of pathology of -160 mm H2( and -240 mm H2O, the occurrence of pathology in the different groups was analyzed. A medical history of each child was obtained by questionnaires answered by parents, giving information concerning allergy, previous adenoidectomy, previous exposure to respiratory tract infections and the social group of the family. A score of dental caries was obtained in each child. Furthermore, the relationship to antibiotic treatment and the child's use of swimming pools was analyzed, based on single measurements. The use of swimming pools seems to be beneficial to children suffering from a negative middle ear pressure. However, the other variables showed no relationship to negative middle ear pressure. It is concluded that other unknown factors must be involved in the development of negative middle ear pressure and chronic OME in children.

The diagnosis of negative middle ear pressure in children. The accuracy of symptoms and signs assessed by tympanometry.

Over a period of one year, we studied 352 children at random in order to determine whether or not a diagnosis of negative middle ear pressure can be made reliably without using tympanometry. Each child was tested repeatedly by screening audiometry at 20 dB and by tympanometry, and was examined once by otoscopy. Information about upper respiratory tract infections, feelings of oppression in the ears, and the parents' opinion of the child's hearing ability were obtained from questionnaires. Otoscopy correlated poorly with the tympanometry, while screening audiometry and the parents' opinion of the child's hearing ability were more reliable measures. It is concluded that tympanometry is an absolutely necessary tool in the clinical diagnosis of negative middle ear pressure.

Duration and type of prehospital emergency therapy.

Prehospital on-scene time (OST) has only been recorded sporadically and has not been related to different types of therapy. In order to create a reference standard for a European emergency medical system involving field stabilization (FS) by physicians, a retrospective analysis was performed of 639 consecutive missions over 81 months in relation to the extent of therapy evaluated by the Emergency Therapy Index (ETI). An OST was not registered in ETI-0-2. The median OST in ETI-3 was 14.0 minutes, slightly increasing with mission grade to 19.5 minutes in ETI-6, and then suddenly increasing to 23.5 minutes in cases of intubation (ETI-7) and to 26.0 minutes when cardiopulmonary resuscitation was performed with subsequent admission (ETI-8). A variety of prehospital therapy is demonstrated. The study supports the view that only exceptional conditions can justify an OST exceeding 20 minutes in ETI-3-4, 24 minutes in ETI-5-6 and 33 minutes in ETI-7.

Major interventions in the field stabilization of trauma patients: what is possible?

Previous studies on prehospital care are mostly hampered by a large number of less-urgent missions and lack of utilization of the possibilities which blur the effect of an advanced medical service. The current analysis of the most aggressive trauma care on-scene concludes that largely all vital stabilization can be carried out prehospitally, except performing an X-ray (with its possible consequences) and an operation. The latter measure does, however, also represent the current limits of field stabilization: circulatory unstable patients with penetrating bleeding trauma or presumed internal haemorrhagia will require a minimal stabilization--concentrating on securing the airway--and then fast transport to the nearest hospital with capability to carry out an acute operation (the 'scoop and run' principle). Novel principles and pathophysiological understanding indicate that new principles of field stabilization may actually offer further support and thereby increase the chances of survival for these patients, provided the necessary new techniques acknowledge the need for speed. In this development, the principles in prehospital care often exceeds what is actually offered in the hospitals' emergency rooms. Since the majority of advanced prehospital methods depends on comparatively safe anaesthesia and analgesia techniques, the particular responsibility for anaesthetists in this field is stressed.

Delayed mobilization of the emergency physician in prehospital missions.

A retrospective analysis of 118 prehospital missions involving vitally important therapy (anaesthesia or resuscitation with admission) was carried out. Primary mobilization of the emergency physician (EP) (i.e. before arrival of the rescue ambulance) was carried out by the alarm dispatch centre in only 36% of these missions. In the 74 missions utilizing secondary alarm (i.e. request for the EP after the arrival of the ambulance), detrimental delay of 8 minutes or more was found in 30%. In two of the 27 missions of cardiopulmonary resuscitation with subsequent admission, the physician was only mobilized after the patient developed cardiac arrest during unescorted transport although acute myocardial infarction had been suspected prior to transport. The observations suggest that an improved assessment of possible involvement of an EP is necessary, both at the alarm central and the emergency site. Moreover, continued monitoring (quality control) of this delay is necessary.

Use of non-pneumatic antishock garments for ruptured abdominal aortic aneurysm.

Two cases of near-fatal aortic abdominal aneurysm (AAA) are described which were successfully stabilized by a new principle for exerting abdominal compression, the non-pneumatic medical antishock trousers (NP-MAST). Obviously, the compression obtained with the NP-MAST suffices for this dramatic emergency. Moreover, compared with pneumatic antishock garments (PASG), the NP-MAST has the advantage of being light, independent of flight height and unable to produce dangerously high pressures. Moreover, it contains no manometers, which could detract the doctor's attention from more important measures. The need for endotracheal intubation in advance to application of any kind of abdominal compression (PASG or NP-MAST) is stressed.

In search of the most suitable technique for truncal spinal immobilization with associated radiography.

The spineboard (SB) and the vacuum mattress (VM) are utilized for prehospital and emergency department (ED) immobilization of the spine. While permitting excellent pictures to be taken, the SB is a very painful device that can only be used for a limited time. The current study investigated the feasibility of different models of the VM for radiography. Computed tomography for each of seven VMs showed different degrees of shadows from the sac containing the polystyrole balls. This was related first of all to a high contrast of the sac in comparison with its contents and to a sometimes considerable shrinkage of the latter that resulted in further folding into the sac and, secondly, also to very broad mattresses, additional chambers within the VM and various grips and supports for lifting the mattress. Therefore, some features designed for prehospital use of the VM are actually acting against its use for diagnostic purposes. The aim of this study was to discuss and identify possible properties of a device that is useful for both immobilization and diagnostic purposes.