Robust optimization of the Gross Tumor Volume compared to conventional Planning Target Volume-based planning in photon Stereotactic Body Radiation Therapy of lung tumors.

BACKGROUND: Robust optimization has been suggested as an approach to reduce the irradiated volume in lung Stereotactic Body Radiation Therapy (SBRT). We performed a retrospective planning study to investigate the potential benefits over Planning Target Volume (PTV)-based planning. MATERIAL AND METHODS: Thirty-nine patients had additional plans using robust optimization with 5-mm isocenter shifts of the Gross Tumor Volume (GTV) created in addition to the PTV-based plan used for treatment. The optimization included the mid-position phase and the extreme breathing phases of the 4D-CT planning scan. The plans were compared for tumor coverage, isodose volumes, and doses to Organs At Risk (OAR). Additionally, we evaluated both plans with respect to observed tumor motion using the peak tumor motion seen on the planning scan and cone-beam CTs. RESULTS: Statistically significant reductions in irradiated isodose volumes and doses to OAR were achieved with robust optimization, while preserving tumor dose. The reductions were largest for the low-dose volumes and reductions up to 188 ccm was observed. The robust evaluation based on observed peak tumor motion showed comparable target doses between the two planning methods. Accumulated mean GTV-dose was increased by a median of 4.46 Gy and a non-significant increase of 100 Monitor Units (MU) was seen in the robust optimized plans. INTERPRETATION: The robust plans required more time to prepare, and while it might not be a feasible planning strategy for all lung SBRT patients, we suggest it might be useful for selected patients.

Multidisciplinary interventions increase weekly working hours and quality of life in persons with post-concussion syndrome.

OBJECTIVES: To improve labor market attachment, general health and quality of life in persons suffering from post-concussion syndrome. Labor market attachment often changes after mTBI, and especially in persons suffering from post-concussion syndrome, and constitutes a huge societal burden. METHODS: Eighty-two adults with persistent post-concussion syndrome participated in this single-center and uncontrolled interventional efficacy open-label investigation. The primary endpoint was to increase weekly working hours. Outcome measures ranged from self-reported cognitive symptoms to objective performance testing. Multidisciplinary interventions were used to reduce symptoms of fatigue, stress, pain, oculomotor malfunction, and sensitivity to both sound and light. RESULTS: Workhours improved from median 0 to 6 hours (p = 0.00002). Several significant improvements were observed in quality of life measured by the SF-36. General fatigue measured by the MFI-20 was reduced (p < 0.0001), and symptoms of depression were reduced (p < 0.0001). The COPM results were improved for task completion satisfaction and for ability to perform a task (p < 0.0001). Reading speed, and performances in the Groffman Visual Tracing Test and the King-Devick Test, all improved (p < 0.01). The intervention did not reduce perception of pain intensity (p = 0.11). CONCLUSION: After the intervention, participants increased weekly workhours and improved in many aspects of life - including quality of life, performance in everyday activities, fatigue and depression. Perception of pain intensity was not improved.

Does coronary artery calcium score have an impact on overall survival for locally advanced non-small cell lung cancer treated with definitive radiotherapy.

BACKGROUND AND PURPOSE: Coronary artery calcium score (CACs) is an excellent marker for survival in non-cancer patients, but its role in locally advanced non-small cell lung cancer (LA-NSCLC) patients remains uncertain. In this study, we hypothesize that CACs is a prognostic marker for survival in a competing risk analysis in LA-NSCLC patients treated with definitive radiotherapy. MATERIALS AND METHODS: We included 644 patients with LA-NSCLC treated in 2014-2015 in Denmark. Baseline patient characteristics were derived from the Danish Lung Cancer Registry. Radiotherapy planning CT scans were used for manual CACs measurements, and the patients were divided into four groups, CACs 0, 1-99, 100-399, and ≥400. A multivariable Cox model utilizing bootstrapping for cross-validation modeled overall survival (OS). RESULTS: The median follow-up time was seven years, and the median OS was 26 months (95% CI 24-29). Within each CAC group 0, 1-99, 100-399, and ≥400 were 172, 182, 143, and 147 patients, respectively. In the univariable analysis, the survival decreased with increasing CACs. However, after adjustment for age, PS, radiotherapy dose, and logarithmic GTV, CACs did not have a statistically significant impact on OS with hazard ratios of 1.04 (95% CI 0.85-1.28), 1.11 (95%CI 0.89-1.43), and 1.16 (95%CI 0.92-1.47) for CACs 1-99, CACs 100-399 and ≥400, respectively. Elevated CACs was observed in 73 % of the patients suggesting a high risk of cardiac comorbidity before radiotherapy. CONCLUSION: CACs did not add prognostic information to our population's classical risk factors, such as tumor volume, performance status, and age; the lung cancer has the highest priority despite the risk of baseline cardiac comorbidity.

Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign.

BACKGROUND AND PURPOSE: The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants. METHODS: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status. RESULTS: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88). CONCLUSIONS: Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214.

Nanoreporter of an Enzymatic Suicide Inactivation Pathway.

Enzymatic suicide inactivation, a route of permanent enzyme inhibition, is the mechanism of action for a wide array of pharmaceuticals. Here, we developed the first nanosensor that selectively reports the suicide inactivation pathway of an enzyme. The sensor is based on modulation of the near-infrared fluorescence of an enzyme-bound carbon nanotube. The nanosensor responded selectively to substrate-mediated suicide inactivation of the tyrosinase enzyme via bathochromic shifting of the nanotube emission wavelength. Mechanistic investigations revealed that singlet oxygen generated by the suicide inactivation pathway induced the response. We used the nanosensor to quantify the degree of enzymatic inactivation by measuring response rates to small molecule tyrosinase modulators. This work resulted in a new capability of interrogating a specific route of enzymatic death. Potential applications include drug screening and hit-validation for compounds that elicit or inhibit enzymatic inactivation and single-molecule measurements to assess population heterogeneity in enzyme activity.

Consequences of past and present harvest management in a declining flyway population of common eiders Somateria mollissima.

Harvested species population dynamics are shaped by the relative contribution of natural and harvest mortality. Natural mortality is usually not under management control, so managers must continuously adjust harvest rates to prevent overexploitation. Ideally, this requires regular assessment of the contribution of harvest to total mortality and how this affects population dynamics.To assess the impact of hunting mortality on the dynamics of the rapidly declining Baltic/Wadden Sea population of common eiders Somateria mollissima, we first estimated vital rates of ten study colonies over the period 1970-2015. By means of a multi-event capture-recovery model, we then used the cause of death of recovered individuals to estimate proportions of adult females that died due to hunting or other causes. Finally, we adopted a stochastic matrix population modeling approach based on simulations to investigate the effect of past and present harvest regulations on changes in flyway population size and composition.Results showed that even the complete ban on shooting females implemented in 2014 in Denmark, where most hunting takes place, was not enough to stop the population decline given current levels of natural female mortality. Despite continued hunting of males, our predictions suggest that the proportion of females will continue to decline unless natural mortality of the females is reduced.Although levels of natural mortality must decrease to halt the decline of this population, we advocate that the current hunting ban on females is maintained while further investigations of factors causing increased levels of natural mortality among females are undertaken. Synthesis and applications. At the flyway scale, continuous and accurate estimates of vital rates and the relative contribution of harvest versus other mortality causes are increasingly important as the population effect of adjusting harvest rates is most effectively evaluated within a model-based adaptive management framework.

Inter-rater reliability of ratings on the six-item Positive and Negative Syndrome Scale (PANSS-6) obtained using the Simplified Negative and Positive Symptoms Interview (SNAPSI).

PURPOSE: The six-item version of the Positive And Negative Syndrome Scale (PANSS-6) is a brief rating scale focusing on core symptoms of schizophrenia. In order to facilitate rating of PANSS-6 and selected items from other common psychiatric rating scales, we recently developed the Simplified Negative and Positive Symptoms Interview (SNAPSI). The objective of the present study was to test the inter-rater reliability of PANSS-6 ratings obtained using the SNAPSI. MATERIALS AND METHODS: Using the SNAPSI, seven raters (psychiatrists, first-year psychiatry residents and psychologists) performed a total of 56 PANSS-6 ratings of 12 in- or outpatients with schizophrenia. As a measure of inter-rater reliability, we calculated the intra-class correlation coefficient (ICC, ≥0.75 = excellent, 0.40-0.74 = fair to good, <0.40 = poor) for the PANSS-6 total score and individual item scores. Furthermore, for the PANSS-6 total scores obtained by the six noncertified PANSS raters, we calculated the median deviation from the PANSS-6 total scores obtained by the only certified PANSS rater. RESULTS: The ICC for the PANSS-6 total score was 0.74 (F = 2.84, p = .03). The ICCs for the six individual PANSS-6 items ranged from 0.45 (N6 - Lack of spontaneity & flow of conversation) to 0.76 (P3 - Hallucinatory behavior). The PANSS-6 total scores obtained by the six noncertified PANSS raters deviated by a median of 12.7% (interquartile range: 6.2-20.0) from the PANSS-6 total scores obtained by the certified PANSS rater. CONCLUSIONS: We found a good level of inter-rater reliability of PANSS-6 ratings obtained using the SNAPSI for seven raters with varying levels of clinical and research experience.

Performance of short ECG recordings twice daily to detect paroxysmal atrial fibrillation in stroke and transient ischemic attack patients.

Aims Prolonged cardiac monitoring after stroke is recommended though there is no consensus on optimal methods. Short-term ECG recordings with a "thumb-ECG" device have shown promising preliminary results regarding effectiveness and cost benefit. We aimed to examine the performance of thumb-ECG and five days' Holter monitoring in a prospective trial. A secondary endpoint was the inter-observer agreement of the thumb-ECG. Methods Patients older than 65 years with no history of atrial fibrillation who suffered an acute stroke or transient ischemic attack of unknown origin were prospectively included. Patients were monitored for atrial fibrillation with five days' Holter and concurrent 30 s thumb-ECG twice daily, the latter continuing for 30 days. Inter-observer agreement for the thumb-ECG was determined. Results One hundred patients were included and 95 patients were analyzed. Paroxysmal atrial fibrillation was diagnosed in 20 patients with the thumb-ECG recordings and 17 patients on the Holter monitoring. Only 10 were diagnosed with both methods. The difference between the detection rates of the two devices was not significant ( p = 0.63). The inter-observer agreement of the thumb-ECG had a kappa value of 0.65. Conclusion Thirty days' thumb-ECG recordings twice daily for 30 s detect a high proportion of paroxysmal atrial fibrillation in a stroke or transient ischemic attack cohort. The proportion was comparable to five days' Holter monitoring but the agreement between the two methods was poor and the trial was not powered to detect a minor difference between the devices. The inter-observer agreement for the thumb-ECG was substantial. www.clinicalTrials.gov UI: NCT02261766.

The Hypothermic Influence on CHOP and Ero1-α in an Endoplasmic Reticulum Stress Model of Cerebral Ischemia.

Hypoxia induced endoplasmic reticulum stress causes accumulation of unfolded proteins in the endoplasmic reticulum and activates the unfolded protein response, resulting in apoptosis through CCAAT-enhancer-binding protein homologous protein (CHOP) activation. In an in vitro and in vivo model of ischemic stroke, we investigated whether hypothermia regulates the unfolded protein response of CHOP and Endoplasmic reticulum oxidoreductin-α (Ero1-α), because Ero1-α is suggested to be a downstream CHOP target. The gene expression of CHOP and Ero1-α was measured using Quantitative-PCR (Q-PCR) in rat hippocampi following global cerebral ischemia, and in hypoxic pheochromocytoma cells during normothermic (37 °C) and hypothermic (31 °C) conditions. As a result of ischemia, a significant increase in expression of CHOP and Ero1-α was observed after three, six and twelve hours of reperfusion following global ischemia. A stable increase in CHOP expression was observed throughout the time course (p < 0.01, p < 0.0001), whereas Ero1-α expression peaked at three to six hours (p < 0.0001). Induced hypothermia in hypoxia stressed PC12 cells resulted in a decreased expression of CHOP after three, six and twelve hours (p < 0.0001). On the contrary, the gene expression of Ero1-α increased as a result of hypothermia and peaked at twelve hours (p < 0.0001). Hypothermia attenuated the expression of CHOP, supporting that hypothermia suppress endoplasmic reticulum stress induced apoptosis in stroke. As hypothermia further induced up-regulation of Ero1-α, and since CHOP and Ero1-α showed differential regulation as a consequence of both disease (hypoxia) and treatment (hypothermia), we conclude that they are regulated independently.

Modulation of fluorescence signals from biomolecules along nanowires due to interaction of light with oriented nanostructures.

High aspect ratio nanostructures have gained increasing interest as highly sensitive platforms for biosensing. Here, well-defined biofunctionalized vertical indium arsenide nanowires are used to map the interaction of light with nanowires depending on their orientation and the excitation wavelength. We show how nanowires act as antennas modifying the light distribution and the emitted fluorescence. This work highlights an important optical phenomenon in quantitative fluorescence studies and constitutes an important step for future studies using such nanostructures.

Drug-induced hypothermia as beneficial treatment before and after cerebral ischemia.

OBJECTIVES: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. METHODS: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. RESULTS: Talipexole induced mild hypothermia (35.1±1.1 to 36.0±0.5°C) for <20 h. Hypothermic pre- and postconditioning reduced infarct sizes by more than 60% as monitored during the first 90 days after experimental stroke (p<0.05). CONCLUSION: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug-induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke.

Comparison of quantitative estimation of intracerebral hemorrhage and infarct volumes after thromboembolism in an embolic stroke model.

BACKGROUND: Strokes have both ischemic and hemorrhagic components, but most studies of experimental stroke only address the ischemic component. This is likely because investigations of hemorrhagic transformation are hindered by the lack of methods based on unbiased principles for volume estimation. AIMS: We evaluated different methods for estimating the volume of infarcts, hemorrhages, after embolic middle cerebral artery occlusion with or without thrombolysis. METHODS: An experimental thromboembolytic rat model was used in this study. The rats underwent surgery and were placed in two groups. Group 1 was treated with saline, and group 2 was treated with 20 mg/kg recombinant tissue plasminogen activator to promote intracerebral hemorrhages. Stereology, semiautomated computer estimation, and manual erythrocyte counting were used to test the precision and efficiency of determining the size of the infarct and intracerebral hemorrhage. RESULTS: No differences were observed in the infarct volume or amount of bleeding when comparing the three methods of volume estimation. Although semiautomated computer estimation and manual erythrocyte counting provided similar results as the stereological measurements, the stereological method was the most efficient and advantageous. CONCLUSIONS: We found that stereology was the superior method for quantification of hemorrhagic volume, especially for rodent petechial bleeding, which is otherwise difficult to measure. Our results suggest the possibility of measuring both the ischemic and the hemorrhagic components of stroke, two parameters that may be differentially regulated when therapeutic regimens are tested.

Vertical nanowire arrays as a versatile platform for protein detection and analysis.

Protein microarrays are valuable tools for protein assays. Reducing spot sizes from micro- to nano-scale facilitates miniaturization of platforms and consequently decreased material consumption, but faces inherent challenges in the reduction of fluorescent signals and compatibility with complex solutions. Here we show that vertical arrays of nanowires (NWs) can overcome several bottlenecks of using nanoarrays for extraction and analysis of proteins. The high aspect ratio of the NWs results in a large surface area available for protein immobilization and renders passivation of the surface between the NWs unnecessary. Fluorescence detection of proteins allows quantitative measurements and spatial resolution, enabling us to track individual NWs through several analytical steps, thereby allowing multiplexed detection of different proteins immobilized on different regions of the NW array. We use NW arrays for on-chip extraction, detection and functional analysis of proteins on a nano-scale platform that holds great promise for performing protein analysis on minute amounts of material. The demonstration made here on highly ordered arrays of indium arsenide (InAs) NWs is generic and can be extended to many high aspect ratio nanostructures.

Patient-specific scatter correction in clinical cone beam computed tomography imaging made possible by the combination of Monte Carlo simulations and a ray tracing algorithm.

PURPOSE: Cone beam computed tomography (CBCT) image quality is limited by scattered photons. Monte Carlo (MC) simulations provide the ability of predicting the patient-specific scatter contamination in clinical CBCT imaging. Lengthy simulations prevent MC-based scatter correction from being fully implemented in a clinical setting. This study investigates the combination of using fast MC simulations to predict scatter distributions with a ray tracing algorithm to allow calibration between simulated and clinical CBCT images. MATERIAL AND METHODS: An EGSnrc-based user code (egs_cbct), was used to perform MC simulations of an Elekta XVI CBCT imaging system. A 60 keV x-ray source was used, and air kerma scored at the detector plane. Several variance reduction techniques (VRTs) were used to increase the scatter calculation efficiency. Three patient phantoms based on CT scans were simulated, namely a brain, a thorax and a pelvis scan. A ray tracing algorithm was used to calculate the detector signal due to primary photons. A total of 288 projections were simulated, one for each thread on the computer cluster used for the investigation. RESULTS: Scatter distributions for the brain, thorax and pelvis scan were simulated within 2% statistical uncertainty in two hours per scan. Within the same time, the ray tracing algorithm provided the primary signal for each of the projections. Thus, all the data needed for MC-based scatter correction in clinical CBCT imaging was obtained within two hours per patient, using a full simulation of the clinical CBCT geometry. CONCLUSIONS: This study shows that use of MC-based scatter corrections in CBCT imaging has a great potential to improve CBCT image quality. By use of powerful VRTs to predict scatter distributions and a ray tracing algorithm to calculate the primary signal, it is possible to obtain the necessary data for patient specific MC scatter correction within two hours per patient.

Effects of buffer composition and dilution on nanowire field-effect biosensors.

Nanowire-based field-effect transistors (FETs) can be used as ultra-sensitive and label-free biosensors for detecting protein-protein interactions. A way to increase the performance of such sensors is to dilute the sensing buffer drastically. However, we show here that this can have an important effect on the function of the proteins. Moreover, it is demonstrated that this dilution significantly affects the pH stability of the sensing buffer, which consequently impacts the charge of the protein and thus the response and signal-to-noise ratio in the sensing experiments. Three model systems are investigated experimentally to illustrate the impact on ligand-protein and protein-protein interactions. Simulations are performed to illustrate the effect on the performance of the sensors. Combining various parameters, the current study provides a means for evaluating and selecting the most appropriate buffer composition for bioFET measurements.

The effect of voluntarily ingested buprenorphine on rats subjected to surgically induced global cerebral ischaemia.

The effect of perioperatively administered buprenorphine analgesia on rats subjected to surgically induced global ischaemia was assessed. Rats supplied with buprenorphine, mixed in nut paste for voluntary ingestion, displayed significant reductions in postoperative excretions of faecal corticosterone, in both magnitude and variance. This is indicative of lowered stress levels and less inter-animal metabolic variation. Although corticosterone has been reported to modulate the extent of cerebral damage, histology of coronal sections exhibited no differences in the extent of the ischaemia in buprenorphine-treated and untreated animals. A part from a slightly higher hyperthermia immediately after surgery and typical opiate-associated behaviour, the buprenorphine treatment had no apparent adverse effects on the experimental model. In contrast, the analgesic treatment improved the model by minimizing stress-associated confounding variables in the experimental animals.

The site of embolization related to infarct size, oedema and clinical outcome in a rat stroke model - further translational stroke research.

BACKGROUND AND PURPOSE: Reliable models are essential for translational stroke research to study the pathophysiology of ischaemic stroke in an effort to find therapies that may ultimately reduce oedema, infarction and mortality in the clinic. The purpose of this study was to investigate the relation between the site of arterial embolization and the subsequent oedema, infarction and clinical outcome in a rat embolic stroke model. METHODS: Thirty-six male Sprague-Dawley rats were thromboembolized into the internal carotid artery. The site of occlusion was demonstrated by arteriography. Following histological preparation and evaluation, the size of the hemispheres and the infarcts were measured by quantitative histology and planimetry. Another parallel stroke model study was subsequently examined to investigate if the conclusions from the first study could be applied to the second study. RESULTS: The median size of the infarct was 40% of the ipsilateral hemisphere in both the 19 animals with occlusion localised to the intracranial part of the internal carotid artery and in the 11 animals where the main trunk of the middle cerebral artery was occluded. In 5 animals, occlusion of the extracranial part of the internal carotid artery resulted in significantly smaller infarcts compared to other groups (p < 0.01). Another independent study re-confirmed these results. Furthermore, significant correlations (R > 0.76, p < 0.0001) were found between 1) cortical, subcortical, and total infarct volumes, 2) oedema in percent of the left hemisphere, 3) clinical score before termination and 4) postoperative weight loss. CONCLUSIONS: Distal occlusions of the intracranial part of the internal carotid or middle cerebral arteries resulted in comparable large sized infarctions and oedema. This indicates that investigators do not need a similar number of such occlusions in each experimental group. Contrary to observations in the clinic, distal internal carotid artery occlusions did not result in worse outcome than middle cerebral stem occlusions, but this finding may be explained by the controlled emboli size in this experimental stroke model.

Strained silicon as a new electro-optic material.

For decades, silicon has been the material of choice for mass fabrication of electronics. This is in contrast to photonics, where passive optical components in silicon have only recently been realized. The slow progress within silicon optoelectronics, where electronic and optical functionalities can be integrated into monolithic components based on the versatile silicon platform, is due to the limited active optical properties of silicon. Recently, however, a continuous-wave Raman silicon laser was demonstrated; if an effective modulator could also be realized in silicon, data processing and transmission could potentially be performed by all-silicon electronic and optical components. Here we have discovered that a significant linear electro-optic effect is induced in silicon by breaking the crystal symmetry. The symmetry is broken by depositing a straining layer on top of a silicon waveguide, and the induced nonlinear coefficient, chi(2) approximately 15 pm V(-1), makes it possible to realize a silicon electro-optic modulator. The strain-induced linear electro-optic effect may be used to remove a bottleneck in modern computers by replacing the electronic bus with a much faster optical alternative.

Eradication of Helicobacter pylori compared with long-term acid suppression in duodenal ulcer disease. A randomized trial with 2-year follow-up. The Danish Ulcer Study Group.

BACKGROUND: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition. METHODS: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/ day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was discontinuation of treatment, irrespective of reason. RESULTS: Two hundred and seventy-six patients were randomized (139 in the eradication treatment group). In the maintenance phase there were no differences in the reporting of dyspeptic symptoms or in premature withdrawal. In the passive follow-up phase only five patients in the eradication therapy group discontinued owing to relapse of dyspeptic symptoms or ulcer, compared with 51 patients initially randomized to long-term omeprazole. There were no differences in reflux symptoms or in the development of reflux oesophagitis. CONCLUSIONS: Eradication therapy and long-term omeprazole are equally effective in controlling dyspeptic symptoms and reflux in duodenal ulcer patients with healed ulcers. One-quarter of the duodenal ulcer patients who start eradication therapy continue to be symptomatic or fail therapy for other reasons over a 2-year period. Eradication therapy does not increase the risk of reflux in ulcer patients.

Identifying responders to acid suppression in dyspepsia using a random starting day trial.

BACKGROUND: Functional dyspepsia is a heterogeneous condition and a uniform response to drug treatment is not likely. This may be the reason for the general failure of acid suppression in clinical trials in these patients. It may be more rewarding to identify true responders to drug treatment by a single subject trial. AIM: To develop and to test a novel single subject trial design (random starting day trial) in dyspeptic patients. PATIENTS AND METHODS: A total of 301 dyspeptic patients entered a 16-day trial. All patients received placebo for the first 4 days and switched to omeprazole at a randomized and blinded day between day 5 and day 14. Response was defined as a sustained >/= 50% decrease in symptom score occurring in relation to drug shifting. RESULTS: Spontaneous response varied between 0.3% and 10.6% per day, uniformly distributed over time. Overall, 53-61% of patients with organic dyspepsia had a symptom response in relation to shifting to active treatment, compared to only 23% of patients with functional dyspepsia. The only predictor of response was symptoms suggesting gastro-oesophageal reflux. CONCLUSIONS: A random starting day trial may be a valuable tool to identify response to acid suppression in dyspeptic patients.