Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891)

OBJECTIVE: EORTC trial 30891 compared immediate versus deferred androgen-deprivation therapy (ADT) in T0-4 N0-2 M0 prostate cancer (PCa). Many patients randomly assigned to deferred ADT did not require ADT because they died before becoming symptomatic. The question arises whether serum prostate-specific antigen (PSA) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment. METHODS: PSA data at baseline, PSA doubling time (PSADT) in patients receiving no ADT, and time to PSA relapse (>2 ng/ml) in patients whose PSA declined to <2 ng/ml within the first year after immediate ADT were analyzed in 939 eligible patients randomly assigned to immediate (n=468) or deferred ADT (n=471). RESULTS: In both arms, patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSA12 mo. Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. CONCLUSIONS: Patients with a baseline PSA>50 ng/ml and/or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT, whereas patients with a baseline PSA<50 ng/ml and a slow PSADT (>12 mo) were likely to die of causes unrelated to PCa, and thus could be spared the burden of immediate ADT.

Experimental investigation of regular fluids and nanofluids during flow boiling in a single microchannel at different heat fluxes and mass fluxes

The dissipation of high heat flux from integrated circuit chips and the maintenance of acceptable junction temperatures in high powered electronics require advanced cooling technologies. One such technology is two-phase cooling in microchannels under confined flow boiling conditions. In macroscale flow boiling bubbles will nucleate on the channel walls, grow, and depart from the surface. In microscale flow boiling bubbles can fill the channel diameter before the liquid drag force has a chance to sweep them off the channel wall. As a confined bubble elongates in a microchannel, it traps thin liquid films between the heated wall and the vapor core that are subject to large temperature gradients. The thin films evaporate rapidly, sometimes faster than the incoming mass flux can replenish bulk fluid in the microchannel. When the local vapor pressure spike exceeds the inlet pressure, it forces the upstream interface to travel back into the inlet plenum and create flow boiling instabilities. Flow boiling instabilities reduce the temperature at which critical heat flux occurs and create channel dryout. Dryout causes high surface temperatures that can destroy the electronic circuits that use two-phase micro heat exchangers for cooling. Flow boiling instability is characterized by periodic oscillation of flow regimes which induce oscillations in fluid temperature, wall temperatures, pressure drop, and mass flux. When nanofluids are used in flow boiling, the nanoparticles become deposited on the heated surface and change its thermal conductivity, roughness, capillarity, wettability, and nucleation site density. It also affects heat transfer by changing bubble departure diameter, bubble departure frequency, and the evaporation of the micro and macrolayer beneath the growing bubbles. Flow boiling was investigated in this study using degassed, deionized water, and 0.001 vol% aluminum oxide nanofluids in a single rectangular brass microchannel with a hydraulic diameter of 229 µm for one inlet fluid temperature of 63°C and two constant flow rates of 0.41 ml/min and 0.82 ml/min. The power input was adjusted for two average surface temperatures of 103°C and 119°C at each flow rate. High speed images were taken periodically for water and nanofluid flow boiling after durations of 25, 75, and 125 minutes from the start of flow. The change in regime timing revealed the effect of nanoparticle suspension and deposition on the Onset of Nucelate Boiling (ONB) and the Onset of Bubble Elongation (OBE). Cycle duration and bubble frequencies are reported for different nanofluid flow boiling durations. The addition of nanoparticles was found to stabilize bubble nucleation and growth and limit the recession rate of the upstream and downstream interfaces, mitigating the spreading of dry spots and elongating the thin film regions to increase thin film evaporation.

IMPROVING STARTABILITY AND REDUCING EMISSIONS IN FLEXFUEL SPARK IGNITION DIRECT INJECTION VARIABLE CAM TIMING ENGINE

Experimental work and analysis was done to investigate engine startup robustness and emissions of a flex-fuel spark ignition (SI) direct injection (DI) engine. The vaporization and other characteristics of ethanol fuel blends present a challenge at engine startup. Strategies to reduce the enrichment requirements for the first engine startup cycle and emissions for the second and third fired cycle at 25°C ± 1°C engine and intake air temperature were investigated. Research work was conducted on a single cylinder SIDI engine with gasoline and E85 fuels, to study the effect on first fired cycle of engine startup. Piston configurations that included a compression ratio change (11 vs 15.5) and piston geometry change (flattop vs bowl) were tested, along with changes in intake cam timing (95,110,125) and fuel pressure (0.4 MPa vs 3 MPa). The goal was to replicate the engine speed, manifold pressure, fuel pressure and testing temperature from an engine startup trace for investigating the first fired cycle for the engine. Results showed bowl piston was able to enable lower equivalence ratio engine starts with gasoline fuel, while also showing lower IMEP at the same equivalence ratio compared to flat top piston. With E85, bowl piston showed reduced IMEP as compression ratio increased at the same equivalence ratio. A preference for constant intake valve timing across fuels seemed to indicate that flattop piston might be a good flex-fuel piston. Significant improvements were seen with higher CR bowl piston with high fuel pressure starts, but showed no improvement with low fuel pressures. Simulation work was conducted to analyze initial three cycles of engine startup in GT-POWER for the same set of hardware used in the experimentations. A steady state validated model was modified for startup conditions. The results of which allowed an understanding of the relative residual levels and IMEP at the test points in the cam phasing space. This allowed selecting additional test points that enable use of higher residual levels, eliminating those with smaller trapped mass incapable of producing required IMEP for proper engine turnover. The second phase of experimental testing results for 2nd and 3rd startup cycle revealed both E10 and E85 prefer the same SOI of 240°bTDC at second and third startup cycle for the flat top piston and high injection pressures. E85 fuel optimal cam timing for startup showed that it tolerates more residuals compared to E10 fuel. Higher internal residuals drives down the Ø requirement for both fuels up to their combustion stability limit, this is thought to be direct benefit to vaporization due to increased cycle start temperature. Benefits are shown for an advance IMOP and retarded EMOP strategy at engine startup. Overall the amount of residuals preferred by an engine for E10 fuel at startup is thought to be constant across engine speed, thus could enable easier selection of optimized cam positions across the startup speeds.

The role of the human posterior parietal cortex in memory-guided saccade execution: a double-pulse transcranial magnetic stimulation study

The present study investigated the role of the right posterior parietal cortex (PPC) in the triggering of memory-guided saccades by means of double-pulse transcranial magnetic stimulation (dTMS). Shortly before saccade onset, dTMS with different interstimulus intervals (ISI; 35, 50, 65 or 80 ms) was applied. For contralateral saccades, dTMS significantly decreased saccadic latency with an ISI of 80 ms and increased saccadic gain with an ISI of 65 and 80 ms. Together with the findings of a previous study during frontal eye field (FEF) stimulation the present results demonstrate similarities and differences between both regions in the execution of memory-guided saccades. Firstly, dTMS facilitates saccade triggering in both regions, but the timing is different. Secondly, dTMS over the PPC provokes a hypermetria of contralateral memory-guided saccades that was not observed during FEF stimulation. The results are discussed within the context of recent neurophysiological findings in monkeys.

Lhermitte-Duclos disease with atypical vascularization--case report and review of the literature

OBJECTIVE: A case of Lhermitte-Duclos disease (LDD, dysplastic gangliocytoma) with atypical vascularization is reported. LDD is a rare cerebellar mass lesion which may be associated with Cowden's syndrome and the PTEN germline mutation. CASE MATERIAL: A 61-year-old male presented 15 years before with a transient episode of unspecific gait disturbance. Initial magnetic resonance (MR) imaging revealed a right-sided, diffuse, nonenhancing cerebellar mass lesion. No definitive diagnosis was made at that time, and the symptoms resolved spontaneously. 15 years later, the patient presented with acute onset of vomiting associated with headache and ataxic gait. MR imaging showed a progression of the lesion with occlusive hydrocephalus. The lesion depicted a striated pattern characteristic for LDD with T1-hypointense and T2-hyperintense bands, nonenhancing with contrast. After resection of the mass lesion, the cerebellar and hydrocephalic symptoms improved rapidly. The pathological examination confirmed the diagnosis of dysplastic gangliocytoma (WHO Grade I) with enlarged granular and molecular cell layers, reactive gliosis and dysplastic blood vessels. No other clinical features associated with Cowden's syndrome were present. CONCLUSIONS: This case illustrates that LDD with atypical vascularization is a slow-growing posterior fossa mass lesion which may remain asymptomatic for many years. Timing of surgical treatment and extent of resection in patients with LDD is controversial. The typical features on standard T1-/T2-weighted MR imaging allow a diagnosis without surgery in most cases. The authors believe that the decision to treat in these cases should be based on clinical deterioration.

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

Parameter-free extraction of the functional network topology from intracranial EEG recordings: a time-resolved study of graph properties in focal onset seizures

Rationale: Focal onset epileptic seizures are due to abnormal interactions between distributed brain areas. By estimating the cross-correlation matrix of multi-site intra-cerebral EEG recordings (iEEG), one can quantify these interactions. To assess the topology of the underlying functional network, the binary connectivity matrix has to be derived from the cross-correlation matrix by use of a threshold. Classically, a unique threshold is used that constrains the topology [1]. Our method aims to set the threshold in a data-driven way by separating genuine from random cross-correlation. We compare our approach to the fixed threshold method and study the dynamics of the functional topology. Methods: We investigate the iEEG of patients suffering from focal onset seizures who underwent evaluation for the possibility of surgery. The equal-time cross-correlation matrices are evaluated using a sliding time window. We then compare 3 approaches assessing the corresponding binary networks. For each time window: * Our parameter-free method derives from the cross-correlation strength matrix (CCS)[2]. It aims at disentangling genuine from random correlations (due to finite length and varying frequency content of the signals). In practice, a threshold is evaluated for each pair of channels independently, in a data-driven way. * The fixed mean degree (FMD) uses a unique threshold on the whole connectivity matrix so as to ensure a user defined mean degree. * The varying mean degree (VMD) uses the mean degree of the CCS network to set a unique threshold for the entire connectivity matrix. * Finally, the connectivity (c), connectedness (given by k, the number of disconnected sub-networks), mean global and local efficiencies (Eg, El, resp.) are computed from FMD, CCS, VMD, and their corresponding random and lattice networks. Results: Compared to FMD and VMD, CCS networks present: *topologies that are different in terms of c, k, Eg and El. *from the pre-ictal to the ictal and then post-ictal period, topological features time courses that are more stable within a period, and more contrasted from one period to the next. For CCS, pre-ictal connectivity is low, increases to a high level during the seizure, then decreases at offset. k shows a ‘‘U-curve’’ underlining the synchronization of all electrodes during the seizure. Eg and El time courses fluctuate between the corresponding random and lattice networks values in a reproducible manner. Conclusions: The definition of a data-driven threshold provides new insights into the topology of the epileptic functional networks.