Spatially resolved diagnostics for optimization of large ion beam sources.

Giant negative ion sources for neutral beam injectors deliver huge negative ion currents, thanks to their multi-beamlet configuration. As the single-beamlet optics defines the transmission losses along the beamline, the extraction of a similar current for all beamlets is extremely desirable, in order to facilitate the beam source operation (i.e., around perveance match). This Review investigates the correlation between the vertical profile of beam intensity and the vertical profiles of plasma properties at the extraction region of the source, focusing on the influence of increasing cesium injection. Only by the combined use of all available source diagnostics, described in this Review, can beam features on the scale of the non-uniformities be investigated with a sufficient space resolution. At RF power of 50 kW/driver, with intermediate bias currents and a filter field of 2.4 mT, it is found that the central part of the four vertical beam segments exhibits comparable plasma density and beamlet currents; at the edges of the central segments, both the beam and electron density appear to decrease (probably maintaining fixed electron-to-ion ratio); at the bottom of the source, an increase of cesium injection can compensate for the vertical drifts that cause a much higher presence of electrons and a lower amount of negative ions.

CRISP: A compact RF ion source prototype for emittance scanner testing.

A movable Allison type emittance scanner is being developed to characterize the phase-space distribution of the beamlets of spectral phase interferometry for direct electric-field reconstruction, the prototype RF negative ion source of the ITER heating neutral beam injector. To test the electronics and verify the capability of the device to resolve nearby beamlets, a compact RF ion source prototype has been set up, capable of accelerating 1 mA of helium ions up to a voltage of 2 kV. A commercial 100 W RF generator creates a plasma inside a Pyrex tube, with a density between 1015 and 1016 m-3 and an electron temperature up to 15 eV. Three multi-aperture grids in accel-decel configuration extract and accelerate the ions, which are measured with a Faraday cup. We present in this paper the characterization of the ion source and its first operation, showing that it is suitable for the commissioning of the Allison scanner.

First operation in SPIDER and the path to complete MITICA.

The requirements of ITER neutral beam injectors (1 MeV, 40 A negative deuterium ion current for 1 h) have never been simultaneously attained; therefore, a dedicated Neutral Beam Test Facility (NBTF) was set up at Consorzio RFX (Padova, Italy). The NBTF includes two experiments: SPIDER (Source for the Production of Ions of Deuterium Extracted from Rf plasma), the full-scale prototype of the source of ITER injectors, with a 100 keV accelerator, to investigate and optimize the properties of the ion source; and MITICA, the full-scale prototype of the entire injector, devoted to the issues related to the accelerator, including voltage holding at low gas pressure. The present paper gives an account of the status of the procurements, of the timeline, and of the voltage holding tests and experiments for MITICA. As for SPIDER, the first year of operation is described, regarding the solution of some issues connected with the radiofrequency power, the source operation, and the characterization of the first negative ion beam.

Beam and installation improvements of the NIO1 ion source.

The NIO1 (Negative Ion Optimization phase 1) source can provide continuous beam operation, which is convenient for systematic parameter and equipment studies. Even in the pure volume production regime, the source yield was found to depend on conditioning procedures. Magnetic configuration tests continued adding magnets to the existing setup; the filter field component Bx has been progressively extended to span the -12 to 5 mT range, and as a trend, source performances improved with |Bx|. The progress of camera beam diagnostics and of the quality of the volume-produced H- beam is also shown. The status, off-line results, and reliability of a first NIO1 cesium oven are discussed; other upgrades in preparation (cavity ring down spectrometer, the end calorimeter, and conceptual tests of the energy recovery system) are also listed.

Beamlet scraping and its influence on the beam divergence at the BATMAN Upgrade test facility.

For the ITER fusion experiment, two neutral beam injectors are required for plasma heating and current drive. Each injector supplies a power of about 17 MW, obtained from neutralization of 40 A (46 A), 1 MeV (0.87 MeV) negative deuterium (hydrogen) ions. The full beam is composed of 1280 beamlets, formed in 16 beamlet groups, and strict requirements apply to the beamlet core divergence (<7 mrad). The test facility BATMAN Upgrade uses an ITER-like grid with one beamlet group, which consists of 70 apertures. In a joint campaign performed by IPP and Consorzio RFX to better assess the beam optics, the divergence of a single beamlet was compared to a group of beamlets at BATMAN Upgrade. The single beamlet is measured with a carbon fiber composite tile calorimeter and by beam emission spectroscopy, whereas the divergence of the group of beamlets is measured by beam emission spectroscopy only. When increasing the RF power at low extraction voltages, the divergence of the beamlet and of the group of beamlets is continuously decreasing and no inflection point toward an overperveant beam is found. At the same time, scraping of the extracted ion beam at the second grid (extraction grid) takes place at higher RF power, supported by the absence of the normally seen linear behavior between the measured negative ion density in the plasma close to the extraction system and the measured extracted ion current. Beside its influence on the divergence, beamlet scraping needs to be considered for the determination of the correct perveance and contributes to the measured coextracted electron current.

Colistin-based Treatment of Multidrug-resistant Gram-negative Bacterial Pulmonary Infections After Lung Transplantation.

BACKGROUND: Lung transplantation (LT) is a viable option for a select group of patients with end-stage lung disease. However, infections are a major complication after LT, accounting for significant morbidity and mortality. Several germs may be responsible; multidrug-resistant Gram-negative (MDR-GN) bacteria are emerging. Colistin is widely used in the treatment of these infections and is administered by inhalation and/or parenterally. At our institution, in patients with tracheostomy, colistin is administered by direct instillation in the airway during bronchoscopy. We reviewed a series of patients who underwent LT complicated by postoperative MDR-GN bacterial pulmonary infection. METHODS: From January 2015 to May 2017, 26 lung transplants were performed. In the postoperative course, 14 (54%) developed MDR-GN bacterial infection; respiratory specimen culture, blood tests, and chest X-ray were considered. Colistin was the only antibiotic usable. Thirteen patients received intravenous (IV) colistin; in the subgroup of patients with tracheostomy, colistin was instilled directly in the airway, and 6 patients received inhaled colistin. RESULTS: Seven patients needed tracheostomy. Pseudomonas aeruginosa was the predominant infection (86%), with Acinetobacter baumanii seen in 2 cases (14%). An early clinical-laboratory response was observed in 9 patients (64%). White blood cell count and C-reactive protein values improved (P = .02 and P = .001, respectively). A significant reduction in bacterial load was observed on microbiologic bronchoalveolar lavage specimens. CONCLUSION: Colistin instilled directly in the airway did not show side effects. The combination of IV and inhaled/instilled colistin could be a useful treatment option for MDR-GN infections after LT.

Survival After Lung Transplant for Cystic Fibrosis in Italy: A Single Center Experience With 20 Years of Follow-up.

OBJECTIVES: Lung transplantation is currently the only treatment for end-stage respiratory failure in patients with cystic fibrosis (CF). In this study we retrospectively analyzed our experience since the start of the transplantation program in 1996 with focus on survival analysis. METHODS: All patients with CF who underwent lung transplant at our center were included (1996-2016). Survival analysis after lung transplant was performed using the Kaplan-Meier estimate, comparing by sex and by 4 eras (1996-2000, 2001-2005, 2006-2010, and 2011-2016). RESULTS: In a 20-year period, 243 patients with CF were listed for lung transplant; 123 patients (61 male, 62 female) underwent transplant, and 85 died while waiting for donor organs. The mean (SD) and median age at transplant was 27.7 (8.7) years and 26.9 years (range, 9.1 - 52.1 years), respectively. Mean (SD) forced expiratory volume in the first second was 27.6 (9.7)% predicted; 115 patients (92.0%) were pancreatic insufficient, and 43 patients (34.0%) had CF-related diabetes. Removing patients with CF who died within the first 3 postoperative months, the mean (SD) and median survival after transplant were 8.2 (5.7) years and 7.5 years (range, 3 months-20 years), respectively. Overall post-lung transplant 1-year survival was 93.6%, 5-year survival was 71.4%, 10-year survival was 53.6%, 15-year survival was 36.7%, and 20-year survival was 31.6%. We found no difference in survival between sex (P = .22) and among the 4 eras (P = .56). CONCLUSIONS: Survival after lung transplant in our single center is similar to international data.

Helical water wires.

A helitetrahedral model has been proposed to help explain reports of low-frequency oscillations in pure water following electromagnetic excitation at the hydronium ion cyclotron resonance frequency. The Lorentz force and the intrinsic structure constrain the motion of the H3O+ ion so that it enjoys a unique form of proton-hopping, one whose path is helical. This model may also explain the numerous previously observed cyclotron resonance (ICR) biological couplings for cations other than hydronium by merely substituting hydrogen-bonded versions of these for hydronium in the tetrahedral structure. Thus the effectiveness of resonance stimulation in biological systems is explained in terms of the enhanced conductivity and reduced scattering associated with proton-hopping. It is further shown that the addition of charge-balancing hydroxyl ions act to enable oscillatory electric dipole moments that propagate along the helical axis, giving rise to weak power (≈ femtoWatts) radiation patterns. It is conceivable that the radiation associated with this process may play a role in the interactions at the interface between water and living matter.

Analysis of diagnostic calorimeter data by the transfer function technique.

This paper describes the analysis procedure applied to the thermal measurements on the rear side of a carbon fibre composite calorimeter with the purpose of reconstructing the energy flux due to an ion beam colliding on the front side. The method is based on the transfer function technique and allows a fast analysis by means of the fast Fourier transform algorithm. Its efficacy has been tested both on simulated and measured temperature profiles: in all cases, the energy flux features are well reproduced and beamlets are well resolved. Limits and restrictions of the method are also discussed, providing strategies to handle issues related to signal noise and digital processing.

Persistent pulmonary hypertension of the newborn refractory to inhaled nitric oxide and prostacyclin, responsive to neuromuscular blockade.

Neonatal pulmonary hypertension refractory to high frequency ventilation (HFOV) and inhaled nitric oxide (iNO) is an occasional occurrence. We report a full-term neonate with severe pulmonary hypertension unresponsive to the treatment with HFOV and iNO, later associated with prostacyclin, who rapidly improved after the addition of vecuronium, a neuromuscular blocker.

[T4 lung cancer: results of surgical treatment]. / Il tumore polmonare T4: risultati del trattamento chirurgico.

Stage T4 non small cell lung cancer (NSCLC) includes an heterogeneous group of locally advanced tumors. Results of surgery alone and of chemo and/or radiotherapy are disappointing with 5-year survival rates under 10%. Although palliative chemo-radiotherapy is the treatment of choice in most cases, radical resection has shown prognostic benefit in selected groups of patients with tumor infiltrating Superior Vena Cava, carina, aorta, left atrium and vertebral bodies. Completeness of resection and absence of mediastinal nodal involvement are fundamental conditions for the long-term success of surgery. Increased postoperative 30-day mortality and 90-day mortality rates have been reported up to 8% and 18% respectively. Neoadjuvant therapy, in the last decades, has shown to improve survival of T4 NSCLC patients undergoing surgery and to increase the number of patients suitable for surgical resection. Surgical resection is not indicated in patients with neoplastic pleural effusion since it is generally related to a worse prognosis in such cases. Conversely, patients with T4 tumor due to neoplastic satellite nodule in the same lobe are good surgical candidates. In some studies, these patients show a significant survival advantage after surgical treatment with respect to patients with other types of T4 tumors, when no mediastinal nodal involvement is associated.

Autologus platelet gel for the management of persistent alveolar fistula after lung resection.

Postoperative alveolar fistula (AF) associated with pleural cavity (PC) is a serious complication and a therapeutic challenge in thoracic surgery. The purpose of this study was to assess the efficacy of the use of the autologous platelet gel for the treatment of AF and PC. We treated a patient with post lung resection persistent alveolar fistula using a autologous platelet gel, a cellular compose produces at the Division of Immunohaematoligy and Trasfusion. The platelet gel-PRP (Platelet-Rich Plasma) is a biological material made of autologous platelets, extracted from a small amount of the patient's blood, centrifuged at 1100 g for 9 min. The PRP obtained was activated by addition of autologous thrombin and calcium chloride to form a matrix of fibrin (PRFM) thick. The patient presented important air leak after middle lobe wedge resection for solitary lung lesion with standard open decortication for important pleural adhesions post pleuritis. On postoperative day XIII the patient developed a thoracic empyema and consequently underwent a antibiotic pleural irrigation through the chest drainage based on the microbiological analysis of the pleural fluid. After a week we obtained the resolution of the empyema but a residual space remained and air leak persisted. We treated the patient with autologous platelet gel. We administer 7.5 mL of the autologous platelet gel across the chest drainage ever 72 hours for 3 times. After the third application we had the closure of the cavity and the cessation of air leak. Autologous platelet gel is easy to use, safe and inexpensive. It can be considered a valid therapeutic option in selected patients with a alveolar fistula and a lung partial re-expansion. The product consist of a significant amount of cellular components with healing anti-inflammatory an proregenerative properities that permit the body to heal tissue wounds faster and more efficiently. A sterile pleural cavity is fundamental conditions for the final success of the procedure.

Improvement in underwater phase measurement of an amplitude-modulated laser beam by polarimetric techniques.

The phase of the amplitude-modulated radiation reflected by a Lambertian target immersed in water was measured by using a linearly and circularly polarized sounding laser beam. Different values of the water extinction coefficient in the range of 0.06 - 2 m(-1) were realized by adding skim milk as a scattering element. It is shown that very efficient rejection of optical noise, resulting in reliable phase measurements, is accomplished with a cross-polarized and copolarized detection scheme for linear and circular polarization, respectively. The experiment demonstrates that phase measurements are very sensitive to optical noise suppression and that, as far as single scattering is the main involved mechanism, significant improvements can be achieved by adopting a polarization control on both the transmitter and the receiver stages of the apparatus.

Predictors of plasma human immunodeficiency virus type 1 RNA control after discontinuation of highly active antiretroviral therapy initiated at acute infection combined with structured treatment interruptions and immune-based therapies.

Thirty patients with acute human immunodeficiency virus (HIV) type 1 infection received a combination of 3 antiretroviral drugs (n=15) or 4 antiretroviral drugs plus hydroxyurea and interleukin-2 (n=15) for 24 months, followed by 1-3 structured therapeutic interruptions (STIs). Viral control, defined as maintaining plasma viremia <5000 copies/mL without therapy, was achieved in 14 cases. Lymphocyte subsets, plasma HIV-1 RNA loads, proviral DNA loads in peripheral blood mononuclear cells (PBMCs), residual HIV-1 RNA loads in PBMCs and in lymph node cells, and anti-p24 lymphoproliferative response were measured. In the multivariate analysis, proviral DNA loads in PBMCs and anti-p24 lymphoproliferative response assessed at 24 months were independently correlated with viral control after STI. These results enabled us to define a subgroup of patients for whom safe discontinuation of therapy initiated at acute infection was suitable and contributed to ascertaining priority for biological parameter assessment in future clinical trials.

Impact of immune interventions on proviral HIV-1 DNA decay in patients receiving highly active antiretroviral therapy.

OBJECTIVE: To measure the evolution of proviral HIV-1 DNA levels in patients receiving highly active antiretroviral therapy (HAART) compared to those treated with HAART plus interleukin-2 (IL-2) and hydroxyurea. DESIGN: Prospective randomised trial. METHODS: Twenty-two HIV-1 infected patients were randomly assigned to a five-drug antiretroviral regimen for 72 weeks, with or without IL-2, followed by a three-drug regimen up to week 120 with additional hydroxyurea in patients having received IL-2. HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were measured regularly using the Amplicor Monitor kit from Roche Diagnostics (Meylan, France). Potentially infectious HIV-1 was cultured in enhanced conditions from circulating CD4 T cells at week 120. RESULTS: During the study period of 120 weeks, HIV-1 DNA levels in PBMC decreased by -1.1 log in patients treated with HAART only compared with -1.8 log in patients with additional IL-2 and hydroxyurea. A two-phase decay rate was observed, with an inflexion point at 12 weeks. The second decay was slow, with mean half-lives of 130.1 +/- 21.3 weeks and 95.1 +/- 26.3 weeks for patients on HAART and those receiving additional IL-2 and hydroxyurea, respectively. At week 120, one out of 11 patients with HAART alone compared to six out of 11 in the group with IL-2 and hydroxyurea had undetectable proviral DNA levels and three of them had unsuccessful recovery of replication-competent HIV-1 from blood CD4 T cells. CONCLUSION: Therapeutic strategies combining HAART and immune interventions have higher potency to decrease the number of infected cells than HAART alone.

Phenotypic and genotypic resistance to nucleoside reverse transcriptase inhibitors in HIV-1 clinical isolates.

OBJECTIVE: To assess phenotypic and genotypic cross-resistance to nucleoside reverse transcriptase inhibitors in patients treated with a combination including zidovudine, who were switched to a combination including stavudine. METHODS: We analysed 24 clinical HIV-1 isolates from 12 patients before and several months after therapeutic switching. Plasma HIV-1 RNA was measured using quantitative polymerase chain reaction (Roche). Genotypic resistance was measured by sequencing the reverse transcriptase gene from plasma HIV-1 RNA. Phenotypic resistance was measured using a recombinant assay (Virco). RESULTS: Patients were treated with a combination including zidovudine for a mean (+/- SEM) period of 21.8 +/- 3.5 months and had a plasma viral load of 4.1 +/- 0.2 log HIV-1 RNA copies/mL (time 1). After a mean period of 19.3 +/- 1.6 months following the therapeutic change, the plasma viral load was 3.6 +/- 0.1 log copies/mL (time 2). At time 1, genotypic resistance to zidovudine was found in all cases (41L: four cases; 41L, 215Y: five cases; 41L, 210W, 215Y: two cases; K70R: one case) with a mean 6.6 +/- 1.6-fold increase in the median inhibitory concentration (IC50) to zidovudine and 1.7 +/- 0.4-fold to stavudine. At time 2, genotypic resistance to zidovudine was found in 11 out of 12 cases (41L: two cases; 41L, 215Y: six cases; 41L, 210W, 215Y: two cases; M41L, D67N, L210W, T215Y: one case) with a mean 18.9 +/- 8.8-fold increase in the IC50 to zidovudine and 1.4 +/- 0.4-fold to stavudine CONCLUSIONS: In this clinical series of patients with suboptimal control of plasma HIV-1 RNA using a combination including zidovudine, the presence of zidovudine-related mutations was associated with a decreased phenotypic sensitivity to this drug. Despite persistent HIV-1 replication, switching to stavudine was associated with a further decrease in phenotypic sensitivity to zidovudine but not to stavudine after 19 months. These data suggest that stavudine remains a possible option in zidovudine-experienced patients.

HIV-1 induction-maintenance at the lymph node level: the "Apollo-97" Study.

OBJECTIVE: To assess the effects of five-drug combination therapy on HIV-1 load in lymph nodes and subsequent maintenance with four and three drugs. METHODS: Ten pharmacotherapeutically naive patients received a combination of zidovudine, lamivudine, didanosine, ritonavir, and saquinavir for 24 weeks, then zidovudine, lamivudine, didanosine, and saquinavir for the next 24 weeks, and finally zidovudine, lamivudine, and saquinavir for the last 24 weeks. HIV-1 RNA in lymph nodes was measured using quantitative polymerase chain reaction (PCR) at baseline, after 12, 24, 48, and 78 weeks. Plasma HIV-1 RNA, proviral DNA in peripheral blood mononuclear cells (PBMCs), circulating lymphocyte subsets, and protease inhibitor levels in blood were also regularly measured. Genotypic resistance was assessed in the different compartments in 2 patients who were failed by therapy. RESULTS: HIV-1 RNA decreased in lymph nodes in 9 patients and was stable in 1 despite initial control of plasma replication <20 copies/ml in each patient. Lymph node levels rebounded in 1 patient at week 72 as a result of lack of adherence and remained stable in the 8 others despite maintenance regimens. This represents a mean drop of -3.17 log in lymph nodes for the 8 patients maintaining undetectable viremia at 72 weeks. In the patient with stable lymph node viral RNA, selection of the M184V mutation was demonstrated at this level before detection in plasma and low blood saquinavir levels were found throughout the study. Continuous improvements in immune parameters were observed in all cases, although PBMC proviral DNA levels either showed a continuous decrease or stabilized to a plateau. CONCLUSIONS: More complex regimens do not perform better in lymph nodes than classic triple therapy. The persistence of HIV-1 RNA in lymph nodes could be related with cellular resistance mechanisms rather than an insufficient potency of the regimens.