Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714). PATIENTS AND METHODS: Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each). CONCLUSIONS: Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

Single-shot terahertz time-domain spectrometer using 1550 nm probe pulses and diversity electro-optic sampling.

Classical terahertz spectroscopy usually requires the use of Fourier transform or Time-Domain Spectrometers. However, these classical techniques become impractical when using recent high peak power terahertz sources - based on intense lasers or accelerators - which operate at low repetition rate. We present and test the design of a novel Time-Domain Spectrometer, that is capable of recording a whole terahertz spectrum at each shot of the source, and that uses a 1550 nm probe fiber laser. Single-shot operation is obtained using chirped-pulse electro-optic sampling in Gallium Arsenide, and high bandwidth is obtained by using the recently introduced Diversity Electro-Optic Sampling (DEOS) method. We present the first real-time measurements of THz spectra at the TeraFERMI Coherent Transition Radiation source. The system achieves 2.5 THz bandwidth with a maximum dynamic range reaching up to 25 dB. By reducing the required measurement time from minutes to a split-second, this strategy dramatically expands the application range of high power low-repetition rate THz sources.

Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies.

BACKGROUND: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. METHODS: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. RESULTS: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. CONCLUSIONS: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

A Variational Bayesian inference method for parametric imaging of PET data.

In dynamic Positron Emission Tomography (PET) studies, compartmental models provide the richest information on the tracer kinetics of the tissue. Inverting such models at the voxel level is however quite challenging due to the low signal-to-noise ratio of the time activity curves. In this study, we propose the use of a Variational Bayesian (VB) approach to efficiently solve this issue and thus obtain robust quantitative parametric maps. VB was adapted to the non-uniform noise distribution of PET data. Moreover, we propose a novel hierarchical scheme to define the model parameter priors directly from the images in case such information are not available from the literature, as often happens with new PET tracers. VB was initially tested on synthetic data generated using compartmental models of increasing complexity, providing accurate (%bias<2%±2%, root mean square error<15%±5%) parameter estimates. When applied to real data on a paradigmatic set of PET tracers (L-[1-11C]leucine, [11C]WAY100635 and [18F]FDG), VB was able to generate reliable parametric maps even in presence of high noise in the data (unreliable estimates<11%±5%).

Statutory prevention of work injuries in Italy: an effectiveness evaluation with interrupted time series analysis in a sample of 5000 manufacturing plants from the Veneto region.

OBJECTIVES: According to Italian law, prevention of injuries in the workplace falls under the National Health System Service of Prevention, Health and Safety at Work (SPISAL). In a sample of about 5000 industrial firms in the Veneto region (North-Eastern Italy), the study examines the impact of SPISAL safety programmes on injuries. METHODS: The study is based on the before-and-after comparison of injury rates in 795 industrial settings that were subject to SPISAL interventions and 4186 reference firms, which were all manufacturing industries with >10 employees; construction companies were excluded. The time window (2001-2007) was chosen in order to have 8 quarters of observation before and 8 after the intervention. The National Institute for Workers' Compensation provided data on injuries and plants, while SPISAL gave information on interventions carried out. The preintervention and postintervention rates of injuries were compared by means of interrupted time series analyses, estimating the rate ratio (RR) with a 95% CI. RESULTS: Inspection after injury reduced by 24% (RR=0.76; 95% CI 0.65 to 0.90; p=0.001) all injuries, and by 36% (RR=0.64; 95% CI 0.50 to 0.83; p=0.001) severe injuries (fatalities, lost workdays >30, degree of permanent disability >0). These changes occurred immediately and persisted for 2 years. The effects of programmed inspections were never significant. CONCLUSIONS: It can be presumed that, after a severe injury, the employees raised their standard of what they considered good work safety and, at the same time, the employers were pushed to improve the work environment as a result of the sudden attention from the workplace hygiene and safety authority and court authority. Inspection after injury was an effective strategy; however, confirmatory evidence is needed.

The FERMI free-electron lasers.

FERMI is a seeded free-electron laser (FEL) facility located at the Elettra laboratory in Trieste, Italy, and is now in user operation with its first FEL line, FEL-1, covering the wavelength range between 100 and 20 nm. The second FEL line, FEL-2, a high-gain harmonic generation double-stage cascade covering the wavelength range 20-4 nm, has also completed commissioning and the first user call has been recently opened. An overview of the typical operating modes of the facility is presented.

Multicolor High-Gain Free-Electron Laser Driven by Seeded Microbunching Instability.

Laser-heater systems are essential tools to control and optimize high-gain free-electron lasers (FELs) working in the x-ray wavelength range. Indeed, these systems induce a controllable increase of the energy spread of the electron bunch. The heating suppresses longitudinal microbunching instability which otherwise would limit the FEL performance. Here, we demonstrate that, through the action of the microbunching instability, a long-wavelength modulation of the electron beam induced by the laser heater at low energy can persist until the beam entrance into the undulators. This coherent longitudinal modulation is exploited to control the FEL spectral properties, in particular, multicolor extreme-ultraviolet FEL pulses can be generated through a frequency mixing of the modulations produced by the laser heater and the seed laser in the electron beam. We present an experimental demonstration of this novel configuration carried out at the FERMI FEL.

Parametric imaging of ¹8F-fluoro-3-deoxy-3-L-fluorothymidine PET data to investigate tumour heterogeneity.

PURPOSE: [(18)F]Fluoro-3'-deoxy-3'-L-fluorothymidine ([(18)F]FLT) is a tissue proliferation marker which has been widely validated as a tumour-specific imaging tracer for PET. [(18)F]FLT uptake in breast cancer is generally quantified at the region level or through first-order statistical descriptors (mean or maximum value), approaches that ignore the known complexity and heterogeneity of cancer tissues. Our aims were: (1) to validate a robust and reproducible voxel-wise approach to the quantification of [(18)F]FLT PET data in breast cancer patients, and (2) to exploit the entire distribution of the [(18)F]FLT retention estimates and their variability in the tumour region for the prediction of early treatment response. METHODS: The dataset was derived from 15 patients with stage II-IV breast cancer, scanned twice before chemotherapy and once 1 week after therapy. Using RECIST criteria (after 60 days) nine patients were categorized as responders or nonresponders to treatment. Kinetic modelling (compartmental modelling, Patlak analysis and spectral analysis with iterative filter), tissue-to-plasma ratio and standardized uptake value were applied at the voxel level. Test-retest estimates were used to assess reproducibility and reliability of the [(18)F]FLT uptake values before and after therapy for responder/nonresponder prediction. RESULTS: All the methods provided a measure of [(18)F]FLT uptake that was reliable and reproducible with ICC >0.94. Moreover, a very strong correlation was found among the methods (R (2) > 0.81). All the methods provided a limited number of outliers (<20 % in tumour), with the exception of compartmental modelling (>25 %) which was therefore excluded from the prediction analysis. Differences between before and after therapy in mean voxel-wise uptake in tumour did not allow a complete responder/nonresponder classification. In contrast, considering the full estimate distributions within the tumour (changes in median and mode between before and after therapy) improved therapy response for all the analysed methods. CONCLUSION: We showed that kinetic modelling (Patlak and spectral analysis with iterative filter) applied voxel-wise allows appropriate [(18)F]FLT uptake estimation in breast cancer with good reproducibility. Notably, this study indicated that a more comprehensive statistical investigation could improve tumour characterization and prediction of treatment response.

Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.

BACKGROUND: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here. PATIENTS AND METHODS: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK). RESULTS: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively. CONCLUSIONS: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. PATIENTS AND METHODS: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. CONCLUSIONS: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202.

Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation.

Mechanisms of tumor development were studied in SCID mice injected with human lymphoid cells from Epstein-Barr virus-positive (EBV+) donors. About 80% of peripheral blood mononuclear cell (PBMC)-injected animals developed a lymphoproliferative disease associated with oligoclonal EBV+ tumors of human B cell origin. No change in tumor development rate occurred when monocyte-depleted PBMC were inoculated. No tumors developed when purified B cells were injected. B cell lymphoproliferative disease was also prevented in most cases when PBMC-injected animals were treated with agents that prevent T cell activation, such as cyclosporin A. Both CD4+ and CD8+ T cell subpopulations were able to provide putative factor(s) necessary for EBV+ B cell expansion and progression to tumors. These data suggest that the transfer alone of potentially tumorigenic human cells into an immunodeficient environment, such as the SCID mouse, might not be sufficient for cell progression to tumor, and raise the possibility that chronic activation events could play a major role in the pathogenesis of some EBV+ lymphomas in the immunocompromised host.

Correlated electrons step by step: itinerant-to-localized transition of fe impurities in free-electron metal hosts.

High-resolution photoemission spectroscopy and ab initio calculations have been employed to analyze the onset and progression of d-sp hybridization in Fe impurities deposited on alkali metal films. The interplay between delocalization, mediated by the free-electron environment, and Coulomb interaction among d electrons gives rise to complex electronic configurations. The multiplet structure of a single Fe atom evolves and gradually dissolves into a quasiparticle peak near the Fermi level with increasing host electron density. The effective multiorbital impurity problem within the exact diagonalization scheme describes the whole range of hybridizations.

PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers.

Depression is associated with peripheral inflammation, but its link with brain microglial activity remains unclear. In seven healthy males, we used repeated translocator protein-Positron Emission Tomography (TSPO-PET) dynamic scans with [11C]PBR28 to image brain microglial activation before and 24 h after the immune challenge interferon (IFN)-α. We also investigated the association between changes in peripheral inflammation, changes in microglial activity, and changes in mood. IFN-α administration decreased [11C]PBR28 PET tissue volume of distribution (Vt) across the brain (-20 ± 4%; t6 = 4.1, p = 0.01), but after correction for radioligand free-plasma fraction there were no longer any changes (+23 ± 31%; t = 0.1, p = 0.91). IFN-α increased serum IL-6 (1826 ± 513%, t6 = -7.5, p < 0.001), IL-7 (39 ± 12%, t6 = -3.6, p = 0.01), IL-10 (328 ± 48%, t6 = -12.8, p < 0.001), and IFN-γ (272 ± 64%, t6 = -7.0, p < 0.001) at 4-6 h, and increased serum TNF-α (49 ± 7.6%, t6 = -7.5, p < 0.001), IL-8 (39 ± 12%, t6 = -3.5, p = 0.013), and C-reactive protein (1320 ± 459%, t6 = -7.2, p < 0.001) at 24 h. IFN-α induced temporary mood changes and sickness symptoms after 4-6 h, measured as an increase in POMS-2 total mood score, confusion and fatigue, and a decrease in vigor and friendliness (all p ≤ 0.04). No association was found between changes in peripheral inflammation and changes in PET or mood measures. Our work suggests that brain TSPO-PET signal is highly dependent of inflammation-induced changes in ligand binding to plasma proteins. This limits its usefulness as a sensitive marker of neuroinflammation and consequently, data interpretation. Thus, our results can be interpreted as showing either that [11C]PBR28 is not sensitive enough under these conditions, or that there is simply no microglial activation in this model.

Characterisation of microbunching instability with 2D Fourier analysis.

The optimal performance of high-brightness free-electron lasers (FELs) is limited by the microbunching instability, which can cause variations in both the slice energy spread and longitudinal profile of electron beams. In this paper, we perform 2D Fourier analysis of the full bunch longitudinal phase space, such that modulations in both planes can be studied simultaneously. Unlike the standard 1D analysis, this method is able to reveal modulations in a folded phase space, which would otherwise remain uncovered. Additionally, the plasma oscillation between energy and density modulations is also revealed by this method. The damping of the microbunching instability, through the use of a laser heater, is also analysed with this technique. We confirm a mitigation of the amplitude of modulation and a red-shift of the microbunching frequency as the energy spread added increases. As an outcome of this work, a systematic experimental comparison of the development of the instability in the presence of different compression schemes is here presented for the first time.

Correction: Regulation of dopaminergic function: An [18F]-DOPA PET apomorphine challenge study in humans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Coherent THz Emission Enhanced by Coherent Synchrotron Radiation Wakefield.

We demonstrate that emission of coherent transition radiation by a ∼1 GeV energy-electron beam passing through an Al foil is enhanced in intensity and extended in frequency spectral range, by the energy correlation established along the beam by coherent synchrotron radiation wakefield, in the presence of a proper electron optics in the beam delivery system. Analytical and numerical models, based on experimental electron beam parameters collected at the FERMI free electron laser (FEL), predict transition radiation with two intensity peaks at ∼0.3 THz and ∼1.5 THz, and extending up to 8.5 THz with intensity above 20 dB w.r.t. the main peak. Up to 80-µJ pulse energy integrated over the full bandwidth is expected at the source, and in agreement with experimental pulse energy measurements. By virtue of its implementation in an FEL beam dump line, this work promises dissemination of user-oriented multi-THz beamlines parasitic and self-synchronized to EUV and x-ray FELs.

Impactos de la implementación del programa Proadi-SUS en la reducción de infecciones en UCI / Impactos da implantação do programa Proadi-SUS na redução de infecções em UTIq / Impact of the implementation of the Proadi-SUS program on the reduction of infections in ICUs

Introducción: las infecciones relacionadas con la asistencia sanitaria (IRAS) son complicaciones frecuentes en los entornos de cuidados intensivos con alta morbilidad y mortalidad y altos costos para el sistema de salud, por lo que comprometen la seguridad del paciente y requieren medidas de prevención adecuadas. Objetivo: analizar los resultados obtenidos en cuanto a la reducción de la incidencia de IRAS tras la ejecución del Programa de Apoyo al Desarrollo Institucional del Sistema Único de Salud (Proadi-SUS) en un hospital universitario. Materiales y método: estudio retrospectivo, observacional y cuantitativo realizado en una unidad de cuidado intensivo general de 10 camas en un hospital universitario. El periodo evaluado fue de 2015 a 2019. Para el análisis estadístico se utilizó ANOVA y prueba de Kruskal Wallis. Resultados: se reportó una reducción significativa en la incidencia media de IRAS (p = 0,000), muertes por iras (p = 0,042), neumonía asociada al ventilador (p = 0,000) e infección del tracto urinario aso-ciado a sonda vesical (p = 0,004). Sin embargo, no hubo diferencias estadísticamente significativas en la incidencia media de infección del torrente sanguíneo asociada a catéter vascular central (p = 0,871). Conclusiones: los cambios en la atención implementados durante el proyecto Proadi-sus fueron efectivos para mejorar las tasas de IRAS y asegurar una mejor práctica de atención con mayor seguridad para el paciente.

Introdução: as infecções relacionadas à assistência à saúde (IRAS) são complicações frequentes em ambientes de terapia intensiva, com alta morbidade e mortalidade, altos custos para o sistema de saúde que comprometem a segurança do paciente e requerem medidas de prevenção adequadas. Objetivo: analisar os resultados obtidos na redução da incidência de IRAS, durante o Programa de Apoio ao Desenvolvimento Institucional do Sistema Único de Saúde (Proadi-SUS) em um hospital universitário. Materiais e método: estudo retrospectivo, observacional, quantitativo, realizado em uma unidade de terapia intensiva geral de 10 leitos de um hospital universitário. O período avaliado foi de 2015 a 2019. Para a análise estatística, foram utilizados ANOVA e teste de Kruskal Wallis. Resultados: houve uma redução significativa na incidência média de IRAS (p = 0,000), mortes por IRAS (p = 0,042), pneumonia associada à ventilação mecânica (p = 0,000) e infecção do trato urinário associada a cateteres vesicais (p = 0,004). No entanto, não houve diferenças estatisticamente significativas na incidência média de infecção da corrente sanguínea associada ao cateter vascular central (p = 0,871). Conclusões: as mudanças assistenciais implantadas durante o projeto Proadi-SUS foram efetivas em melhorar os índices de IRAS e garantir uma melhor prática assistencial com mais segurança ao paciente.

Introduction: Health Care Related Infections (HAIS) are frequent complications in intensive care settings with high morbidity and mortality rates and high costs for the health system. Therefore, HAIS compromise patient safety and require adequate prevention measures. Objective: To analyze the results obtained in the course of the Support Program for the Institutional Development of the Unified Health System (Proadi-SUS) in a university hospital in terms of the reduction of HAIS incidence. Materials and method: Retrospective, observational, and quantitative study conducted in a 10-bed general intensive care unit (ICU) at a university hospital. The period evaluated was from 2015 to 2019. anova and the Kruskal Wallis test were used for statistical analysis. Results: There was a significant reduction in the mean incidence of HAIS (p = 0.000), HAIS deaths (p = 0.042), ventilator-associated pneumonia (p = 0.000), and urinary tract infection associated with bladder catheters (p = 0.004). However, there were no statistically significant differences in the mean incidence of central vascular catheter-associated bloodstream infection (p = 0.871). Conclusion: The care changes implemented during the Proadi-SUS project were effective in improving HAIS rates and ensure better care practices and more patient safety.

Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.

Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicer under resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two 18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two 18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg-1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=-0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=-0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinson's disease.

The t(6;16)(p21;q22) chromosome translocation in the LNCaP prostate carcinoma cell line results in a tpc/hpr fusion gene.

Very little is known about the molecular and genetic mechanisms involved in prostate cancer. Previous studies have shown frequent loss of heterozygosity (40%) at chromosomal regions 8p, 10q, and 16q, suggesting the presence of tumor suppressor genes in these regions. The LNCaP cell line, established from a metastatic lesion of human prostatic adenocarcinoma, carries a t(6;16)(p21;q22) translocation. To determine whether this translocation involved genes important in the process of malignant transformation, we cloned and sequenced the t(6;16) breakpoint of this cell line. Sequence analysis showed that the breakpoint is within the haptoglobin gene cluster on chromosome 16, and that, on chromosome 6, the break occurs within a novel gene, tpc, similar to the prokaryotic S10 ribosomal protein gene. The translocation results in the production of a fusion transcript, tpc/hpr.