A review of design approaches for the implementation of low-frequency noise measurement systems.

Electronic noise has its roots in the fundamental physical interactions between matter and charged particles, carrying information about the phenomena that occur at the microscopic level. Therefore, Low-Frequency Noise Measurements (LFNM) are a well-established technique for the characterization of electron devices and materials and, compared to other techniques, they offer the advantage of being non-destructive and of providing a more detailed view of what happens in the matter during the manifestation of physical or chemical phenomena. For this reason, LFNM acquire particular importance in the modern technological era in which the introduction of new advanced materials requires in-depth and thorough characterization of the conduction phenomena. LFNM also find application in the field of sensors, as they allow to obtain more selective sensing systems even starting from conventional sensors. Performing meaningful noise measurements, however, requires that the background noise introduced by the measurement chain be much smaller than the noise to be detected and the instrumentation available on the market does not always meet the specifications required for reaching the ultimate sensitivity. Researchers willing to perform LFNM must often resort to the design of dedicated instrumentation in their own laboratories, but their cultural background does not necessarily include the ability to design, build, and test dedicated low noise instrumentation. In this review, we have tried to provide as much theoretical and practical guidelines as possible, so that even researchers with a limited background in electronic engineering can find useful information in developing or customizing low noise instrumentation.

Impact and trends in embedding field programmable gate arrays and microcontrollers in scientific instrumentation.

Microcontrollers and field-programmable gate arrays have been largely leveraged in scientific instrumentation since decades. Recent advancements in the performance of these programmable digital devices, with hundreds of I/O pins, up to millions of logic cells, >10 Gb/s connectivity, and hundreds of MHz multiple clocks, have been accelerating this trend, extending the range of functions. The diversification of devices from very low-cost 8-bit microcontrollers up to 32-bit ARM-based ones and a system of chip combining programmable logic with processors make them ubiquitous in modern electronic systems, addressing diverse challenges from ultra-low power operation, with sub-µA quiescent current in sleep mode for portable and Internet of Things applications, to high-performance computing, such as in machine vision. In this Review, the main motivations (compactness, re-configurability, parallelization, low latency for sub-ns timing, and real-time control), the possible approaches of the adoption of embedded devices, and the achievable performances are discussed. Relevant examples of applications in opto-electronics, physics experiments, impedance, vibration, and temperature sensing from the recent literature are also reviewed. From this bird-eye view, key paradigms emerge, such as the blurring of boundaries between digital platforms and the pervasiveness of machine learning algorithms, significantly fostered by the possibility to be run in embedded devices for distributing intelligence in the environment.

Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort.

BACKGROUND: Reliable and affordable prognostic and predictive biomarkers for urothelial carcinoma treated with immunotherapy may allow patients' outcome stratification and drive therapeutic options. The SAUL trial investigated the safety and efficacy of atezolizumab in a real-world setting on 1004 patients with locally advanced or metastatic urothelial carcinoma who progressed to one to three prior systemic therapies. PATIENTS AND METHODS: Using the SAUL Italian cohort of 267 patients, we investigated the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) and the best performing one of these in combination with programmed death-ligand 1 (PD-L1) with or without lactate dehydrogenase (LDH). Previously reported cut-offs (NLR >3 and NLR >5; SII >1375) in addition to study-defined ones derived from receiver operating characteristic (ROC) analysis were used. RESULTS: The cut-off values for NLR and SII by the ROC analysis were 3.65 (sensitivity 60.4; specificity 63.0) and 884 (sensitivity 64.4; specificity 67.5), respectively. The median overall survival (OS) was 14.7 months for NLR <3.65 [95% confidence interval (CI) 9.9-not reached (NR)] versus 6.0 months for NLR ≥3.65 (95% CI 3.9-9.4); 14.7 months for SII <884 (95% CI 10.6-NR) versus 6.0 months for SII ≥884 (95% CI 3.7-8.6). The combination of SII, PD-L1, and LDH stratified OS better than SII plus PD-L1 through better identification of patients with intermediate prognosis (77% versus 48%, respectively). Multivariate analyses confirmed significant correlations with OS and progression-free survival for both the SII + PD-L1 + LDH and SII + PD-L1 combinations. CONCLUSION: The combination of immune-inflammatory biomarkers based on SII, PD-L1, with or without LDH is a potentially useful and easy-to-assess prognostic tool deserving validation to identify patients who may benefit from immunotherapy alone or alternative therapies.

Advances in measurements and instrumentation leveraging embedded systems.

The expression "embedded systems" is used in different contexts and with broad meanings, but in electronics, it refers to systems that contain peripherals and a firmware for local digital data processing, often on a single board. Embedded systems are often associated with the field of computer science, emphasizing the software and programming aspects of systems. However, the progress made on the hardware side cannot be ignored, and without such technological advances, embedded systems would not exist. In fact, the progress in the field of microelectronics drives a constant evolution of variegated digital platforms, which gradually become easier to program and configure, thus reducing the development and prototyping phase and causing a strong impact on different research and application fields.

De-escalation of complexity in oncoplastic breast surgery: Case series from a specialized breast center.

INTRODUCTION: Oncoplastic breast surgery has evolved the surgical treatment of breast cancer over the past two decades. This practice still lacks validation and poses several dilemmas in terms of safety, local and systemic control, timing of adjuvant treatments and cost-effectiveness. Our case series investigates the effects of a reduced surgical complexity on cosmetic results and quality of life. METHODS: We treated 76 consecutive patients affected by early stage breast cancer from January 2016 to April 2017. We employed a decision support system to assist the final shared decision making. The communication process before surgery included new specific information on recent evidence about local control of disease and outcomes after multimodality treatment. In order to estimate the oncoplastic complexity, we created a new score based on scars, bilateral procedures and type and timing of reconstructions. We compared the outcomes of this series to that of a previous one from the same institution. RESULTS: The medium complexity score (CS) in the current series was significantly lower compared to that of the previous series (medium CS cohort 1 = 3.1 vs medium CS cohort 2 = 1.51; p = 0.001). Complications according to Clavien-Dindo classification did not vary significantly between the two series (p = 0.7). The increased use of primary systemic treatment did not translate into a significantly lower mastectomy rate (cohort 1 = 20% vs cohort 2 = 16%; p = n.s.). There was no significant difference in breast deformities after breast conserving surgery (p = 0.2). The BCCT.Core demonstrated a 67.1% occurrence of "good" results. Quality of life in patients who underwent breast-conserving surgery measured using the Breast-Q demonstrated similar results in the pre-post-op assessment. CONCLUSIONS: This study hypothesizes that a proper information may impact on patient's decisions and may reduce surgical complexity. This reduction likely has no effects on the main surgical outcomes estimated using standard tools. More investigations should be performed on a larger multi-institutional scale to confirm these conclusions.

High sensitivity measurement system for the direct-current, capacitance-voltage, and gate-drain low frequency noise characterization of field effect transistors.

Measurements of current fluctuations originating in electron devices have been largely used to understand the electrical properties of materials and ultimate device performances. In this work, we propose a high-sensitivity measurement setup topology suitable for the automatic and programmable Direct-Current (DC), Capacitance-Voltage (CV), and gate-drain low frequency noise characterization of field effect transistors at wafer level. Automatic and programmable operation is particularly useful when the device characteristics relax or degrade with time due to optical, bias, or temperature stress. The noise sensitivity of the proposed topology is in the order of fA/Hz(1/2), while DC performances are limited only by the source and measurement units used to bias the device under test. DC, CV, and NOISE measurements, down to 1 pA of DC gate and drain bias currents, in organic thin film transistors are reported to demonstrate system operation and performances.

Programmable, very low noise current source.

We propose a new approach for the realization of very low noise programmable current sources mainly intended for application in the field of low frequency noise measurements. The design is based on a low noise Junction Field Effect Transistor (JFET) acting as a high impedance current source and programmability is obtained by resorting to a low noise, programmable floating voltage source that allows to set the sourced current at the desired value. The floating voltage source is obtained by exploiting the properties of a standard photovoltaic MOSFET driver. Proper filtering and a control network employing super-capacitors allow to reduce the low frequency output noise to that due to the low noise JFET down to frequencies as low as 100 mHz while allowing, at the same time, to set the desired current by means of a standard DA converter with an accuracy better than 1%. A prototype of the system capable of supplying currents from a few hundreds of µA up to a few mA demonstrates the effectiveness of the approach we propose. When delivering a DC current of about 2 mA, the power spectral density of the current fluctuations at the output is found to be less than 25 pA/√Hz at 100 mHz and less than 6 pA/√Hz for f > 1 Hz, resulting in an RMS noise in the bandwidth from 0.1 to 10 Hz of less than 14 pA.

A bovine macrophage screening system for identifying attenuated transposon mutants of Mycobacterium avium subsp. paratuberculosis with vaccine potential.

Johne's disease is a chronic granulomatous enteritis in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). The disease is responsible for considerable economic losses in the livestock industry and in particular within the dairy sector. A more effective vaccine against Johne's disease would be of major benefit. In this study, we developed an efficient procedure for identifying mutants of MAP with reduced virulence that are potential live vaccine candidates against Johne's disease. A mariner transposon was used to create random insertional libraries in two different MAP strains (989 and k10), an effective cattle macrophage survival system was developed, and a total of 1890 insertion mutants were screened by using a 96-prong multi-blot replicator (frogger) system. Two of the transposon mutants with poor survival ability in macrophages were tested in mice. These strains were found to be attenuated in vivo, thereby validating the further use of this macrophage screening system to identify MAP mutants with potential as candidate vaccines against Johne's disease.

Inactivation of the Mycobacterium tuberculosis fadB4 gene results in increased virulence in host cell and mice.

The genome of Mycobacterium tuberculosis encodes many proteins involved in fatty acid metabolism, a subset of which are required for virulence. The Mycobacterium tuberculosis fadB4 gene, which shares strong similarity with oxidoreductases and fatty acid synthases, is up-regulated during infection of macrophages and is predicted to protect the bacterium from the hostile environment of the host cell. In order to determine if fadB4 plays a role in the virulence of M. tuberculosis, we constructed a M. tuberculosis mutant in which the fadB4 had been disrupted (DeltafadB4). Surprisingly, DeltafadB4, grew more rapidly in host cells compared to wild-type M. tuberculosis or the DeltafadB4 or the gene-disrupted strain complemented with fadB4. In addition, macrophages infected with DeltafadB4 displayed reduced secretion of the cytokine TNF-alpha, suggesting a role for the FadB4 protein in influencing the pro-inflammatory host response to M. tuberculosis. After infection of mice, DeltafadB4 demonstrated an increased replication at early time-points post-infection compared to the growth of wild-type M. tuberculosis. This increased capacity of DeltafadB4 to replicate in vivo was reflected in the decreased time to death of immuno-deficient RAG-1(-/-) mice infected with M. tuberculosis lacking the fadB4 gene. Therefore fadB4 is part of the family of genes whose expression serves to regulate the virulence of M. tuberculosis within the host.

Effect of phthiocerol dimycocerosate deficiency on the transcriptional response of human macrophages to Mycobacterium tuberculosis.

The control of mycobacterial infections is dependent on the finely tuned synergism between the innate and adaptive immune responses. The macrophage is the major host cell for Mycobacterium tuberculosis and the degree of virulence of mycobacteria may influence the initial macrophage response to infection. The cell wall molecule, phthiocerol dimycocerosate (DIM), is an important virulence factor that influences the early growth of M. tuberculosis in the lungs. To explore the basis for this effect we have compared the early gene response of human THP-1 macrophages to infection with virulent M. tuberculosis and the DIM-deficient DeltafadD26 M. tuberculosis strain using microarrays. Detailed analysis revealed a common core of macrophage genes, which were rapidly induced following infection with both strains, and deficiency of DIM had no significant effect on this initial macrophage transcriptional responses. In addition to chemokines and pro-inflammatory cytokines, the early response genes included components of the Toll-like receptor signalling, antigen presentation and apoptotic pathways, interferon response genes, cell surface receptors and their ligands, including TNF-related apoptosis inducing ligand (TRAIL) and CD40, and other novel genes. Therefore, although fadD26 deficiency is responsible for the early attenuation of the growth of M. tuberculosis in vivo, this effect is not associated with differences in the initial macrophage transcriptional response.

Phase II study of gemcitabine and cisplatin in patients with advanced or metastatic bladder cancer: long-term follow-up of a 3-week regimen.

BACKGROUND: Bladder cancer is the fifth most common cancer among men and the seventh among women. At diagnosis, at least 25% of bladder cancer tumors are locally or systemically advanced. Systemic chemotherapy is the only current modality for advanced or metastatic transitional cell carcinoma of the bladder. Recently, a phase III randomized study has demonstrated that the regimen with gemcitabine (GMC) and cisplatin (CDDP) had a survival advantage similar to the standard M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin), with a better safety profile. AIM: It was the aim of this study to evaluate the tumor response rate, the median time to progression, the median survival and toxicity in a 21-day schedule with GMC and CDDP in patients with advanced/metastatic bladder cancer. PATIENTS AND METHODS: From September 1998 to December 2000, 27 patients with advanced/metastatic transitional cell carcinoma were enrolled. All patients received 1,200 mg/m(2) GMC administered as a 30-min intravenous infusion on days 1 and 8, and 75 mg/m(2) CDDP as a 1-hour infusion on day 2. Cycles were repeated every 21 days. The patients had a median age of 59.8 years (range 39-75) and an Eastern Cooperative Oncology Group performance status of 0-2. RESULTS: Twenty-five patients were valuable for toxic effects, length of survival and tumor response. The statistical analysis was performed in May 2004. Mean and median follow-up were 20.23 and 13.2 months (range 2-68), respectively. The overall remission rate (complete response + partial response) was 48% (95% CI 28.4-67.6%). The median time to progression was 9 months (range 2-56). The median duration of survival for all patients was 13.2 months (range 2-68+), with 1-year and 23-month survival rates of 60 and 20%, respectively. There was no grade 4 toxicity or treatment-related death. Grade 3 anemia was observed in 4 patients (16%) and grade 3 thrombocytopenia occurred in 6 patients (24%). No grade 3-4 nausea/vomiting or neutropenia was observed. CONCLUSION: GMC and CDDP is an active schedule with a good safety profile in a 21-day regimen. It may be a valid alternative to the standard 28-day regimen due to its high tumor response and survival with a low incidence of toxicity, especially in pretreated and metastatic patients.

[Operator exposure levels in nuclear medicine studies]. / Livelli di esposizione dell'operatore in alcune indagini di medicina nucleare.

In diagnostic examinations performed in nuclear medicine, radio-isotopes with a relatively short half-life are used, the quantity varying according to the type of examination. After administration of the labelled substance, the patient becomes a large source of ionizing radiations. During the course of a scintigraphic examination, the operator is obliged to go near the couch to assist the patient in the positions and will therefore inevitably be in this radiation field. The paper reports the radio-activity levels recorded at gonad and eye levels of the operator in positions most frequently held during the course of the most commonly performed scintigraphic examinations using a G.E. STARCAM 500 A gamma-camera.

[Levels of the electromagnetic field in the vicinity of therapeutic devices using radiofrequency and microwaves]. / Livelli di campo elettromagnetico nelle vicinanze di apparati terapeutici a RF e MW.

The paper presents the results of an analysis made on the electromagnetic field levels around RF and MW equipment used for medical purposes to achieve induced thermogenesis in body areas affected by disease. An irradiation diagram was constructed for some of the most widely used devices in clinical practice and measurements were made on RF devices to identify the influence of obstacles in determining electric field levels, such as accessories or persons present in the working environment. Electric field and power density levels were checked, as can be measured at a distance of 100 cm at identical selected power during a typical "lumbar-dorsal spine" treatment using different types of RF and MW devices, to identify the different degree of electromagnetic pollution that each of the devices causes.

Radio-hyperthermia for subcutaneous metastasis of hemangiopericytoma of the mediastinum: case report.

Hemangiopericytoma is a rare type of neoplasia originating from the Zimmermann pericytes and can arise in numerous sites. As it is difficult to correlate the histologic aspect with the prognosis, it was considered advisable to take account of other factors such as age and tumoral site. Aggressive surgery followed by irradiation therapy is suggested as the most suitable management. Hyperthermia also was adopted in treating subcutaneous metastasis, but its role has yet to be fully defined.