Design of CMOS Digital Silicon Photomultipliers with ToF for Positron Emission Tomography

This thesis presents a contribution to the design of single-photon detectors for medical imaging. Specifically, the focus has been on the development of a pixel capable of single-photon counting in CMOS technology, and the associated sensor thereof. These sensors can work under low light conditions and provide timing information to determine the time-stamp of the incoming photons. For instance, this is particularly attractive for applications that rely either on time-of-flight measurements or on exponential decay determination of the light source, like positron emission tomography or fluorescence-lifetime imaging, respectively. This thesis proposes the study of the pixel architecture to optimize its performance in terms of sensitivity, linearity and signal to noise ratio. The design of the pixel has followed a bottom-up approach, taking care of the smallest building block and studying how the different architecture choices affect performance. Among the various building blocks needed, special emphasis has been placed on the following: • the Single-Photon Avalanche Diode (SPAD), a photodiode able to detect photons one by one; • the front-end circuitry of this diode, commonly called quenching and recharge circuit; • the Time-to-Digital Converter (TDC), which determines the timing performance of the pixel. The proposed architectural exploration provides a comprehensive insight into the design space of the pixel, allowing to determine the optimum design points in terms of sensor sensitivity, linearity or signal to noise ratio, thus helping designers to navigate through non-straightforward trade-offs. The proposed TDC is based on a voltage-controlled ring oscillator, since this architecture provides moderate time resolutions while keeping the footprint, the power, and conversion time relatively small. Two pseudo-differential delay stages have been studied, one with cross-coupled PMOS transistors and the other with cross-coupled inverters. Analytical studies and simulations have shown that cross-coupled inverters are the most appropriate to implement the TDC because they achieve better time resolution with smaller energy per conversion than cross-coupled PMOS transistor stages. A 1.3×1.3 mm2 pixel has been implemented in an 110 nm CMOS image sensor technology, to have the benefits of sub-micron technologies along with the cleanliness of CMOS image sensor technologies. The fabricated chips have been used to characterize the single-photon avalanche diodes. The results agree with expectations: a maximum photon detection probability of 46 % and a median dark count rate of 0.4 Hz/µm2 with an excess voltage of 3 V. Furthermore, the characterization of the TDC shows that the time resolution is below 100 ps, which agrees with post-layout simulations. The differential non-linearity is ±0.4LSB, and the integral non-linearity is ±6.1LSB. Photoemission occurs during characterization - an indication that the avalanches are not quenched properly. The cause of this has been identified to be in the design of the SPAD and the quenching circuit. SPADs are sensitive devices which maximum reverse current must be well defined and limited by the quenching circuit, otherwise unwanted effects like excessive cross-talk, noise, and power consumption may happen. Although this issue limits the operation of the implemented pixel, the information obtained during the characterization will help to avoid mistakes in future implementations

Design of a compact and low-power TDC for an array of SiPM's in 110nm CIS technology

Silicon photomultipliers (SiPMs) are meant to substitute photomultiplier tubes in high-energy physics detectors and nuclear medicine. This is because of their -to name a few interesting properties- compactness, lower bias voltage, tolerance to magnetic fields and finer spatial resolution. SiPMs can also be built in CMOS technology. This allows the incorporation of active quenching and recharge schemes at cell level and processing circuitry at pixel level. One of the elements that can lead to finer temporal resolutions is the time-to-digital converter (TDC). In this paper we describe the architecture of a compact TDC to be included at each pixel of an array of SiPMs. It is compact and consumes low power. It is based on a voltage controlled oscillator that generates multiple internal phases that are interpolated to provide time resolution below the time delay of a single gate. Simulation results of a 11b TDC based on a 4-stage VCRO in 110nm CIS technology yield a time resolution of 80.0ps, a DNL of ±0.28 LSB, a INL ±0.52 LSB, and a power consumption of 850μW.Ministerio de Economía y Competitividad TEC2015-66878-C3-1-RJunta de Andalucía TIC 2012-2338Office of Naval Research (USA) N00014141035

A CMOS Digital SiPM With Focal-Plane Light-Spot Statistics for DOI Computation

Silicon photomultipliers can be used to infer the depth-of-interaction (DOI) in scintillator crystals. DOI can help to improve the quality of the positron emission tomography images affected by the parallax error. This paper contemplates the computation of DOI based on the standard deviation of the light distribution. The simulations have been carried out by GAMOS. The design of the proposed digital silicon photomultiplier (d-SiPM) with focal plane detection of the center of mass position and dispersion of the scintillation light is presented. The d-SiPM shares the same off-chip time-to-digital converter such that each pixel can be individually connected to it. A miniature d-SiPM 8×8 single-photon avalanche-diode (SPAD) array has been fabricated as a proof of concept. The SPADs along each row and column are connected through an OR combination technique. It has 256×256μm2 without peripherals circuits and pads. The fill factor is about 11%. The average dark count rate of the mini d-SiPM is of 240 kHz. The average photon detection efficiency is 5% at 480 nm wavelength, room temperature, and 0.9 V excess voltage. The dynamic range is of 96 dB. The sensor array features a time resolution of 212 ps. The photon-timing SNR is 81 dB. The focal plane statistics of the light-spot has been proved as well by measurements.Office of Naval Research (USA) ONR N000141410355Ministerio de Economía y Competitividad TEC2015-66878-C3- 1-RJunta de Andalucía P12-TIC 233

20-ps resolution Clock Distribution Network for a fast-timing single photon detector

The time resolution of active pixel sensors whose timestamp mechanism is based on Time-to-Digital Converters is critically linked to the accuracy in the distribution of the master clock signal that latches the timestamp values across the detector. The Clock Distribution Network that delivers the master clock signal must compensate process-voltage-temperature variations to reduce static time errors (skew), and minimize the power supply bounce to prevent dynamic time errors (jitter). To achieve sub-100ps time resolution within pixel detectors and thus enable a step forward in multiple imaging applications, the network latencies must be adjusted in steps well below that value. Power consumption must be kept as low as possible. In this work, a self-regulated Clock Distribution Network that fulfills these requirements is presented for the FastICpix single photon detector ¿ aiming at a 65nm process. A 40 MHz master clock is distributed to 64x64 pixels over an area of 2.4x2.4 cm2 using digital Delay-Locked Loops, achieving clock leaf skew below 20 ps with a power consumption of 26 mW. Guidelines are provided to adapt the system to arbitrary chip area and pixel pitch values, yielding a versatile design with very fine time resolution

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Targeting IL-17A in Multiple Myeloma: A Potential Novel Therapeutic Approach in Myeloma

We have previously demonstrated that interleukin-17A (IL-17) producing Th17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co-culture. AIN-457 also significantly inhibited osteoclast cell–differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN-457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report here, that MM cells express IL-17A. We also observed that IL-17A knock-down inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN 457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Estudio de eventos transitorios generados por pulsos láser ultracortos en fotodiodos

[spa] La miniaturización de los circuitos integrados trae consigo numerosas ventajas, como el aumento de la densidad de integración y la mayor frecuencia de trabajo, no obstante, trae consigo problemas de alimentación, fabricación y compatibilidad electromagnética con el entorno. Ahora, los problemas que sufrían los satélites por atravesar determinadas órbitas empiezan a preocupar a las empresas y autoridades aéreas que buscan blindar sus sistemas ante cualquier tipo de fallo crítico. Esto supone un interés común entre empresas, administración y investigadores para estudiar los efectos producidos por las partículas de alta energía en dispositivos electrónicos, y diseñar sistemas más robustos ante el entorno. Se ha demostrado que las partículas de alta energía pueden ser emuladas con pulsos láser ultracortos, gracias al efecto fotoeléctrico. Para entender mejor los mecanismos de generación de carga en una dispositivo electrónico se ha optado por estudiar el elemento más básico de la electrónica en estado sólido, el fotodiodo. Así, se estudiará la respuesta del fotodiodo a diferentes tensiones e intensidades lumínicas con el fin de estudiar a respuesta dinámica, la carga colectada y demás parámetros de interés para compararlos con los obtenidos por otros grupos de investigación. Los resultados logrados concuerdan con las hipótesis planteadas en diferentes artículos y la caracterización del fotodiodo, estudiando su respuesta dinámica, resulta una técnica prometedora que ayudará a esclarecer las contribuciones de los mecanismos que gobiernan los movimientos de portadores libres. Por otro lado, Parte del trabajo realizado servirá para entender mejor el funcionamiento de las instalaciones y poder sacarles el mejor partido posible. De las comparaciones con los otros grupos de investigación, puede verse que no existe un montaje mejor que otro, cada uno con sus características ofrece ventajas y desventajas dependiendo de los parámetros que se estén buscando y del dispositivo en sí mismo. Por la tecnología de fabricación algunos circuitos integrados serán difíciles de trabajar con determinadas configuraciones de láser, como circuitos digitales con gran densidad de capas de metal, mientras que otros resultarán relativamente simples, como el fotodiodo