Measuring count rates free from correlated noise in digital silicon photomultipliers

Abstract : The characterization of nuisance parameters in digital silicon photomultipliers (SiPMs) is important to their understanding and future development. Methods able to distinguish the types of events are necessary to obtain fair and legitimate measurements. In this work, the zero photon probability (ZPP) method and the time delay (TD) method are used to measure the dark noise of digital SiPMs free from the contribution of correlated noise such as afterpulsing and crosstalk. It highlights the unique features of digital SiPMs such as the holdoff delay, the digital output signal, and the embedded processing (e.g. the selection of the interval sampling width). The two methods correctly separate the correlated and uncorrelated events in digital SiPMs and therefore the determination of a true photon detection efficiency (PDE) is possible. The ZPP method is also implemented inside a digital SiPM using embedded digital signal processing

Multi-center real-world comparison of the fully automated Idylla (TM) microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla (TM) MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla (TM) testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla (TM) results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla (TM) MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had >= 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla (TM) MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla (TM) MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla (TM) MSI Assay and routine tests.Peer reviewe

Optimisation des méthodes d'analyse et de séquence manuelle des peptides et leurs applications à la dynorphine immunoréactive isolée de la médullo-surrénale de bœuf

Une méthode manuelle de dégradation d'Edman combinée à l'analyse des acides aminés, de leurs dérivés phénylthiohydantoins (PTH) et des dérivés phénylthiocarbamyl-peptides par chromatographie liquide à haute pression (HPLC) est proposée. Tout d'abord, une technique d'analyse d'acides aminés fut développée en faisant réagir les acides aminés avec l'orthophtalaIdéhyde (OPA). Les dérivés fluorescents sont séparés sur une colonne C-18 Résolve (Waters) et détecté avec un fluorimètre, lequel permet d'atteindre une limite de 5 pmol. Chacune des étapes de la dégradation d'Edman fut étudiée soigneusement afin d'optimiser le rendement total de la séquence. La réaction de couplage entre le phénylisothiocyanate (PITC) et le résidu en N-terminal du peptide a lieu dans un tampon de diméthylallylamine (pH 9.5) à 56°C durant 30 min. Les sous-produits de réaction et les excès de réactif sont éliminés avec le 1-chloro-butane, tout en minimisant les pertes de peptide à cette étape. L'utilisation de l'acide chlorhydrique concentré (HCl 12 N) pour cliver l'acide aminé en N-terminal réduit l'accumulation de sels observée avec l'acide trifluoroacétique, ceci nous permet de séquencer un plus grand nombre de résidus dans un peptide. Le thiazolinone est converti en dérivé PTH en présence de HCl 1 N à 80°C durant 10 min. Le PTH-acide aminé est détecté directement par son absorbance dans l'ultraviolet à 254 nm après passage sur HPLC. L'utilisation d'un gradient de métanol:acétonitrile (17:3) dans un tampon d'acétate de sodium 0.02 M (pH 5.4) permet une bonne résolution des PTH-acides aminés sur une colonne Nova Pak (Waters). L'application de ces techniques à la dynorphine immunoréactive isolée de la médullo-surrénale de bœuf confirme la présence des fragments Dyn-(1-11) et -(1-13) à ce niveau

Optimisation des méthodes d'analyse et de séquence manuelle des peptides et leurs applications à la dynorphine immunoréactive isolée de la médullo-surrénale de bœuf

Une méthode manuelle de dégradation d'Edman combinée à l'analyse des acides aminés, de leurs dérivés phénylthiohydantoins (PTH) et des dérivés phénylthiocarbamyl-peptides par chromatographie liquide à haute pression (HPLC) est proposée. Tout d'abord, une technique d'analyse d'acides aminés fut développée en faisant réagir les acides aminés avec l'orthophtalaIdéhyde (OPA). Les dérivés fluorescents sont séparés sur une colonne C-18 Résolve (Waters) et détecté avec un fluorimètre, lequel permet d'atteindre une limite de 5 pmol. Chacune des étapes de la dégradation d'Edman fut étudiée soigneusement afin d'optimiser le rendement total de la séquence. La réaction de couplage entre le phénylisothiocyanate (PITC) et le résidu en N-terminal du peptide a lieu dans un tampon de diméthylallylamine (pH 9.5) à 56°C durant 30 min. Les sous-produits de réaction et les excès de réactif sont éliminés avec le 1-chloro-butane, tout en minimisant les pertes de peptide à cette étape. L'utilisation de l'acide chlorhydrique concentré (HCl 12 N) pour cliver l'acide aminé en N-terminal réduit l'accumulation de sels observée avec l'acide trifluoroacétique, ceci nous permet de séquencer un plus grand nombre de résidus dans un peptide. Le thiazolinone est converti en dérivé PTH en présence de HCl 1 N à 80°C durant 10 min. Le PTH-acide aminé est détecté directement par son absorbance dans l'ultraviolet à 254 nm après passage sur HPLC. L'utilisation d'un gradient de métanol:acétonitrile (17:3) dans un tampon d'acétate de sodium 0.02 M (pH 5.4) permet une bonne résolution des PTH-acides aminés sur une colonne Nova Pak (Waters). L'application de ces techniques à la dynorphine immunoréactive isolée de la médullo-surrénale de bœuf confirme la présence des fragments Dyn-(1-11) et -(1-13) à ce niveau

Quenching Circuit and SPAD Integrated in CMOS 65 nm with 7.8 ps FWHM Single Photon Timing Resolution

This paper presents a new quenching circuit (QC) and single photon avalanche diode (SPAD) implemented in TSMC CMOS 65 nm technology. The QC was optimized for single photon timing resolution (SPTR) with a view to an implementation in a 3D digital SiPM. The presented QC has a timing jitter of 4 ps full width at half maximum (FWHM) and the SPAD and QC has a 7.8 ps FWHM SPTR. The QC adjustable threshold allows timing resolution optimization as well as SPAD excess voltage and rise time characterization. The adjustable threshold, hold-off and recharge are essential to optimize the performances of each SPAD. This paper also provides a better understanding of the different contributions to the SPTR. A study of the contribution of the SPAD excess voltage variation combined to the QC time propagation delay variation is presented. The proposed SPAD and QC eliminates the SPAD excess voltage contribution to the SPTR for excess voltage higher than 1 V due to its fixed time propagation delay

Quenching Circuit Discriminator Architecture Impact on a Sub-10 ps FWHM Single-Photon Timing Resolution SPAD

In the field of radiation instrumentation, there is a desire to reach a sub-10 ps FWHM timing resolution for applications such as time-of-flight positron emission tomography, time-of-flight positron computed tomography and time-resolved calorimetry. One of the key parts of the detection chain for these applications is a single-photon detector and, in recent years, the first single-photon avalanche diode (SPAD) with a sub-10 ps timing resolution was presented. To reach such a timing resolution, the SPAD was read out by an operational amplifier operated in open-loop as a comparator. This paper presents a comparison between comparators and inverters to determine which type of leading-edge discriminator can obtain the best single-photon timing resolution. Six different quenching circuits (QCs) implemented in TSMC 65 nm are tested with SPADs of the same architecture and in the same operation conditions. This allows us to compare experimental results between the different QCs. This paper also presents a method to measure the SPAD signal slope, the SPAD excess voltage variation and simulations to determine the added jitter of different leading-edge discriminators. For some discriminator architectures, a cascode transistor was required to increase the maximum excess voltage of the QC. This paper also presents the impact on the single-photon timing resolution of adding a cascode transistor for a comparator or an inverter-based discriminator. This paper reports a 6.3 ps FWHM SPTR for a SPAD read out by a low-threshold comparator and a 6.8 ps FWHM SPTR for an optimized 1 V inverter using a cascode transistor for a higher excess voltage

3D Photon-To-Digital Converter for Radiation Instrumentation: Motivation and Future Works

Analog and digital SiPMs have revolutionized the field of radiation instrumentation by replacing both avalanche photodiodes and photomultiplier tubes in many applications. However, multiple applications require greater performance than the current SiPMs are capable of, for example timing resolution for time-of-flight positron emission tomography and time-of-flight computed tomography, and mitigation of the large output capacitance of SiPM array for large-scale time projection chambers for liquid argon and liquid xenon experiments. In this contribution, the case will be made that 3D photon-to-digital converters, also known as 3D digital SiPMs, have a potentially superior performance over analog and 2D digital SiPMs. A review of 3D photon-to-digital converters is presented along with various applications where they can make a difference, such as time-of-flight medical imaging systems and low-background experiments in noble liquids. Finally, a review of the key design choices that must be made to obtain an optimized 3D photon-to-digital converter for radiation instrumentation, more specifically the single-photon avalanche diode array, the CMOS technology, the quenching circuit, the time-to-digital converter, the digital signal processing and the system level integration, are discussed in detail

3D Photon-To-Digital Converter for Radiation Instrumentation: Motivation and Future Works

Analog and digital SiPMs have revolutionized the field of radiation instrumentation by replacing both avalanche photodiodes and photomultiplier tubes in many applications. However, multiple applications require greater performance than the current SiPMs are capable of, for example timing resolution for time-of-flight positron emission tomography and time-of-flight computed tomography, and mitigation of the large output capacitance of SiPM array for large-scale time projection chambers for liquid argon and liquid xenon experiments. In this contribution, the case will be made that 3D photon-to-digital converters, also known as 3D digital SiPMs, have a potentially superior performance over analog and 2D digital SiPMs. A review of 3D photon-to-digital converters is presented along with various applications where they can make a difference, such as time-of-flight medical imaging systems and low-background experiments in noble liquids. Finally, a review of the key design choices that must be made to obtain an optimized 3D photon-to-digital converter for radiation instrumentation, more specifically the single-photon avalanche diode array, the CMOS technology, the quenching circuit, the time-to-digital converter, the digital signal processing and the system level integration, are discussed in detail