Performance evaluation of the FastIC readout ASIC with emphasis on Cherenkov emission in TOF-PET.

Objective.The efficient usage of prompt photons like Cherenkov emission is of great interest for the design of the next generation, cost-effective, and ultra-high-sensitivity time-of-flight positron emission tomography (TOF-PET) scanners. With custom, high power consuming, readout electronics and fast digitization the prospect of sub-300 ps FWHM with PET-sized BGO crystals have been shown. However, these results are not scalable to a full system consisting of thousands of detector elements.Approach.To pave the way toward a full TOF-PET scanner, we examine the performance of the FastIC ASIC with Cherenkov-emitting scintillators (BGO), together with one of the most recent SiPM detector developments based on metal trenching from FBK. The FastIC is a highly configurable ASIC with 8 input channels, a power consumption of 12 mW ch-1and excellent linearity on the energy measurement. To put the timing performance of the FastIC into perspective, comparison measurements with high-power consuming readout electronics are performed.Main results.We achieve a best CTR FWHM of 330 ps for 2 × 2 × 3 mm3and 490 ps for 2 × 2 × 20 mm3BGO crystals with the FastIC. In addition, using 20 mm long LSO:Ce:Ca crystals, CTR values of 129 ps FWHM have been measured with the FastIC, only slightly worse to the state-of-the-art of 95 ps obtained with discrete HF electronics.Significance.For the first time, the timing capability of BGO with a scalable ASIC has been evaluated. The findings underscore the potential of the FastIC ASIC in the development of cost-effective TOF-PET scanners with excellent timing characteristics.

Continuous Phase Estimation in a Variety of Locomotion Modes Using Adaptive Dynamic Movement Primitives.

Accurate gait phase estimation algorithms can be used to synchronize the action of wearable robots to the volitional user movements in real time. Current-day gait phase estimation methods are designed mostly for rhythmic tasks and evaluated in highly controlled walking environments (namely, steady-state walking). Here, we implemented adaptive Dynamic Movement Primitives (aDMP) for continuous real-time phase estimation in the most common locomotion activities of daily living, which are level-ground walking, stair negotiation, and ramp negotiation. The proposed method uses the thigh roll angle and foot-contact information and was tested in real time with five subjects. The estimated phase resulted in an average root-mean-square error of 3.98% ± 1.33% and a final estimation error of 0.60% ± 0.55% with respect to the linear phase. The results of this study constitute a viable groundwork for future phase-based control strategies for lower-limb wearable robots, such as robotic prostheses or exoskeletons.

Decoding Upper-Limb Movement Intention Through Adaptive Dynamic Movement Primitives: A Proof-of-Concept Study with a Shoulder-Elbow Exoskeleton.

This work presents an intention decoding algorithm that can be used to control a 4 degrees-of-freedom shoulder-elbow exoskeleton in reaching tasks. The algorithm was designed to assist the movement of users with upper-limb impairments who can initiate the movement by themselves. It relies on the observation of the initial part of the user's movement through joint angle measures and aims to estimate in real-time the phase of the movement and predict the goal position of the hand in the reaching task. The algorithm is based on adaptive Dynamic Movement Primitives and Gaussian Mixture Models. The performance of the algorithm was verified in robot-assisted planar reaching movements performed by one healthy subject wearing the exoskeleton. Tests included movements of different amplitudes and orientations. Results showed that the algorithm could predict the hand's final position with an error lower than 5 cm after 0.25 s from the movement onset, and that the final position reached during the tests was on average less than 4 cm far from the target position. Finally, the effects of the assistance were observed in a reduction of the activation of the Biceps Brachii and of the time to execute the reaching tasks.

A Locomotion Mode Recognition Algorithm Using Adaptive Dynamic Movement Primitives.

Control systems of robotic prostheses should be designed to decode the users' intent to start, stop, or change locomotion; and to select the suitable control strategy, accordingly. This paper describes a locomotion mode recognition algorithm based on adaptive Dynamic Movement Primitive models used as locomotion templates. The models take foot-ground contact information and thigh roll angle, measured by an inertial measurement unit, for generating continuous model variables to extract features for a set of Support Vector Machines. The proposed algorithm was tested offline on data acquired from 10 intact subjects and 1 subject with transtibial amputation, in ground-level walking and stair ascending/descending activities. Following subject-specific training, results on intact subjects showed that the algorithm can classify initiatory and steady-state steps with up to 100.00% median accuracy medially at 28.45% and 27.40% of the swing phase, respectively. While the transitory steps were classified with up to 87.30% median accuracy medially at 90.54% of the swing phase. Results with data of the transtibial amputee showed that the algorithm classified initiatory, steady-state, and transitory steps with up to 92.59%, 100%, and 93.10% median accuracies medially at 19.48%, 51.47%, and 93.33% of the swing phase, respectively. The results support the feasibility of this approach in robotic prosthesis control.

On timing-optimized SiPMs for Cherenkov detection to boost low cost time-of-flight PET.

Objective.Recent SiPM developments and improved front-end electronics have opened new doors in TOF-PET with a focus on prompt photon detection. For instance, the relatively high Cherenkov yield of bismuth-germanate (BGO) upon 511 keV gamma interaction has triggered a lot of interest, especially for its use in total body positron emission tomography (PET) scanners due to the crystal's relatively low material and production costs. However, the electronic readout and timing optimization of the SiPMs still poses many questions. Lab experiments have shown the prospect of Cherenkov detection, with coincidence time resolutions (CTRs) of 200 ps FWHM achieved with small pixels, but lack system integration due to an unacceptable high power uptake of the used amplifiers.Approach.Following recent studies the most practical circuits with lower power uptake (<30 mW) have been implemented and the CTR performance with BGO of newly developed SiPMs from Fondazione Bruno Kessler tested. These novel SiPMs are optimized for highest single photon time resolution (SPTR).Main results.We achieved a best CTR FWHM of 123 ps for 2 × 2 × 3 mm3and 243 ps for 3 × 3 × 20 mm3BGO crystals. We further show that with these devices a CTR of 106 ps is possible using commercially available 3 × 3 × 20 mm3LYSO:Ce,Mg crystals. To give an insight in the timing properties of these SiPMs, we measured the SPTR with black coated PbF2of 2 × 2 × 3 mm3size. We confirmed an SPTR of 68 ps FWHM published in literature for standard devices and show that the optimized SiPMs can improve this value to 42 ps. Pushing the SiPM bias and using 1 × 1 mm2area devices we measured an SPTR of 28 ps FWHM.Significance.We have shown that advancements in readout electronics and SiPMs can lead to improved CTR with Cherenkov emitting crystals. Enabling time-of-flight with BGO will trigger a high interest for its use in low-cost and total-body PET scanners. Furthermore, owing to the prompt nature of Cherenkov emission, future CTR improvements are conceivable, for which a low-power electronic implementation is indispensable. In an extended discussion we will give a roadmap to best timing with prompt photons.

Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases.

Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.

Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients.

Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or ~0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Detection of mixed Leishmania infections in dogs from an endemic area in southeastern Brazil.

In Brazil, the visceral leishmaniasis (VL) is caused by Leishmania infantum, while the tegumentary leishmaniasis (TL) etiological agents are mainly Leishmania braziliensis and Leishmania amazonensis. The canine visceral leishmaniasis (CVL) diagnosis is an important step of the VL control program in Brazil, which involves the elimination of infected dogs, the main urban VL reservoirs. The current serology-based diagnostic tests have shown cross-reactivity between these three species, whereas molecular diagnosis allows high sensitivity and specie identification. In the present study, 349 dogs of the metropolitan region of Belo Horizonte (Minas Gerais state) were screened by conjunctival swab and the samples analyzed by ITS-1 nested PCR. Thirty dogs (8.5%) tested positive. The RFLP of amplicons using HaeIII demonstrated that 17/30 samples presented a banding pattern compatible with L. infantum, 4/30 matched with L. amazonenis, 1/30 with L. braziliensis and 8/30 showed a mixed infection pattern. The samples that were distinct of L. infantum or presented a mixed pattern were submitted to RFPL with HaeIII and RsaI enzymes that confirmed the mixed pattern. Such patterns were also confirmed by Sanger Sequencing. The results pointed eight dogs with mixed infections and the establishment of TL causing species in the Belo Horizonte dog population. These findings highlight the need for more comprehensive epidemiological studies, since the TL transmission profile might be changing. This study also shows the potential of the ITS1-nPCR associated with RFLP for the proper Leishmania diagnosis and typing in the dog population.

Next-generation sequencing reveals new insights about gene usage and CDR-H3 composition in the horse antibody repertoire.

Horse serum antibodies have been used for greater than a century for the treatment and prophylaxis of infectious diseases and envenomations. Little is known, however, about the immunogenetic diversity that produces horse serum antibodies. Here, we employed next-generation sequencing for a first-in-kind comprehensive analysis of the equine B-cell repertoire. Nearly 45,000 and 30,000 clonotypes were obtained for the heavy-chain (IGH) and lambda light-chain (IGL) loci, respectively. We observed skewed use of the common subgroups IGHV2 (92.49%) and IGLV8 (82.50%), consistent with previous reports, but also novel use of the rare genes IGHV6S1 and IGLV4S2. CDR-H3 amino acid composition revealed different amino acid patterns at positions 106 and 116 compared to human, rabbit, and mouse, suggesting that an extended conformation predominates among horse CDR-H3 loops. Our analysis provides new insights regarding the mechanisms employed to generate antibody diversity in the horse, and could be applicable to the optimized design of synthetic antibodies intended for future therapeutic use.

Efeito da goma guar parcialmente hidrolisada no metabolismo de lipídeos e na aterogênese de camundongos / Effect of partially hydrolyzed guar gum on lipid metabolism and atherogenesis of mice

OBJETIVO: Observar os efeitos da goma guar parcialmente hidrolisada no metabolismo de colesterol e na formação de placa aterosclerótica em aorta de camundongos deficientes no receptor LDL, euglicêmicos ou com hiperglicemia induzida por estreptozotocina. MÉTODOS: Trinta e seis camundongos deficientes para o receptor de LDL foram divididos em quatro grupos de nove animais: grupos euglicêmicos, alimentados com dieta aterogênica padrão (controle euglicêmico) ou suplementada com 7,5 por cento de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada euglicêmico) e grupos hiperglicêmicos alimentados com dieta aterogênica padrão (controle hiperglicêmico) ou suplementada com 7,5 por cento de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada hiperglicêmico). Após quatro semanas de experimento foram medidos: ingestão alimentar, ganho de peso, glicemia, colesterol plasmático e hepático, assim como lesão aterosclerótica na aorta torácica e abdominal. RESULTADOS: Os resultados mostram que a suplementação de goma guar parcialmente hidrolisada levou ao aumento do colesterol hepático e plasmático em animais euglicêmicos, mas sem aumento na área de lesão aterosclerótica na aorta. Em animais hiperglicêmicos, a redução no colesterol plasmático não foi estatisticamente significante, mas no que se refere à lesão da aorta, observou-se redução significante. CONCLUSÃO: Os resultados sugerem que a goma guar parcialmente hidrolisada pode reduzir a aterosclerose associada ao Diabetes Mellitus tipo 1.

OBJECTIVE: The objective of this study was to observe the effects of partially hydrolyzed guar gum on cholesterol metabolism and atherosclerosis in the aorta of euglycemic and streptozotocin-induced hyperglycemic LDL receptor deficient mice. METHODS: Thirty six LDL receptor deficient mice were divided into 4 groups of 9 animals: euglycemic groups fed on hypercholesterolemic diet without or supplemented with 7.5 percent of partially hydrolyzed guar gum and streptozotocin-induced hyperglycemic groups also fed an atherogenic diet without or supplemented with 7.5 percent of partially hydrolyzed guar gum. After 4 weeks of experiment, food intake, body weight, glycemia, blood and liver cholesterol and atherosclerotic lesion in the aorta were determined. RESULTS: The results showed that partially hydrolyzed guar gum induced an increase in blood and liver cholesterol in euglycemic mice when compared with euglycemic control groups at the end of the experiment. On the other hand, although not affecting plasma cholesterol, hyperglycemic mice supplemented with partially hydrolyzed guar gum had the lesion area in the aorta significantly reduced. In hyperglycemic animals, plasma cholesterol did not decrease significantly but the lesion area in the aorta did. CONCLUSION: The present study suggests that partially hydrolyzed guar gum can reduce the development of atherosclerosis associated with type 1 diabetes mellitus.