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Most popular superconducting circuits operate on information carried by ps-wide, μV-tall, single flux quantum (SFQ) pulses. These circuits can operate at frequencies of hundreds of GHz with orders of magnitude lower switching energy than complementary-metal-oxide-semiconductors (CMOS). However, under the stringent area constraints of modern superconductor technologies, fully-fledged, CMOS-inspired superconducting architectures cannot be fabricated at large scales. Unary SFQ (U-SFQ) is an alternative computing paradigm that can address these area constraints. In U-SFQ, information is mapped to a combination of streams of SFQ pulses and in the temporal domain. In this work, we extend U-SFQ to introduce novel building blocks such as a multiplier and an accumulator. These blocks reduce area and power consumption by 2 \(\times\) and 4 \(\times\) compared with previously proposed U-SFQ building blocks and yield at least 97% area savings compared with binary approaches. Using these multiplier and adder, we propose a U-SFQ Convolutional Neural Network (CNN) hardware accelerator capable of comparable peak performance with state-of-the-art superconducting binary approach (B-SFQ) in 32 \(\times\) less area. CNNs can operate with 5–8 bits of resolution with no significant degradation in classification accuracy. For 5 bits of resolution, our proposed accelerator yields 5 \(\times\) to 63 \(\times\) better performance than CMOS and 15 \(\times\) to 173 \(\times\) better area efficiency than B-SFQ. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) Tcell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACTmodalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The MAP kinases pathway has shown a key role in the pathogenesis of colorectal cancer. The development of targeted therapy against BRAF-mutated tumors is changing the management of advanced disease. A proper understanding of the mechanisms of acquired resistance is essential to optimize the results of systemic treatment. We aim to review the current knowledge and potential fields of research regarding the use of BRAF inhibitors in metastatic colorectal tumors. Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them. [ABSTRACT FROM AUTHOR]

Segmentation analysis and logistic regression were used to test the probabilistic connection between exposure to high-risk situations and victimization events, as posited by Lifestyle-exposure theory, in a sample of homeless people. The results support the hypothesis put forward. First, those who had engaged in risky behaviors had suffered victimization events to a greater extent. Second, this was particularly true for participants who had done so more frequently or had engaged in a wider range of such behaviors. The highest risk profile included those who had been arrested on several occasions and also reported having used drugs during the previous month or, otherwise, had served a sentence different from prison in the past. Implications of these findings are discussed considering that homeless people's engagement in risky behaviors, as well as, in general, their greater degree of exposure to situations in which risk of victimization is high, often stem from the situation they are going through. A major conclusion is that any effort to eradicate violence against homeless people should contemplate strategies for combating homelessness itself. [ABSTRACT FROM AUTHOR]

Simple Summary: The systemic treatment of advanced sarcoma remains challenging. Conventional chemotherapy and anti-angiogenic agents, even in the most responsive histologic subtypes, result in short responses and poor clinical outcomes. In a context where new therapeutic approaches are required, several strategies of immunotherapy have emerged as promising options, such as immune checkpoint inhibitors, vaccines, and adoptive cell therapy. In this review, we aim to summarize the current state and challenges of immunotherapy in patients with advanced bone and soft-tissue sarcomas. There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine–kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research. [ABSTRACT FROM AUTHOR]

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies. [ABSTRACT FROM AUTHOR]

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer. [ABSTRACT FROM AUTHOR]

Peripheral blood polymorphonuclear neutrophils (PMNs) forming extracellular traps (NETs), as well as endothelial- and platelet-derived parameters, have been analyzed in patients with SARS-CoV-2 pneumonia, and their prognostic role has been evaluated. Eighty-seven consecutive patients hospitalized with SARS-CoV-2 pneumonia were prospectively selected. A sample of 30 healthy individuals served as the control group. Clinical and oxygenation (oxygen saturation to fraction of inspired oxygen ratio—SpO2/FiO2) characteristics and PMNs forming NETs, serum levels of myeloperoxidase, E-selectin, vascular cell adhesion molecule 1—VCAM1—vascular endothelial growth factor, P-selectin, platelet factor 4 and plasma concentrations of D-dimer were evaluated at hospital admission, at discharge and 14 days after discharge. Intensive care unit admission or death was the primary composite endpoint. Patients showed a higher number of PMNs forming NETs than healthy controls. The absolute number of PMNs forming NETs was inversely correlated with oxygen status (SpO2/FiO2) and positively with inflammatory (C-reactive protein, ferritin) markers and VCAM1. A decrease in, but not a normalization of NETs and endothelial-derived parameters was observed in patients who survived. In conclusion, the formation of NETs runs parallel to that of other inflammatory and endothelial activation markers, and is inverse to the oxygenation parameters, supporting a pathogenic role for PMNs in this entity. [ABSTRACT FROM AUTHOR]

Fear extinction is not permanent but is instead more vulnerable than the original fear memory, as traditionally shown by the return of fear phenomena. Because of this, techniques to mitigate the return of fear are needed in the clinical treatment of related psychological conditions. One promising strategy is the occasional reinforced extinction treatment, introducing a gradual and sparse number of conditioned stimulus–unconditioned stimulus (CS-US) pairings within the extinction treatment. We present the results of three experiments in which we used a threat conditioning procedure in humans. Our main aim was to evaluate whether occasional reinforced extinction could reduce two different forms of relapse: spontaneous recovery (Experiments 1 and 2) and reinstatement (Experiment 3). Contrary to our predictions and previous literature, the results indicate that an occasional reinforcement treatment did not mitigate relapse compared with standard extinction. From a theoretical standpoint, these results are more consistent with the idea that extinction entails the acquisition of new knowledge than with the idea that there are conditions in which extinction leads to a weakening of the original fear memory. These findings also question the generality of the potential benefits of using occasional reinforced extinction in clinical settings. [ABSTRACT FROM AUTHOR]

To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements. In contrast, patients with PNS involvement showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) in comparison with patients without NS. Neurosarcoidosis was identified in 5.5% of patients. CNS involvement prevails significantly over PNS involvement, and both conditions do not overlap in any patient. The systemic phenotype associated to each involvement was clearly differentiated, and can be helpful not only in the early identification of neurological involvement, but also in the systemic evaluation of patients diagnosed with neurosarcoidosis. [ABSTRACT FROM AUTHOR]

We propose a novel architecture to enable low-power, complex on-node data processing, for the next generation of sensors for the internet of things (IoT), smartdust, or edge intelligence. Our architecture combines near-analog-memory-computing (NAM) and asynchronous-computing-with-streams (ACS), eliminating the need for ADCs. ACS enables ultra-low power, massive computational resources required to execute on-node complex Machine Learning (ML) algorithms; while NAM addresses the memory-wall that represents a common bottleneck for ML and other complex functions. In ACS an analog value is mapped to an asynchronous stream that can take one of two logic levels (vh, vl). This stream-based data representation enables area/power-efficient computing units such as a multiplier implemented as an AND gate yielding savings in power of ~90% compared to digital approaches. The generation of streams for NAM and ACS in a brute forcemanner, using analog-to-digital-converters (ADCs) and digital-to-streams-converters, would sky-rocket the power-latency-energy cost making the approach impractical. Our NAM-ACS architecture eliminates expensive conversions, enabling an end-to-end processing on asynchronous streams data-path. We tailor the NAM-ACS architecture for random forest (RaF), an ML algorithm, chosen for its ability to classify using a reduced number of features. Simulations show that our NAM-ACS architecture enables 75% of savings in power compared with a single ADC, obtaining a classification accuracy of 85% using an RaF-inspired algorithm. [ABSTRACT FROM AUTHOR]

BACKGROUND: The lung diffusion capacity (DLCO) determined by the single-breath technique greatly helps in the differential diagnosis and classification of severity of common lung diseases. However, widespread use of single-breath DLCO tests in Latin America has been limited, in part, by the lack of appropriate reference values. Our objective was to derive robust reference equations for single-breath DLCO from healthy Hispanic adults, using the most recent guidelines and taking into account altitude above sea level and hemoglobin. METHODS: We recruited healthy adults from Caracas (690 m), Santiago (650 m), Mexico City (2,240 m), and Bogota (2,640 m). DLCO testing was completed using an instrument that exceeds American Thoracic Society/European Respiratory Society 2005 guidelines for spirometry and single-breath DLCO and provided centralized training and a quality assurance program. RESULTS: We included 480 healthy Hispanic adults (58.3% women) with a mean age of 46 y (range 22-83 y). Their mean ± SD single-breath DLCO was 30.4 ± 9.2 mL/min/mm Hg. Results as a percentage of predicted by Crapo's reference values (the closest to obtained values) were 83 ± 10% (Caracas), 91 ± 10% (Santiago), 104 ± 17% (Mexico City), and 118 ± 19% (Bogota), and current suggested adjustments by hemoglobin or altitude did not correct differences, especially in Santiago and Caracas. CONCLUSIONS: We recommend these new single-breath DLCO reference equations to predict single-breath DLCO in Latin America performed with current instruments and procedures and including as a predictor altitude above sea level. [ABSTRACT FROM AUTHOR]