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Introduction and Objectives: The treatment of vulnerable populations must be prioritized to accomplish the WHO HCV elimination goals by 2030, including patients with mental health disorders, incarcerated patients or homeless patients. Simplifying the treatment cascade and rapid treatment start is key to achieving this goal, even more so in the COVID-19 era. Sofosbuvir/velpatasvir (SOF/VEL) is a protease inhibitor-free, pangenotypic, panfibrotic, single duration, single tablet regimen, to be taken without regards to food and with limited drug-drug interactions, allowing treatment simplification. Purpose: This real world data (RWD) analysis evaluates the effectiveness and safety of SOF/VEL for 12 weeks in a heterogeneous HCV population who suffer a mental health disorder, are incarcerated, or homeless. Materials and Methods: 33 clinical cohorts across Australia, Canada, Europe & USA included 1,888 patients, 280 of them (from 6 clinical cohorts) were treated in Canada and overall managed following local standards of care. Adults were included if SOF/VEL for 12 weeks was started before November 2019 and completed while suffering a mental health disorder, being incarcerated or homeless, irrespective of genotype (GT), presence of compensated cirrhosis (CC) or treatment experience. Exclusion criteria were history of decompensation, prior NS5A-inhibitor exposure, treatment duration >12 weeks or addition of ribavirin. Sustained virological response (SVR; ≥12 weeks after end-of-treatment) and time to treatment initiation were assessed. Results: Overall analysis includes 1,888 (71.3% male) patients (1,422 with a mental health disorder, 526 incarcerated, 153 homeless) aged 50 years, 24.4% were taking antipsychotic drugs and 52.2% of patients had former or current intravenous drug use. 43.2% patients had HCV GT1, 11.6% GT2, 36.3% GT3, 5.9% GT4-6, and 3.0% mixed/unknown GT. 19.0% patients had CC and 12.4% were treatment-experienced. In 257 patients (13.6%), SVR was not evaluated due to non-virological or unknown reasons; 79.9% of those were lost to follow-up (LTFU). When SVR was measured, 98.0% (n=1598/1631) achieved SVR, with 97.6%, 98.9% and 100% in patients with a mental health disorder, incarcerated or homeless patients, respectively. SVR was 98.5% in non-cirrhotic and 95.4% in CC patients. SVR remained >95% under antipsychotic use or coexistence of two negative factors of non-response such as GT3 plus active drug use or psychiatric disorder. SVR was similar, irrespective of time from diagnosis to treatment. Detailed analysis of the Canadian cohort data will be presented at the conference. Conclusion: A test-and-treat strategy, easily implemented with SOF/VEL, and supported by the AASLD/ALEH/APASL/EASL joint call to action, could further enhance the population-level efficacy of HCV therapy by reducing the rate of non-virologic failure due to LTFU and related factors.

Analog In-Memory computing (AIMC) is a novel paradigm looking for solutions to prevent the unnecessary transfer of data by distributing computation within memory elements. One such operation is matrix-vector multiplication (MVM), a workhorse of many fields ranging from linear regression to Deep Learning. The same concept can be readily applied to the encoding stage in Compressed Sensing (CS) systems, where an MVM operation maps input signals into compressed measurements. With a focus on an encoder built on top of a Phase-Change Memory (PCM) AIMC platform, the effects of device non-idealities, namely programming spread and drift over time, are observed in terms of the reconstruction quality obtained for synthetic signals, sparse in the Discrete Cosine Transform (DCT) domain. PCM devices are simulated using statistical models summarizing the properties experimentally observed in an AIMC prototype, designed in a 90 nm STMicroelectronics technology. Different families of decoders are tested, and tradeoffs in terms of encoding energy are analyzed. Furthermore, the benefits of a hardware drift compensation strategy are also observed, highlighting its necessity to prevent the need for a complete reprogramming of the entire analog array. The results show >30 dB average reconstruction quality for mid-range conductances and a suitably selected decoder right after programming. Additionally, the hardware drift compensation strategy enables robust performance even when different drift conditions are tested.

Biomarkers can be defined as measurable characteristics to be evaluated as indicators of normal or pathogenic biological processes, or as predictors of treatment response [...]

Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor vs tumor areas (p

Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced magnetic resonance imaging (MRI) protocols.Objective: The presented cross-sectional study evaluated the utility of four different MRI relaxation metrics and diffusion-weighted imaging in PPMS.Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ in combination with diffusion-weighted parameters were acquired in 13 PPMS patients and 13 age- and sex-matched controls.Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, the sensorimotor cortex, and the cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus an indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols outperformed both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches, methods previously used in the MRI research of PPMS.Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical gray matter, cerebellar, and white matter alterations in PPMS invisible to other in vivo biomarkers.

The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.

In this study, we investigated the sorption–desorption behavior of imazamox (IMZ) and 2,4-DB (DB) in two typical acidic Mediterranean agricultural soils and the impact of these herbicides on culturable soil bacterial populations, enzyme activities and functional diversity when applied at concentrations higher than recommended doses (10×, 50×, 500×). Herbicide sorption was similar in both soils and IMZ was less retained compared to DB (~0.5 vs. 40 µg g−1 soil, respectively). IMZ desorption was remarkable (70–100%) while that of DB was more limited, i.e., ~40%. Three days after spiking (DAS), IMZ and DB significantly increased the number of soil-culturable heterotrophic bacteria, actinomycetes and Pseudomonas spp., soil respiration and the potential catabolic capacity of soil microbial communities. Soil dehydrogenase activity increased by ~56–70% in IMZ-treated soils while being reduced by ~33–41% in DB-treated ones. β-glucosidase activity showed a soil-dependent behavior, while the pattern of C source utilization suggested a change of soil microbial community structure after herbicide (especially DB) spiking. At 30 DAS, the herbicides’ impact on soil microorganisms, enzyme activity and functional diversity was still visible. Moreover, a toxic effect of DB (at 50× and 500×), but not IMZ, was recorded vs. Rhizobium sullae, the bacterial symbiont of Hedysarum coronarium. The obtained results indicated that IMZ and DB are poorly sorbed and highly desorbed by both soils. Moreover, at the tested concentrations, IMZ and DB can have short- and medium-term impacts on the microbial component and the related activity of the investigated soils, likely affecting a range of ecosystem services provided by soil microorganisms.

Although therapy with direct-acting antiviral (DAA) agents achieves high hepatitis C virus (HCV) cure rates and is forgiving of missed doses, certain patient populations, such as people who inject drugs (PWID), are often denied therapy because of a perceived high risk of nonadherence. However, a relationship between adherence to DAAs for various patient populations and efficacy has not been well defined. The lack of a standardized method for evaluating adherence complicates making comparisons between studies, making it difficult to develop and implement novel measures that may improve adherent behavior. Traditional methods for assessing adherence may overestimate medication adherence, while newer, technology-based methods may assist with accurately assessing and maintaining patient adherence to therapy. Data demonstrate that special populations of patients with HCV, such as PWID, can be successfully treated, with relatively high rates of sustained virologic response (SVR) despite less-than-optimal adherence. While rates of adherence, and subsequently SVR, can be improved, antiviral therapy should not be withheld because of fear of nonadherence. This article addresses medication adherence and forgiveness of DAA regimens, such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, in different patient populations with HCV. Considerations in evaluating adherence in HCV therapy and available methods for assessing adherence are detailed. [ABSTRACT FROM AUTHOR]

During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2) resulting in blood hyperoxygenation, the basis of BOLD-fMRI contrast. Explanations for the high CBF versus CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO2, and pO2 as a function of baseline OEF (OEF0), CBF, CMRO2, and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO2, and pO2 in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0. We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO2, and pO2 were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease. [ABSTRACT FROM AUTHOR]

This study aims to find more efficient ways to manufacture highly reactive polyisobutylene (HRPIB) and modified conventional PIB materials (MCPIB) industrially with high vinyl exo‐group contents through cationic polymerization at mild temperatures. The study performed polymerizations using aluminum trichloride (AlCl3) as a catalyst with different nonpolar solvents (hexane and toluene), reaction temperatures (10 and 30°C), and co‐catalysts (water and dibutyl ether [DBE]). At 30°C, toluene can provide vinyl contents above 30 mol%. Particularly, an important synergetic effect was observed between toluene and ether, as corroborated by statistical analyses, resulting in vinyl contents above 50 mol%, while reactions performed in n‐hexane provided maximum vinyl content of 20 mol%. In all cases, number average molar masses ranged from 200 to 1000 Da, which are typical of CPIB and MCPIB materials. Moreover, addition of excess of ether indicated the likely inhibition of reaction rates in presence of high ether concentrations (≥1.18 × 10 −1 mol/L). The obtained results indicated that AlCl3 can be used successfully to manufacture MCPIB products with terminal vinyl contents above 50 mol% at mild temperatures in common nonpolar solvents (n‐hexane and toluene) and in presence of common co‐catalysts (water and DBE) with high rates of reactions. [ABSTRACT FROM AUTHOR]