Search

This work introduces a boost converter with quadratic gain. Its main advantage compared to well-known similar quadratic boost converters is that it requires capacitors with a relatively small capacitance and inductors with small inductance, leading to a reduction in the size or stored energy while performing a power conversion of similar power rating and the same switching ripples in both the input current and the output voltage. It is inspired by the recently introduced ISB converter and uses a specific PWM method. This results in achieving switching ripple constraints while using smaller energy storage elements (capacitors and inductors). The updated converter offers the same voltage gain compared to the conventional quadratic boost topology with the benefit of compact component sizes. While it has more passive elements, they are of reduced size. An analysis of energy storage revealed that this new converter uses only half the energy in inductors and 14% in capacitors when compared to specific design parameters.

Background & aimsFALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers.MethodsBlood-based composite fibrosis scores, blood-based biomarkers, and imaging biomarkers were evaluated for patients with available data from FALCON 1 at baseline through week 24. SomaSignal tests assessed protein signatures of NASH steatosis, inflammation, ballooning, and fibrosis in blood. Linear mixed-effect models were fit for each biomarker. Correlations and concordance were assessed between blood-based biomarkers, imaging, and histological metrics.ResultsAt week 24, pegbelfermin significantly improved blood-based composite fibrosis scores (ELF, FIB-4, APRI), fibrogenesis biomarkers (PRO-C3 and PC3X), adiponectin, CK-18, hepatic fat fraction measured by MRI-proton density fat fraction, and all four SomaSignal NASH component tests. Correlation analyses between histological and non-invasive measures identified four main categories: steatosis/metabolism, tissue injury, fibrosis, and biopsy-based metrics. Concordant and discordant effects of pegbelfermin on the primary endpoint vs. biomarker responses were observed; the most clear and concordant effects were on measures of liver steatosis and metabolism. A significant association between hepatic fat measured histologically and by imaging was observed in pegbelfermin arms.ConclusionsPegbelfermin improved NASH-related biomarkers most consistently through improvement of liver steatosis, though biomarkers of tissue injury/inflammation and fibrosis were also improved. Concordance analysis shows that non-invasive assessments of NASH support and exceed the improvements detected by liver biopsy, suggesting that greater consideration should be given to the totality of available data when evaluating the efficacy of NASH therapeutics.Clinical trial numberPost hoc analysis of NCT03486899.Impact and implicationsFALCON 1 was a study of pegbelfermin vs. placebo in patients with non-alcoholic steatohepatitis (NASH) without cirrhosis; in this study, patients who responded to pegbelfermin treatment were identified through examination of liver fibrosis in tissue samples collected through biopsy. In the current analysis, non-invasive blood- and imaging-based measures of fibrosis, liver fat, and liver injury were used to determine pegbelfermin treatment response to see how they compared with the biopsy-based results. We found that many of the non-invasive tests, particularly those that measured liver fat, identified patients who responded to pegbelfermin treatment, consistent with the liver biopsy findings. These results suggest that there may be additional value in using data from non-invasive tests, along with liver biopsy, to evaluate how well patients with NASH respond to treatment.

Thirty years since the first report on the PilY1 protein in bacteria, only the C-terminal domain has been crystallized; there is no study in which the N-terminal domain, let alone the complete protein, has been crystallized. In our laboratory, we are interested in characterizing the Type IV Pili (T4P) of Acidithiobacillus thiooxidans. We performed an in silico characterization of PilY1 and other pilins of the T4P of this acidophilic bacterium. In silico characterization is crucial for understanding how proteins adapt and function under extreme conditions. By analyzing the primary and secondary structures of proteins through computational methods, researchers can gain valuable insights into protein stability, key structural features, and unique amino acid compositions that contribute to resilience in harsh environments. Here, it is presented a description of the particularities of At. thiooxidans PilY1 through predictor software and homology data. Our results suggest that PilY1 from At. thiooxidans may have the same role as has been described for other PilY1 associated with T4P in neutrophilic bacteria; also, its C-terminal interacts (interface interaction) with the minor pilins PilX, PilW and PilV. The N-terminal region comprises domains such as the vWA and the MIDAS, involved in signaling, ligand-binding, and protein-protein interaction. In fact, the vWA domain has intrinsically disordered regions that enable it to maintain its structure over a wide pH range, not only at extreme acidity to which At. thiooxidans is adapted. The results obtained helped us design the correct methodology for its heterologous expression. This allowed us partially experimentally characterize it by obtaining the N-terminal domain recombinantly and evaluating its acid stability through fluorescence spectroscopy. The data suggest that it remains stable across pH changes. This work thus provides guidance for the characterization of extracellular proteins from extremophilic organisms.

Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants (n = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P

Educational inequity is widely prevalent in United States (U.S.) public schools and creates barriers to STEM education for underserved and underrepresented populations, including racial minority, low-income, and first-generation college students. Scientists at the Walter Reed Army Institute of Research (WRAIR) recognized a need in its community, the greater Washington, DC metropolitan area, to improve access to high-quality STEM education, and founded the WRAIR Gains in the Education of Mathematics and Science (GEMS) program for this purpose. In pursuit of this goal, the GEMS program engages students using innovative learning strategies and authentic STEM experiences with the hopes of fostering interest in STEM and motivating more underserved and underrepresented students to persist in STEM education and career pathways. By 1995, WRAIR scientists began investigating how to bring science-enthusiastic but novice high school (HS) students into their laboratories where they could be mentored, along with providing a stipend to mitigate financial barriers; importantly, this process was funded by two Science Education Partnership Awards from 2001-2006. Each year, WRAIR's GEMS program now guides about 600-700 local middle and HS students to take part in hands-on, inquiry-based STEM laboratory investigations led by undergraduate "near peer mentors" (NPMs), so named due to their close age to participants. GEMS is now sustained at 14 sites nationwide through the U.S. Army Educational Outreach Program, and serve about 4,000 students and near-peer mentors annually. Recent evaluations of the program explore service to underrepresented groups in STEM and growth of the local program. Further evaluation of the nationwide programs reveals positive student feedback, especially regarding working with NPMs and hands-on learning.

This article presents a data-driven methodology for modeling lithium-ion batteries, which includes the estimation of the open-circuit voltage and state of charge. Using the proposed methodology, the dynamics of a battery cell can be captured without the need for explicit theoretical models. This approach only requires the acquisition of two easily measurable variables: the discharge current and the terminal voltage. The acquired data are used to build a linear differential system, which is algebraically manipulated to form a space-state representation of the battery cell. The resulting model was tested and compared against real discharging curves. Preliminary results showed that the battery’s state of charge can be computed with limited precision using a model that considers a constant open-circuit voltage. To improve the accuracy of the identified model, a modified recursive least-squares algorithm is implemented inside the data-driven method to estimate the battery’s open-circuit voltage. These last results showed a very precise tracking of the real battery discharging dynamics, including the terminal voltage and state of charge. The proposed data-driven methodology could simplify the implementation of adaptive control strategies in larger-scale solutions and battery management systems with the interconnection of multiple battery cells.

Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1-6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD. This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort. This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. NCT04308681.

Crystal surfaces play a pivotal role in governing various significant processes, such as adsorption, nucleation, wetting, friction, and wear. A fundamental property that influences these processes is the surface free energy, γ. We have directly calculated γ(T) for low-index faces of Lennard-Jones (LJ), germanium, and silicon crystals along their sublimation lines using the computational cleavage technique. Our calculations agree well with experimental values for Si(111) and Ge(111), highlighting the accuracy of the method and models used. For LJ crystals, we identified a premelting onset at Tpm = 0.75Tm, marked by a sharp increase in atom mobility within the second outermost surface layer. Notably, Tpm closely aligned with the endpoint of the LJ melting line at negative pressures, Tend = 0.76Tm. We hypothesize that the emergence and coexistence of a liquid film atop the LJ crystal at Tpm < T < Tm correspond to the metastable melting line under negative pressures experienced by stretched crystal surfaces. Furthermore, our study of thin LJ crystal slabs reveals that premelting-induced failure leads to recrystallization below the homogeneous freezing limit, offering a promising avenue to explore crystal nucleation and growth at extremely deep supercoolings. Finally, no evidence of premelting was detected in the model crystals of Ge and Si, which is consistent with the experimental observations. Overall, our findings offer valuable insights into crystal surface phenomena at the atomic scale. [ABSTRACT FROM AUTHOR]

Abstract BMS‐986263 is a retinoid‐conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen‐specific chaperone protein involved in fibrosis development. This is a phase I, open‐label, two‐part study evaluating pharmacokinetics and safety of BMS‐986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age‐ and body mass index (BMI)‐matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age‐ and BMI‐matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS‐986263 infusion. Compared with normal‐matched participants, geometric mean area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration (AUC(0‐T)) and AUC from zero to infinity (AUC(INF)) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal‐matched group. Overall, single‐dose BMS‐986263 was generally safe and well‐tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS‐986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure‐safety/efficacy relationship becomes available.

Background Obstructive sleep apnoea (OSA) has been described as a risk factor for arterial hypertension (HT). One of the proposed mechanisms linking these conditions is non dipping (ND) pattern in nocturnal blood pressure, however evidence is variable and based on specific populations with underlying conditions. Data for OSA and ND in subjects residing at high altitude are currently unavailable.

The global distribution of hepatitis E virus (HEV) is attributed to its capacity to spread through several routes of transmission; hemodialysis has gained increased amounts of attention in recent years. Although Mexico is considered a hyperendemic region for hepatitis E, no HEV surveillance is performed in the country. The frequency of HEV in hemodialysis (HD) patients has not been determined. Herein, we conducted a cross-sectional single-center analytical study including 67 serum samples from HD patients. Anti-HEV IgG and IgM antibodies and the viral genome were determined; partial regions within the HEV genome were sequenced for further phylogenetic analysis. Globally, 14.9% of the tested patients exhibited reactivity for IgG antibodies against HEV, and none showed reactivity to IgM. A total of 5.9% of the samples showed HEV genome amplification, and sequencing confirmed the identity of genotype 3; subsequent analysis of positive cases revealed two acute cases and chronic hepatitis E infection in one patient. Notably, the chronic patient was negative for anti-HEV IgG antibodies. Our findings highlight the importance of viral genome testing in HD patients and the need to establish guidelines for HEV detection in Mexico.

Introduction and Objectives: Hepatitis E virus (HEV) is not routinely screened in blood banks in low- and middle-income countries, and no specific biomarkers of exposure to this virus have yet been identified. We aimed to identify HEV seropositivity and detect virus RNA among blood donors from Mexico to further correlate risk factors related to infection and levels of interleukin-18 (IL-18) and interferon-gamma (IFN-γ) as potential biomarkers. Materials and Methods: This cross-sectional, single-center study included 691 serum samples of blood donors obtained in 2019. Anti-HEV IgG and IgM antibodies were detected in sera and the viral genome was screened in pooled samples. A statistical comparison of risk factors for infection, demographic and clinical features was performed; IL-18 and IFN- γ values were tested in sera. Results: Of all the individuals, 9.4% were positive for anti-HEV antibodies and viral RNA detection was confirmed in one of the pools positive for anti-HEV. From the analysis of risk factors, age and having pets were statistically significant for anti-HEV antibody detection. Seropositive samples showed significantly higher IL-18 concentrations relative to samples from seronegative donors. Interestingly, IL-18 values were similar when HEV seropositive samples were compared to samples from clinically acute previously confirmed HEV patients. Conclusions: Our findings highlight the need to follow up on HEV in blood banks in Mexico and underscore that IL-18 could represent a biomarker of HEV exposure.