Towards an improved understanding of plasticity, friction and wear mechanisms in precipitate containing AZ91 Mg alloy

This work reports a combined experimental and atomistic simulation study on continuous precipitates (CPs) and discontinuous precipitates (DPs) affecting the scratch induced wear in AZ91 magnesium alloy. Nanoscratching experiments complemented by atomic simulations were performed to understand the directional dependence and origins of plasticity, friction and wear mechanisms as benchmarked to nanocrystalline HCP magnesium. Post scratch deformation analysis was performed using electron back scattering diffraction, scanning electron microscope and molecular dynamics (MD) simulation. The direction of orientation of the precipitates was observed to make a significant influence on the deformation behaviour. For example, regardless of the precipitates type (CP or DP), a ductile-brittle transition becomes pronounced while scratching along the direction (orientation) of precipitates, whilst a fully ductile response was obtained while scratching along the direction normal to the precipitates. However, regardless of the direction of orientation, DPs showed a higher wear resistance and coefficient of friction compared to the CPs. These observations were supported by the quantitative analysis of the planar defects such as coherent twins, extrinsic and intrinsic stacking faults in the deformation zone as well as 1/3〈11¯00〉" role="presentation"> ( and 1/3〈12¯10〉" role="presentation"> dislocations type extracted from the MD analysis.These observations will facilitate an improved design of AZ91 alloys in particular and intermetallic precipitate containing alloys in general

Бесплатный обязательный экземпляр полиграфических и других изданий как один из источников комплектования Латвийской академической библиотеки

Aggregation of amyloid beta (Aβ) into oligomers and fibrils is believed to play an important role in the development of Alzheimer's disease (AD). To gain further insight into the principles of aggregation, we have investigated the induction of β-sheet secondary conformation from disordered native peptide sequences through lipidation, in 1-2% hexafluoroisopropanol (HFIP) in phosphate buffered saline (PBS). Several parameters, such as type and number of lipid chains, peptide sequence, peptide length and net charge, were explored keeping the ratio peptide/HFIP constant. The resulting lipoconjugates were characterized by several physico-chemical techniques: Circular Dichroism (CD), Attenuated Total Reflection InfraRed (ATR-IR), Thioflavin T (ThT) fluorescence, Dynamic Light Scattering (DLS), solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy and Electron Microscopy (EM). Our data demonstrate the generation of β-sheet aggregates from numerous unstructured peptides under physiological pH, independent of the amino acid sequence. The amphiphilicity pattern and hydrophobicity of the scaffold were found to be key factors for their assembly into amyloid-like structures

AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r)

Fractional deuteration applied to biomolecular solid-state NMR spectroscopy

Solid-state Nuclear Magnetic Resonance can provide detailed insight into structural and dynamical aspects of complex biomolecules. With increasing molecular size, advanced approaches for spectral simplification and the detection of medium to long-range contacts become of critical relevance. We have analyzed the protonation pattern of a membrane-embedded ion channel that was obtained from bacterial expression using protonated precursors and D2O medium. We find an overall reduction of 50% in protein protonation. High levels of deuteration at Hα and Hβ positions reduce spectral congestion in (1H,13C,15N) correlation experiments and generate a transfer profile in longitudinal mixing schemes that can be tuned to specific resonance frequencies. At the same time, residual protons are predominantly found at amino-acid side-chain positions enhancing the prospects for obtaining side-chain resonance assignments and for detecting medium to long-range contacts. Fractional deuteration thus provides a powerful means to aid the structural analysis of complex biomolecules by solid-state NMR

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Knowledge, attitudes, and practices related to uterotonic drugs during childbirth in Karnataka, India: a qualitative research study.

BACKGROUND AND OBJECTIVES: India has the highest annual number of maternal deaths of any country. As obstetric hemorrhage is the leading cause of maternal death in India, numerous efforts are under way to promote access to skilled attendance at birth and emergency obstetric care. Current initiatives also seek to increase access to active management of the third stage of labor for postpartum hemorrhage prevention, particularly through administration of an uterotonic after delivery. However, prior research suggests widespread inappropriate use of uterotonics at facilities and in communities-for example, without adequate monitoring or referral support for complications. This qualitative study aimed to document health providers' and community members' current knowledge, attitudes, and practices regarding uterotonic use during labor and delivery in India's Karnataka state. METHODS: 140 in-depth interviews were conducted from June to August 2011 in Bagalkot and Hassan districts with physicians, nurses, recently delivered women, mothers-in-law, traditional birth attendants (dais), unlicensed village doctors, and chemists (pharmacists). RESULTS: Many respondents reported use of uterotonics, particularly oxytocin, for labor augmentation in both facility-based and home-based deliveries. The study also identified contextual factors that promote inappropriate uterotonic use, including high value placed on pain during labor; perceived pressure to provide or receive uterotonics early in labor and delivery, perhaps leading to administration of uterotonics despite awareness of risks; and lack of consistent and correct knowledge regarding safe storage, dosing, and administration of oxytocin. CONCLUSIONS: These findings have significant implications for public health programs in a context of widespread and potentially increasing availability of uterotonics. Among other responses, efforts are needed to improve communication between community members and providers regarding uterotonic use during labor and delivery and to target training and other interventions to address identified gaps in knowledge and ensure that providers and pharmacists have up-to-date information regarding proper usage of uterotonic drugs

Heat Transfer in Supercritical Steam Flowing Through Spiral Tubes

We investigate heat transfer in supercritical steam flowing in a spiral tube by conducting three-dimensional numerical simulations. The current numerical solver has been validated with the existing experimental results, and simulations are performed by varying different geometric parameters of a spiral tube. The flow dynamics and heat transfer in a spiral tube are compared against those in a straight tube. For the parameters range considered in the present study, it is found that the heat transfer coefficient (HTC) in the spiral tube is 29% higher than that in the case of a straight tube for the same flow and thermal conditions. Our results indicate that the tangential velocity component resulting due to the spiraling effect of the steam is the primary reason for the enhancement of the HTC value. It is observed that while the HTC in a spiral tube is inversely related to the spiral diameter, it does not exhibit a strong relationship with the spiral pitch. Moreover, three existing heat transfer correlations are evaluated under the spiral flow condition and it is observed that none of them can calculate the HTC value accurately in spiral tubes. Using the Buckingham p-theorem, three modified correlations are proposed for the low, moderate, and high heat flux regimes, which accurately predict the wall temperature and HTC of supercritical steam in spiral tubes in all the heat flux regimes. The correlations have an error band of less than ±20%