Resilient and agile engineering solutions to address societal challenges such as coronavirus pandemic

The world is witnessing tumultuous times as major economic powers including the US, UK, Russia, India, and most of Europe continue to be in a state of lockdown. The worst-hit sectors due to this lockdown are sales, production (manufacturing), transport (aerospace and automotive) and tourism. Lockdowns became necessary as a preventive measure to avoid the spread of the contagious and infectious “Coronavirus Disease 2019” (COVID-19). This newly identified disease is caused by a new strain of the virus being referred to as Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS CoV-2; formerly called 2019-nCoV). We review the current medical and manufacturing response to COVID-19, including advances in instrumentation, sensing, use of lasers, fumigation chambers and development of novel tools such as lab-on-the-chip using combinatorial additive and subtractive manufacturing techniques and use of molecular modelling and molecular docking in drug and vaccine discovery. We also offer perspectives on future considerations on climate change, outsourced versus indigenous manufacturing, automation, and antimicrobial resistance. Overall, this paper attempts to identify key areas where manufacturing can be employed to address societal challenges such as COVID-19

Horizons of modern molecular dynamics simulation in digitalized solid freeform fabrication with advanced materials

Our ability to shape and finish a component by combined methods of fabrication including (but not limited to) subtractive, additive, and/or no theoretical mass-loss/addition during the fabrication is now popularly known as solid freeform fabrication (SFF). Fabrication of a telescope mirror is a typical example where grinding and polishing processes are first applied to shape the mirror, and thereafter, an optical coating is usually applied to enhance its optical performance. The area of nanomanufacturing cannot grow without a deep knowledge of the fundamentals of materials and consequently, the use of computer simulations is now becoming ubiquitous. This article is intended to highlight the most recent advances in the computation benefit specific to the area of precision SFF as these systems are traversing through the journey of digitalization and Industry-4.0. Specifically, this article demonstrates that the application of the latest materials modelling approaches, based on techniques such as molecular dynamics, are enabling breakthroughs in applied precision manufacturing techniques

Association of IL-4RA single nucleotide polymorphisms, HLA-DR and HLA-DQ in children with Alternaria-sensitive moderate-severe asthma

<p>Abstract</p> <p>Background</p> <p>Asthma afflicts 6% to 8% of the United States population, and severe asthma represents approximately 10% of asthmatic patients. Several epidemiologic studies in the United States and Europe have linked <it>Alternaria </it>sensitivity to both persistence and severity of asthma. In order to begin to understand genetic risk factors underlying <it>Alternaria </it>sensitivity and asthma, in these studies we examined T cell responses to <it>Alternaria </it>antigens, HLA Class II restriction and HLA-DQ protection in children with severe asthma.</p> <p>Methods</p> <p>Sixty children with <it>Alternaria</it>-sensitive moderate-severe asthma were compared to 49 children with <it>Alternaria</it>-sensitive mild asthma. We examined HLA-DR and HLA-DQ frequencies in <it>Alternaria</it>-sensitive asthmatic by HLA typing. To determine ratios of Th1/Th2 <it>Alternaria</it>-specific T-cells, cultures were stimulated in media alone, <it>Alternaria alternata </it>extract and Alt a1. Sensitivity to IL-4 stimulation was measured by up-regulation of CD23 on B cells.</p> <p>Results</p> <p>Children with <it>Alternaria</it>-sensitive moderate-severe asthma trended to have increased sensitivities to <it>Cladosporium </it>(46% versus 35%), to <it>Aspergillus </it>(43% versus 28%), and significantly increased sensitivities to trees (78% versus 57%) and to weeds (68% versus 48%). The IL-4RA ile75val polymorphism was significantly increased in <it>Alternaria</it>-sensitive moderate-severe asthmatics, 83% (0.627 allele frequency) compared to <it>Alternaria</it>-sensitive mild asthmatics, 57% (0.388 allele frequency). This was associated with increased sensitivity to IL-4 stimulation measured by significantly increased IL-4 stimulated CD23 expression on CD19+ and CD86+CD19+ B cells of <it>Alternaria</it>-sensitive moderate-severe asthmatics. IL-5 and IL-13 synthesis was significantly increased in <it>Alternaria</it>-sensitive moderate-severe asthmatics compared to mild asthmatics to <it>Alternaria </it>extract and Alt a1 stimulation. The frequency of HLA-DQB1*03 allele was significantly decreased in <it>Alternaria</it>-sensitive moderate-severe asthmatics compared to mild asthmatics, 39% versus 63%, with significantly decreased allele frequency, 0.220 versus 0.398.</p> <p>Summary</p> <p>In children with <it>Alternaria</it>-sensitive moderate severe asthma, there was an increased Th2 response to <it>Alternaria </it>stimulation and increased sensitivity to IL-4 stimulation. This skewing towards a Th2 response was associated with an increased frequency of the IL-4RA ile75val polymorphism. In evaluating the HLA association, there was a decreased frequency of HLA-DQB1*03 in <it>Alternaria</it>-sensitive moderate severe asthmatic children consistent with previous studies suggest that HLA-DQB1*03 may be protective against the development of mold-sensitive severe asthma.</p

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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

Allergenic Ribosomal P Proteins

Characteristics of ribosomal P proteinsRibosomal P proteins are small molecules (10-11 kDa) that form the ribosomal stalk structure which plays a key role in the elongation step of protein translation [1]. Ribosomal P proteins have an isoelectric point in a very acidic range (pI 3-4), and are phosphorylated. For these reasons, they are also called acidic ribosomal P proteins. In addition to ribosome-bound P proteins, they are also found in a free-state in cytoplasm and an exchange occurs between the nucleus and cytoplasmic sites [2]. Free ribosomal proteins are contained in the nuclear sap and participate in the assembly of ribosome subunits that takes place in the nucleolus. Ribosomal proteins are ubiquitous and abundant in the cell. They are prime candidates for recruitment towards extraribosomal functions that are often related to overall cellular health, such as balancing the synthesis of the RNA and protein components of the ribosome and involving in apoptosis [3].</p

Platinum group metal complexes of bis(2-(diphenylphosphino)ethyl benzylamine and bis(2-(diphenylarsino)ethyl)benzylamine

Rh(I), Ir(I), Pd(II) and Pt(II) metal complexes of bis(2-diphenylphosphino)ethyl)benzylamine(DPBA) and bis(2-diphenylarsino)ethyl)benzylamine (DABA) have been synthesized using various starting materials. Reaction of RhCl(CO)(AsPh3)2 with DPBA or DABA in methanol resulted in the formation of cationic complexes of the composition, [Rh(CO)(L)]Cl (L=DPBA or DABA). Interaction of [IrCl(COD)]2 with DPBA in benzene resulted in the formation of a neutral complex [IrCl(DPBA)]. Reaction of [PdCl2(COD)] with the ligand DPBA in benzene resulted in a cationic complex of the composition [PdCl(DPBA)]Cl. Interaction of [PdCl(DPBA)]BPh4 with SnCl2 gave the complex [Pd(SnCl3)(DPBA)]BPh4. The ligands DPBA and DABA react with PtCl2(COD) in acetone to give neutral, Pt(II) complexes of the type, [PtCl2L] (L=DPBA or DABA). All the complexes were fully characterized by elemental analysis, conductivity measurements, IR and far-IR and 31P{1H} NMR spectral data

D-Erythritol derivatives -versatile C₄ chiral building blocks: Synthesis and applications

1010-1025Among various synthetically important chiral building blocks, four carbon atom (C4) chiral building blocks bearing double and/or multiple functionalities are especially interesting because of their usefulness in synthesis of chiral pharmaceuticals, chiral agrochemicals, chiral polymers, natural products and chiral monosaccharides. This study reviews synthesis of D-erythritol derivatives as chiral C4 synthetic units and their important applications