A selected ion flow tube study of the reactions of gas-phase cations with PSCl3

A selected ion flow tube was used to investigate the positive ion chemistry of thiophosphoryl chloride, PSCl$_3$. Rate coefficients and ion product branching ratios have been determined at room temperature for reactions with nineteen cations ; H$_3$O$^+$, CF$_3^+$, CF$^+$, NO$^+$, NO$_2^+$, SF$_2^+$, SF$^+$, CF$_2^+$, O$_2^+$, H$_2$O$^+$, N$_2$O$^+$, O$^+$, CO$_2^+$, CO$^+$, N$^+$, N$_2^+$, Ar$^+$, F$^+$ and Ne$^+$ (in order of increasing recombination energy). Complementary data described in the previous paper have been obtained for this molecule via the observation of threshold photoelectron photoion coincidences. For ions whose recombination energies are in the range 10-22 eV, comparisons are made between the product ion branching rations of PSCl$_3$ from photoionisation and from ion-molecule reactions. In most instances, the data from the two experiments are well correlated, suggesting that long-range charge transfer is the dominant mechanism for these ion-molecule reactions ; the agreement is particularly good for the atomic ions Ar$^+$, F$^+$ and Ne$^+$. Some reactions (e.g. O$_2^+$ + PSCl$_3$), however, exhibit significant differences; short-range charge transfer must then be occurring following the formation of an ion-molecule complex. For ions whose recombination energies are less than 10 eV (i.e. H$_3$O$^+$, CF$_3^+$, CF$^+$ and NO$^+$), reactions can only occur via a chemical process in which bonds are broken and formed, because the recombination energy of the cation is less than the ionisation energy of PSCl$_3$

Characterisation of a new VUV beamline at the Daresbury SRS using a dispersed fluorescence apparatus incorporating CCD detection

The design and performance of a new normal incidence monochromator at the Daresbury Synchrotron Radiation Source, optimised for experiments requiring high flux of vacuum-UV radiation, are described. The re-developed beamline 3.1, based on the Wadsworth design of monochromator, is the source of tunable vacuum-UV photons in the range 4 – 31 eV, providing over two orders of magnitude more flux than the vacuum-UV, Seya monochromator in its previous manifestation. The undispersed and dispersed fluorescence spectra resulting from photoexcitation of N$_2$, CO$_2$, CF$_4$ and C$_6$F$_6$ are presented. Emitting species observed were N$_2^+$ B$^2\Sigma_u^+$ - X$^2\Sigma_g^+$, CO$_2^+$ A$^2\Pi_u$ - X$^2\Pi_g$ and B$^2\Sigma_u^+$ - X$^2\Pi_g$, CF$_4$$^+$ C$^2$T$_2$ - X$^2$T$_1$ and C$^2$T$_2$ - A$^2$T$_2$, CF$_3$* $^2$A$^’_2$ - $^2$A$^”_2$, and C$_6$F$_6^+$ B$^2$A$_{2u}$ - X$^2$E$_{1g}$. A CCD multi-channel detector has significantly reduced the time period needed to record dispersed fluorescence spectra with a comparable signal-to-noise ratio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

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

State-Resolved Dynamics of the CN(B2Sigma+) and CH(A2Delta) Excited Products Resulting from the VUV Photodissociation of CH3CN

Fourier transform visible spectroscopy, in conjunction with VUV photons produced by a synchrotron, is employed to investigate the photodissociation of CH3CN. Emission is observed from both the CN(B2Sigma+ - X2Sigma+) and CH(A2Delta - X2PI) transitions; only the former is observed in spectra recorded at 10.2 and 11.5 eV, whereas both are detected in the 16 eV spectrum. The rotational and vibrational temperatures of both the CN(B2Sigma+) and CH(A2Delta) radical products are derived using a combination of spectral simulations and Boltzmann plots. The CN(B2Sigma+) fragment displays a bimodal rotational distribution in all cases. Trot(CN(B2Sigma+)) ranges from 375 to 600 K at lower K' and from 1840 to 7700 K at higher K' depending on the photon energy used. Surprisal analyses indicate clear bimodal rotational distributions, suggesting CN(B2Sigma+) is formed via either linear or bent transition states, respectively, depending on the extent of rotational excitation in this fragment. CH(A2Delta) has a single rotational distribution when produced at 16 eV which results in Trot(CH(A2Delta)) = 4895 +- 140 K in nu' = 0 and 2590 +- 110 K in nu' = 1. From thermodynamic calculations, it is evident that CH(A2Delta) is produced along with CN(X2Sigma+) + H2. These products can be formed by a two step mechanism (via excited CH3* and ground state CN(X2Sigma+) or a process similar to the "roaming" atom mechanism; the data obtained here are insufficient to definitively conclude whether either pathway occurs. A comparison of the CH(A2Delta) and CN(B2Sigma+) rotational distributions produced by 16 eV photons allows the ratio between the two excited fragments at this energy to be determined. An expression that considers the rovibrational populations of both band systems results in a CH(A2Delta):CN(B2Sigma+) ratio of (1.2 +- 0.1):1 at 16 eV, thereby indicating that production of CH(A2Delta) is significant at 16 eV

Raman scattering techniques for defense and security applications

In this review we discuss the recent advances in the application of Raman scattering and related techniques to the detection of chemical and biological threat agents. One of the main aims of this review is to provide a new perspective on the application of advanced and emerging Raman techniques such as surface-enhanced Raman, spatially-offset Raman, waveguide-enhanced and coherent Raman spectroscopies, respectively, to the detection of threat agents such as explosives, toxins, viruses and bacteria. Combination with multivariate and computational analysis to augment the analytical abilities of Raman techniques as well as hyphenation and integration with various field deployment strategies such as robotic and stand-off detection are discussed. Importantly this interplay between the detection technique, analysis and engineering technology will be essential for developing powerful solutions for field applications in defence and security