Reactivity of Tetrel-Functionalized Heptaphosphane Clusters toward Azides.

In this work, the reactivity of tetrel-functionalized phosphorus clusters toward organoazides is probed. Clusters (Me3Si)3P7 (1) and (Me3Ge)3P7 (2) were reacted with benzyl azide, phenyl azide, and 4-bromophenyl azide, and it was found that the [RN] (R = benzyl, phenyl, and 4-bromophenyl) unit from the azide inserted into the phosphorus-tetrel bonds on the cluster, accompanied by N2 elimination. Through control of the azide stoichiometry, the mono-, bis-, and tris-inserted products could be observed, consistent with these insertions proceeding in a stepwise manner. The bonding between the amine moieties and clusters was further investigated by computational chemistry, and the findings were consistent with the phosphorus cluster having undergone a formal oxidation. These insertion reactions are a convenient means of accessing Zintl clusters functionalized with exo-nitrogen-bonded moieties, which, to the best of our knowledge, were previously unknown.

Zintl Clusters as a Platform for Lewis Acid Catalysis.

Clusters of the main group elements phosphorus and arsenic, commonly categorized as Zintl clusters, have been known for over a century. And, only now is the application of these systems as catalysts for organic synthesis being investigated. In this work, boranes are tethered via an aliphatic linker to Zintl-based clusters and their Lewis acidity is examined experimentally, by the Gutmann-Beckett test and competency in the hydroborative reduction of six organic substrates, as well as computationally, by fluoride ion affinity and hydride ion affinity methods. The effects of tuning the aliphatic linker length, substituents at the boron, and changing the cluster from a seven-atom phosphorus system to a seven-atom arsenic system on reactivity are studied.

Zintl Ions and Phases Promote the Catalytic Hydrophosphination of Alkynes, Alkenes, and Imines.

Although Zintl ions and phases have been known for more than a century, their application as tools to build organic molecules is underdeveloped. Here, a range of Zintl ions and phases were surveyed in the hydrophosphination of alkynes, alkenes, and imines with diphenylphosphine to afford useful organophosphine products. Further investigations with diphenylphosphine in the absence of the unsaturated organic substrates revealed the formation of the diphenylphosphide anion, allowing for the conclusion that the role of the Zintl species is as an initiator in these transformations.

Facilitating OPAT in rural areas.

A sizable portion of the United States' population lives in a rural setting. Coupled with a limited number of infectious diseases providers, this has created a need for innovative practice models to deliver outpatient antimicrobial therapy and clinical monitoring in rural settings. This article reviews existing literature regarding outpatient parenteral antimicrobial therapy in rural settings and explores existing barriers and potential solutions that may be of assistance to providers looking to provide these services.

A robust Zintl cluster for the catalytic reduction of pyridines, imines and nitriles.

Despite p-block clusters being known for over a century, their application as catalysts to mediate organic transformations is underexplored. Here, the boron functionalized [P7] cluster [(BBN)P7]2- ([1]2-; BBN = 9-borabicyclo[3.3.1]nonane) is applied in the dearomatized reduction of pyridines, as well as the hydroboration of imines and nitriles. These transformations afford amine products, which are important precursors to pharmaceuticals, agrochemicals, and polymers. Catalyst [1]2- has high stability in these reductions: recycling nine times in quinoline hydroboration led to virtually no loss in catalyst performance. The catalyst can also be recycled between two different organic transformations, again with no loss in catalyst competency. The mechanism for pyridine reduction was probed experimentally using variable time normalization analysis, and computationally using density functional theory. This work demonstrates that Zintl clusters can mediate the reduction of nitrogen containing substrates in a transition metal-free manner.

Pushing the agenda for intravenous push administration in outpatient parenteral antimicrobial therapy.

Intravenous push (IVP) antimicrobial administration refers to rapid bolus infusion of medication. This drug delivery method offers improved patient convenience, superior patient and nursing satisfaction, and cost savings when used in outpatient parenteral antimicrobial therapy (OPAT). Antimicrobial agents must demonstrate optimal physiochemical and pharmacologic characteristics, as well as sufficient syringe stability, to be administered in this manner. Additionally, impacts on medication tolerability, patient safety, and effectiveness must be considered. This narrative review summarizes the available data and practical implications of IVP administration of antimicrobials in the OPAT setting.

Reactivity of tetrel functionalized heptapnictogen clusters towards heteroallenes.

Despite being known for decades, the solution-state molecular chemistry of heptapnictogen ([Pn7]3-; Pn = P, As) clusters is not well established. Here we study heavy element derivatives of tetrel functionalized heptapnictogen clusters towards heteroallene capture, specifically isocyanates, an isothiocyanate and CO2 are probed. Clusters (Me3Ge)3P7 (1), (Et3Ge)3P7 (2), (nBu3Sn)3P7 (3), and (Me3Si)3As7 (4) were all found to capture isocyanates between all three of their tetrel-pnictogen bonds. In the case of phenyl isocyanate insertion, tetrel coordination at the isocyanate nitrogen atoms is preferred, while in the case of p-toluenesulfonyl isocyanate insertion, tetrel coordination at oxygen is preferred. Furthermore, the reaction of (Me3Si)3P7 with CO2 gave NMR spectra consistent with the capture of the greenhouse gas. Heteroallene insertion at these clusters was also studied using density functional theory.

A practical update on the management of patients with COVID-19.

While vaccines against COVID-19 are being rolled out, an ongoing need remains for therapies to treat patients who have symptomatic COVID-19 before vaccination or in whom breakthrough infection develops. Dexamethasone and interleukin-6 inhibitors have been the mainstay of treatment for severe to critical COVID-19 requiring hospitalisation. However, in the previous few months, several therapies have been approved in the UK for hospitalised and non-hospitalised patients with COVID-19. In particular, the development of neutralising monoclonal antibodies and novel antivirals represents a welcome expansion in the armamentarium against COVID-19, not only therapeutically to reduce mortality but also because they can be used in mild or moderate disease to prevent hospitalisation. This update is based on guidance from NHS England as well as the World Health Organization, and provides practical support and guidance to all clinicians involved or interested in the management of COVID-19 patients, whether based in community, outpatient or inpatient settings.

A Zintl Cluster for Transition Metal-Free Catalysis: C═O Bond Reductions.

The first fully characterized boron-functionalized heptaphosphide Zintl cluster, [(BBN)P7]2- ([1]2-), is synthesized by dehydrocoupling [HP7]2-. Dehydrocoupling is a previously unprecedented reaction pathway to functionalize Zintl clusters. [Na(18-c-6)]2[1] was employed as a transition metal-free catalyst for the hydroboration of aldehydes and ketones. Moreover, the greenhouse gas carbon dioxide (CO2) was efficiently and selectively reduced to methoxyborane. This work represents the first examples of Zintl catalysis where the transformation is transition metal-free and where the cluster is noninnocent.

Mapping boron catalysis onto a phosphorus cluster platform.

Clusters of main group elements, such as phosphorus, arsenic, germanium, and tin - called Zintl clusters - have been known for more than a century. However, their application in main group catalysis is largely unknown. Here, we tether boranes to a seven-atom phosphorus cluster ({C8H14}BCH2CH2SiMe2)3P7 (2) and we demonstrate Lewis acid catalysis as proof-of-principle that boron chemistry can be mapped onto clusters using this method. Catalyst 2 was employed to mediate key organic transformations, including the hydroboration of carbodiimides, isocyanates, ketones, alkenes, alkynes, and nitriles. To the best of our knowledge, this is the first application of Zintl-based clusters as an innocent platform in metal-free catalysis. By chaining boron, its treasure chest of chemistry can be unlocked at these clusters. Hence, beyond catalysis this method could find applications for main group clusters in neutron capture therapy, stimuli responsive materials, and cross-coupling, and frustrated Lewis pair and functional polymer chemistries.

Incidence and Clinical Features of Pneumomediastinum and Pneumothorax in COVID-19 Pneumonia.

BACKGROUND: Pneumothorax (PTX) and pneumomediastinum (PM), collectively termed here "air leak", are now well described complications of severe COVID-19 pneumonia across several case series. The incidence is thought to be approximately 1% but is not definitively known. OBJECTIVES: To report the incidence and describe the demographic features, risk factors and outcomes of patients with air leak as a complication of COVID-19. METHODS: A retrospective observational study on all adult patients with COVID-19 admitted to Watford General Hospital, West Hertfordshire NHS Trust between March 1st 2020 and Feb 28th 2021. Patients with air leak were identified after reviewing both chest radiographs (CXRs) and axial imaging (CT Thorax) with confirmatory radiology reports inclusive of the terms PTX and/or PM. RESULTS: Air leak occurred with an incidence of 0.56%. Patients with air leak were younger and had evidence of more severe disease at presentation, including a higher median CRP and number of abnormal zones affected on chest radiograph. Asthma was a significant risk factor in the development of air leak (OR 13.4 [4.7-36.4]), both spontaneously and following positive pressure ventilation. CPAP and IMV were also associated with a greater than six fold increase in the risk of air leak (OR 6.4 [2.5-16.6] and 9.8 [3.7-27.8] respectively). PTX, with or without PM, in the context of COVID-19 pneumonia was almost universally fatal whereas those with alone PM had a lower risk of death. CONCLUSION: Despite the global vaccination programme, patients continue to develop severe COVID-19 disease and may require respiratory support. This study demonstrates the importance of identifying that deterioration in such patients may be resultant from PTX or PM, particularly in asthmatics and those managed with positive pressure ventilation.

Heteroallene Capture and Exchange at Functionalised Heptaphosphane Clusters.

Despite being known for decades the chemical reactivity of homoatomic seven-atom phosphorus clusters towards small molecules remains largely unexplored. Here, we report that neutral tris(silyl) functionalised heptaphosphane (P7 (SiR3 )3 ) cages are capable of heteroallene capture between the P-Si bonds of the cluster. A range of isocyanates and an isothiocyanate were investigated. In the case of isocyanates, silyl bonding at oxygen or nitrogen is regioselectively directed by the functional group on the isocyanate and substituents on the silyl moiety. Above all, we find that captured isothiocyanate molecules can be exchanged for isocyanate molecules, indicative of small molecule catch and release. Small molecule catch and release at these Zintl-derived clusters reveals their potential application as chemical storage materials or as reusable probes.

Contemporary trends in the level of evidence in general thoracic surgery clinical research.

OBJECTIVES: The large volume of scientific publications and the increasing emphasis on high-quality evidence for clinical decision-making present daily challenges to all clinicians, including thoracic surgeons. The objective of this study was to evaluate the contemporary trend in the level of evidence (LOE) for thoracic surgery clinical research. METHODS: All clinical research articles published between January 2010 and December 2017 in 3 major general thoracic surgery journals were reviewed. Five authors independently reviewed the abstracts of each publication and assigned a LOE to each of them using the 2011 Oxford Centre for Evidence-Based Medicine classification scheme. Data extracted from eligible abstracts included study type, study size, country of primary author and type of study designs. Three auditing processes were conducted to establish working definitions and the process was validated with a research methodologist and 2 senior thoracic surgeons. Intra-class correlation coefficient was calculated to assess inter-rater agreement. Chi-square test and Spearman correlation analysis were then used to compare the LOE between journals and by year of publication. RESULTS: Of 2028 publications reviewed and scored, 29 (1.4%) were graded level I, 75 (3.7%) were graded level II, 471 (23.2%) were graded level III, 1420 (70.2%) were graded level IV and 33 (1.6%) were graded level V (lowest level). Most publications (94.9%) were of lower-level evidence (III-V). There was an overall increasing trend in the lower LOE (P < 0.001). Inter-rater reliability was substantial with 95.5% (95%, confidence interval: 0.95-0.96) level of agreement between reviewers. CONCLUSIONS: General thoracic surgery literature consists mostly of lower LOE studies. The number of lower levels of evidence is dominating the recent publications, potentially indicating a need to increase the commitment to produce and disseminate higher-level evidence in general thoracic surgery.

Reduction of tert-butylphosphaalkyne and trimethylsilylnitrile with magnesium(I) dimers.

We report on the reactivity of magnesium(I) dimers, [Mg(nacnac)]2 (nacnac = HC[C(Me)N(2,6-iPr2C6H3)]2 ([DippLMg]2) and HC[C(Me)N(2,4,6-Me3C6H2)]2 ([MesLMg]2)), towards the phosphaalkyne tBuCP. The steric profile of the magnesium(I) dimer results in selectivity for different products. The larger diisopropylphenyl derivative yields exclusively the monomeric dimagnesiated phosphaalkene [DippLMg]PC(tBu)([DippLMg]) (1), while the mesityl derivative facilitates reductive coupling of two phosphaalkyne equivalents to give access to the 1,3-diphosphacyclobutadienediide [MesLMg]2[(tBu)2C2P2](2). The reactivity differs in coordinating solvents such as THF, which allowed for the observation of C-P coupled products. For sake of comparison, reactions of magnesium(I) compounds with Me3SiCN were carried out. In contrast to the reactions involving tBuCP, these afforded 1,3-diazabutadienediyl complexes via reductive coupling and silyl migration processes.

Retrospective case-control study to evaluate hypocalcaemia as a distinguishing feature of COVID-19 compared with other infective pneumonias and its association with disease severity.

OBJECTIVES: To investigate whether calcium derangement was a specific feature of COVID-19 that distinguishes it from other infective pneumonias, and its association with disease severity. DESIGN: A retrospective observational case-control study looking at serum calcium on adult patients with COVID-19, and community-acquired pneumonia (CAP) or viral pneumonia (VP). SETTING: A district general hospital on the outskirts of London, UK. PARTICIPANTS: 506 patients with COVID-19, 95 patients with CAP and 152 patients with VP. OUTCOME MEASURES: Baseline characteristics including hypocalcaemia in patients with COVID-19, CAP and VP were detailed. For patients with COVID-19, the impact of an abnormally low calcium level on the maximum level of hospital care, as a surrogate of COVID-19 severity, was evaluated. The primary outcome of maximal level of care was based on the WHO Clinical Progression Scale for COVID-19. RESULTS: Hypocalcaemia was a specific and common clinical finding in patients with COVID-19 that distinguished it from other respiratory infections. Calcium levels were significantly lower in those with severe disease. Ordinal regression of risk estimates for categorised care levels showed that baseline hypocalcaemia was incrementally associated with OR of 2.33 (95% CI 1.5 to 3.61) for higher level of care, superior to other variables that have previously been shown to predict worse COVID-19 outcome. Serial calcium levels showed improvement by days 7-9 of admission, only in survivors of COVID-19. CONCLUSION: Hypocalcaemia is specific to COVID-19 and may help distinguish it from other infective pneumonias. Hypocalcaemia may independently predict severe disease and warrants detailed prognostic investigation. The fact that decreased serum calcium is observed at the time of clinical presentation in COVID-19, but not other infective pneumonias, suggests that its early derangement is pathophysiological and may influence the deleterious evolution of this disease. TRIAL REGISTRATION NUMBER: 20/HRA/2344.

Urban drinking water security in Gujarat.

Gujarat has made important strides to ensure that most parts of the state become water secure. In 2005, Gujarat was one of the few states that recognized that its urban areas were its 'engines of growth' and made significant investments in urban infrastructure. A state-wide water supply grid was constructed to transfer inter-basin water from perennial surface water sources to water-scarce areas. While these schemes have improved household-level access to municipal water supply, service levels have not improved. In this paper, we argue that along with infrastructure creation, there is a need to focus on monitoring, operation and maintenance of existing system and improving efficiency. We analyze information available from the performance assessment system (PAS) setup by the CEPT University for monitoring of urban services in India. It has annual information of water service delivery in all the urban areas of Gujarat from 2010. We assess urban drinking water supply on three key aspects: equity, service quality and financial sustainability. We also identify a few key intervention areas related to increased accountability, efficiency and equity in delivery of water supply services.

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.

Frontiers in the solution-phase chemistry of homoatomic group 15 Zintl clusters.

Although discovered more than a century ago, the study of Zintl anions is experiencing a renaissance. Initial investigations on Zintl anions were focused on the structure, bonding, and physical properties of both the solid-state Zintl phases and solution-state solvated salts. Advances over the last few decades included their reactivity with transition metals where both exo-coordination and encapsulation have been observed, organic derivatization, their oligomerisation chemistry, and the preparation of heteroatomic systems. Reports on these developments have been previously discussed and reviewed. Herein, we present the most recent developments in the solution-state chemistry of homoatomic group 15 Zintl clusters and an outlook for the field. We believe frontiers in this area are best represented by recent additions to the library of homoatomic polybismuthide clusters, new synthetic routes for the preparation and functionlisation of homoatomic group 15 clusters, and small molecule activation using group 15 homoatomic Zintl clusters.