Oxidative Transfer Reactions at a Metal-Metal Bond

Strained, three-membered rings were found to undergo oxidative addition to [iPrNDI]Ni2(C6H6) complex [NDI = napthyridine-diimine). Activation of the C-N bond of 1-tosyl-2-vinylaziridine generates a dinickel metallacyclic product. Based on this reactivity, the [iPrNDI]Ni2(C6H6) complex was shown to be a highly active catalyst for rearranging vinylcyclopropanes to cyclopentenes. Notably, 2-phenyl-1-vinylcyclopropane undergoes regioselective activation at the less hindered C–C bond in contrast to the non-catalytic thermal rearrangement. The dinuclear complex was also found to readily rearrange hetero-atom containing cyclopropanes to their linear products. DFT calculations provide insight into the ability of the Ni–Ni bond to stabilize key intermediates and transition states along the catalytic pathway. Hetero-atom abstraction was also observed in the activation of other strained, three-membered rings with the [iPrNDI]Ni2(C6H6) complex. Crystal structures were obtained from the activation of sulfur containing heterocycles and their characteristics are currently being investigated to design catalytic desulfurization reactions

Direct Molecular Detection and Genotyping of Borrelia burgdorferi from Whole Blood of Patients with Early Lyme Disease

Direct molecular tests in blood for early Lyme disease can be insensitive due to low amount of circulating Borrelia burgdorferi DNA. To address this challenge, we have developed a sensitive strategy to both detect and genotype B. burgdorferi directly from whole blood collected during the initial patient visit. This strategy improved sensitivity by employing 1.25 mL of whole blood, a novel pre-enrichment of the entire specimen extract for Borrelia DNA prior to a multi-locus PCR and electrospray ionization mass spectrometry detection assay. We evaluated the assay on blood collected at the initial presentation from 21 endemic area patients who had both physician-diagnosed erythema migrans (EM) and positive two-tiered serology either at the initial visit or at a follow-up visit after three weeks of antibiotic therapy. Results of this DNA analysis showed detection of B. burgdorferi in 13 of 21 patients (62%). In most cases the new assay also provided the B. burgdorferi genotype. The combined results of our direct detection assay with initial physician visit serology resulted in the detection of early Lyme disease in 19 of 21 (90%) of patients at the initial visit. In 5 of 21 cases we demonstrate the ability to detect B. burgdorferi in early Lyme disease directly from whole blood specimens prior to seroconversion

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

Oxidative Addition Reactions at a Metal-Metal Bond

Strained, three-membered rings were found to undergo oxidative addition to [iPrNDI]Ni2(C6H6) complex [NDI = napthyridine-diimine). Activation of the C-N bond of 1-tosyl-2-vinylaziridine generates a dinickel metallacyclic product. Based on this reactivity, the [iPrNDI]Ni2(C6H6) complex was shown to be a highly active catalyst for rearranging vinylcyclopropanes to cyclopentenes. Notably, 2-phenyl-1-vinylcyclopropane undergoes regioselective activation at the less hindered C–C bond in contrast to the non-catalytic thermal rearrangement. The dinuclear complex was also found to readily rearrange hetero-atom containing cyclopropanes to their linear products. DFT calculations provide insight into the ability of the Ni–Ni bond to stabilize key intermediates and transition states along the catalytic pathway. Hetero-atom abstraction was also observed in the activation of other strained, three-membered rings with the [iPrNDI]Ni2(C6H6) complex. Crystal structures were obtained from the activation of sulfur containing heterocycles and their characteristics are currently being investigated to design catalytic desulfurization reactions

Dinuclear Pathways for the Activation of Strained Three-Membered Rings

Dinuclear, strain-induced ring-opening reactions of vinylaziridines and vinylcyclopropanes are described. The previously reported [NDI]­Ni₂(C₆H₆) complex (NDI = naphthyridine–diimine) reacts with <i>N</i>-tosyl-2-vinylaziridine via C–N oxidative addition to generate a dinickel metallacyclic product. On the basis of this stoichiometric reactivity, the [NDI]­Ni₂(C₆H₆) complex is shown to be a highly active catalyst for the rearrangement of vinylcyclopropane to cyclopentene. Notably, 2-phenyl-1-vinylcyclopropane undergoes regioselective activation at the less hindered C–C bond in contrast to the noncatalytic thermal rearrangement. DFT calculations provide insight into the ability of the Ni–Ni bond to stabilize key intermediates and transition states along the catalytic pathway

Genotypic variation and mixtures of Lyme Borrelia in Ixodes ticks from North America and Europe.

Lyme disease, caused by various species of Borrelia, is transmitted by Ixodes ticks in North America and Europe. Studies have shown the genotype of Borrelia burgdorferi sensu stricto (s.s.) or the species of B. burgdorferi sensu lato (s.l.) affects the ability of the bacteria to cause local or disseminated infection in humans.We used a multilocus PCR electrospray mass spectrometry assay to determine the species and genotype Borrelia from ticks collected in New York, Connecticut, Indiana, Southern Germany, and California and characterized isolates from parts of the United States and Europe. These analyses identified 53 distinct genotypes of B. burgdorferi sensu stricto with higher resolution than ospC typing. Genotypes of other members of the B. burgdorferi sensu lato complex were also identified and genotyped including B. afzelii, B. garinii, B. lusitaniae, B. spielmanii, and B. valaisiana. While each site in North America had genotypes unique to that location, we found genotypes shared between individual regions and two genotypes found across the United States. Significant B. burgdorferi s.s. genotypic diversity was observed between North America and Europe: only 6.6% of US genotypes (3 of 45) were found in Europe and 27% of the European genotypes (3 of 11) were observed in the US. Interestingly, 39% of adult Ixodes scapularis ticks from North America were infected with more than one genotype of B. burgdorferi s.s. and 22.2% of Ixodes ricinus ticks from Germany were infected with more than one genotype of B. burgdorferi s.l.The presence of multiple Borrelia genotypes in ticks increases the probability that a person will be infected with more than one genotype of B. burgdorferi, potentially increasing the risks of disseminated Lyme disease. Our study indicates that the genotypic diversity of Borrelia in ticks in both North America and Europe is higher then previously reported and can have potential clinical consequences

Prevalence of Borrelia miyamotoi in Ixodes Ticks in Europe and the United States

Borrelia miyamotoi, a relapsing fever-related spirochete transmitted by Ixodes ticks, has been recently shown to be a human pathogen. To characterize the prevalence of this organism in questing Ixodes ticks, we tested 2,754 ticks for a variety of tickborne pathogens by PCR and electrospray-ionization mass spectrometry. Ticks were collected from California, New York, Connecticut, Pennsylvania, and Indiana in the United States and from Germany and the Czech Republic in Europe from 2008 through 2012. In addition, an isolate from Japan was characterized. We found 3 distinct genotypes, 1 for North America, 1 for Europe, and 1 for Japan. We found B. miyamotoi infection in ticks in 16 of the 26 sites surveyed, with infection prevalence as high as 15.4%. These results show the widespread distribution of the pathogen, indicating an exposure risk to humans in areas where Ixodes ticks reside