Cefazolin has become a prominent therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, an important concern is the cefazolin inoculum effect (CzIE), a phenomenon mediated by staphylococcal β-lactamases. Four variants of staphylococcal β-lactamases have been described based on serological methodologies and limited sequence information. Here, we sought to reassess the classification of staphylococcal β-lactamases and their correlation with the CzIE. We included a large collection of 690 contemporary bloodstream MSSA isolates recovered from Latin America, a region with a high prevalence of the CzIE. We determined cefazolin MICs at standard and high inoculums by broth microdilution. Whole-genome sequencing was performed to classify the β-lactamase in each isolate based on the predicted full sequence of BlaZ. We used the classical schemes for β-lactamase classification and compared it to BlaZ allotypes found in unique sequences using the genomic information. Phylogenetic analyses were performed based on the BlaZ and core-genome sequences. The overall prevalence of the CzIE was 40%. Among 641 genomes, type C was the most predominant β-lactamase (37%), followed by type A (33%). We found 29 allotypes and 43 different substitutions in BlaZ. A single allotype, designated BlaZ-2, showed a robust and statistically significant association with the CzIE. Two other allotypes (BlaZ-3 and BlaZ-5) were associated with a lack of the CzIE. Three amino acid substitutions (A9V, E112A, and G145E) showed statistically significant association with the CzIE (P = <0.01). CC30 was the predominant clone among isolates displaying the CzIE. Thus, we provide a novel approach to the classification of the staphylococcal β-lactamases with the potential to more accurately identify MSSA strains exhibiting the CzIE.

Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98; P < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward P. vivax malaria elimination.

Ceftobiprole is an advanced-generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, as well as susceptible Gram-negative pathogens, including Pseudomonas sp. pathogens. In the case of Pseudomonas aeruginosa, ceftobiprole acts by inhibiting P. aeruginosa penicillin-binding protein 3 (PBP3). Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3-ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528 to L536 region adopts a conformation previously not observed in PBP3, including partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of β-lactam-PBP interactions that result in major changes in protein structure, as well as suggesting how to fine-tune current inhibitors and to develop novel inhibitors of this PBP.

Inflammasomes assemble in the cytosol of myeloid and epithelial cells on sensing of cellular stress and pathogen-associated molecular patterns and serve as scaffolds for recruitment and activation of inflammatory caspases. Inflammasomes play beneficial roles in host and immune responses against diverse pathogens but may also promote inflammatory tissue damage if uncontrolled. Gasdermin D (GSDMD) is a recently identified substrate of murine caspase-1 and caspase-11, and human caspases-1, -4, and -5 that mediates a regulated lytic cell death mode termed pyroptosis. Recent studies have identified pyroptosis as a critical inflammasome effector mechanism that controls inflammasome-dependent cytokine secretion and contributes to antimicrobial defense and inflammasome-mediated autoinflammatory diseases. Here, we review recent developments on inflammasome-associated effector functions with an emphasis on the emerging roles of gasdermin pores and pyroptosis.

BACKGROUND AND PURPOSE:

Brain metastases are a common finding on brain MRI. However, the factors that dictate their size and distribution are incompletely understood. Our aim was to discover a statistical model that can account for the size distribution of parenchymal metastases in the brain as measured on contrast-enhanced MR imaging.

NASA’s InSight lander has been on the surface of Mars for over a year now – here are five of its strangest and most fascinating discoveries from the Red Planet

Arsenal coach Mikel Arteta has delivered a detailed insight into the meticulous planning that goes into shaping his tactical vision for his side.

Barcelona striker Martin Braithwaite says the club's training plan represents only one third of his lockdown workout routine.

Signing off after 30 years at the ABC, award-winning reporter Margot O'Neill writes about the thrill of the big scoop and gives an insight into the grinding slog of investigative journalism.

The Duke and Duchess of Cambridge's children have been chatting to family members on...

Following meetings with then-Commissioner Scott Gottlieb and senior leadership from the Center for Drug Evaluation and Research on the role of CROs and technology companies in designing and implementing risk-based monitoring (RBM) of clinical trials, ACRO this week submitted extensive comments on recent FDA Guidance.Increasing the use of innovative RBM technologies helps make clinical trials safer, more efficient and higher quality. ACRO’s comments offer unique insights into the recent expansion of RBM implementation and call for further increasing the use of these oversight technologies.

DSM today published the first part of a new report in its Global Insight Series, focused on breakfast habits and behavior in Europe and the US.

Nenko, Yuliia and Кybalna, Nelia and Snisarenko, Yana The COVID-19 Distance Learning: Insight from Ukrainian students. Revista Brasileira de Educação do Campo, 2020, vol. 5, pp. 1-19. [Journal article (Paginated)]

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Mar 27, 2020

Columbia University Professor Scott Barrett assessed the massive global efforts underway to address COVID-19 and the potential impacts of the pandemic on our lives in the future in a special episode of “Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program,” a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Jan 8, 2020

Jos Delbeke, Professor at the European University Institute in Florence and at the KU Leuven in Belgium, recounted the history of carbon pricing and voiced his optimism for further international efforts to combat climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program."

Jan 8, 2020

Jos Delbeke, Professor at the European University Institute in Florence and at the KU Leuven in Belgium, recounted the evolution of carbon pricing and voiced his optimism for further international efforts to combat climate change in the newest episode of “Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program.”

Feb 7, 2020

David Keith, Gordon McKay Professor of Applied Physics at the Harvard John A. Paulson School of Engineering and Applied Sciences, and Professor of Public Policy at Harvard Kennedy School, discussed his groundbreaking research and policy work in the field of solar geoengineering in the newest episode of “Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program.” Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Mar 27, 2020

Columbia University Professor Scott Barrett assessed the massive global efforts underway to address COVID-19 and the potential impacts of the pandemic on our lives in the future in a special episode of “Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program,” a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Dec 3, 2019

For decades, Singapore has been a premier refinery hub and gatekeeper between Asia and the Middle East, but its position is increasingly threatened as producer countries are shifting into the downstream activities that helped make Singapore the “Houston of Asia”. Oil and petrochemicals drive about one quarter of Singapore’s net exports. Greater competition in the global oil and gas value chain could take a heavy toll on the city-state’s national budget and economic growth prospects.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.