Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Conceptualizing handover strategies at change of shift in the emergency department: a grounded theory study

<p>Abstract</p> <p>Background</p> <p>The importance and complexity of handovers is well-established. Progress for intervening in the emergency department change of shift handovers may be hampered by lack of a conceptual framework. The objectives were to gain a better understanding of strategies used for change of shift handovers in an emergency care setting and to further expand current understanding and conceptualizations.</p> <p>Methods</p> <p>Observations, open-ended questions and interviews about handover strategies were collected at a Veteran's Health Administration Medical Center in the United States. All relevant staff in the emergency department was observed; 31 completed open-ended surveys; 10 completed in-depth interviews. The main variables of interest were strategies used for handovers at change of shift and obstacles to smooth handovers.</p> <p>Results</p> <p>Of 21 previously identified strategies, 8 were used consistently, 4 were never used, and 9 were used occasionally. Our data support ten additional strategies. Four agent types and 6 phases of the process were identified via grounded theory analysis. Six general themes or clusters emerged covering factors that intersect to define the degree of handover smoothness.</p> <p>Conclusion</p> <p>Including phases and agents in conceptualizations of handovers can help target interventions to improve patient safety. The conceptual model also clarifies unique handover considerations for the emergency department setting.</p

On the dynamics emerging from pandemics and infodemics

This position paper discusses emerging behavioral, social, and economic dynamics related to the COVID-19 pandemic and puts particular emphasis on two emerging issues: First, delayed effects (or second strikes) of pandemics caused by dread risk effects are discussed whereby two factors which might influence the existence of such effects are identified, namely the accessibility of (mis-)information and the effects of policy decisions on adaptive behavior. Second, the issue of individual preparedness to hazardous events is discussed. As events such as the COVID-19 pandemic unfolds complex behavioral patterns which are hard to predict, sophisticated models which account for behavioral, social, and economic dynamics are required to assess the effectivity and efficiency of decision-making.Comment: 7 pages. Mind & Society (2020

Traumatic physical health consequences of intimate partner violence against women: what is the role of community-level factors?

<p>Abstract</p> <p>Background</p> <p>Intimate partner violence (IPV) against women is a serious public health issue with recognizable direct health consequences. This study assessed the association between IPV and traumatic physical health consequences on women in Nigeria, given that communities exert significant influence on the individuals that are embedded within them, with the nature of influence varying between communities.</p> <p>Methods</p> <p>Cross-sectional nationally-representative data of women aged 15 - 49 years in the 2008 Nigeria Demographic and Health Survey was used in this study. Multilevel logistic regression analysis was used to assess the association between IPV and several forms of physical health consequences.</p> <p>Results</p> <p>Bruises were the most common form of traumatic physical health consequences. In the adjusted models, the likelihood of sustaining bruises (OR = 1.91, 95% CI = 1.05 - 3.46), wounds (OR = 2.54, 95% CI = 1.31 - 4.95), and severe burns (OR = 3.20, 95% CI = 1.63 - 6.28) was significantly higher for women exposed to IPV compared to those not exposed to IPV. However, after adjusting for individual- and community-level factors, women with husbands/partners with controlling behavior, those with primary or no education, and those resident in communities with high tolerance for wife beating had a higher likelihood of experiencing IPV, whilst mean community-level education and women 24 years or younger were at lower likelihood of experiencing IPV.</p> <p>Conclusions</p> <p>Evidence from this study shows that exposure to IPV is associated with increased likelihood of traumatic physical consequences for women in Nigeria. Education and justification of wife beating were significant community-level factors associated with traumatic physical consequences, suggesting the importance of increasing women's levels of education and changing community norms that justify controlling behavior and IPV.</p

Dengue Virus Infection Perturbs Lipid Homeostasis in Infected Mosquito Cells

Dengue virus causes ∼50–100 million infections per year and thus is considered one of the most aggressive arthropod-borne human pathogen worldwide. During its replication, dengue virus induces dramatic alterations in the intracellular membranes of infected cells. This phenomenon is observed both in human and vector-derived cells. Using high-resolution mass spectrometry of mosquito cells, we show that this membrane remodeling is directly linked to a unique lipid repertoire induced by dengue virus infection. Specifically, 15% of the metabolites detected were significantly different between DENV infected and uninfected cells while 85% of the metabolites detected were significantly different in isolated replication complex membranes. Furthermore, we demonstrate that intracellular lipid redistribution induced by the inhibition of fatty acid synthase, the rate-limiting enzyme in lipid biosynthesis, is sufficient for cell survival but is inhibitory to dengue virus replication. Lipids that have the capacity to destabilize and change the curvature of membranes as well as lipids that change the permeability of membranes are enriched in dengue virus infected cells. Several sphingolipids and other bioactive signaling molecules that are involved in controlling membrane fusion, fission, and trafficking as well as molecules that influence cytoskeletal reorganization are also up regulated during dengue infection. These observations shed light on the emerging role of lipids in shaping the membrane and protein environments during viral infections and suggest membrane-organizing principles that may influence virus-induced intracellular membrane architecture

Effect of exploitation and exploration on the innovative as outcomes in entrepreneurial firms

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Transition from high- to low-NOx control of night-time oxidation in the southeastern US

The influence of nitrogen oxides (NOx) on daytime atmospheric oxidation cycles is well known, with clearly defined high- and low-NOx regimes. During the day, oxidation reactions—which contribute to the formation of secondary pollutants such as ozone—are proportional to NOx at low levels, and inversely proportional to NOx at high levels. Night-time oxidation of volatile organic compounds also influences secondary pollutants but lacks a similar clear definition of high- and low-NOx regimes, even though such regimes exist. Decreases in anthropogenic NOx emissions in the US and Europe coincided with increases in Asia over the last 10 to 20 years, and have altered both daytime and nocturnal oxidation cycles. Here we present measurements of chemical species in the lower atmosphere from day- and night-time research flights over the southeast US in 1999 and 2013, supplemented by atmospheric chemistry simulations. We find that night-time oxidation of biogenic volatile organic compounds (BVOC) is NOx-limited when the ratio of NOx to BVOC is below approximately 0.5, and becomes independent of NOx at higher ratios. The night-time ratio of NOx to BVOC in 2013 averaged 0.6 aloft. We suggest that night-time oxidation in the southeast US is in transition between NOx-dominated and ozone-dominated

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca