In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This ...meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings.
Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects.
We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 9% deaths in 3336 procalcitonin-guided patients vs 336 10% in 3372 controls; adjusted odds ratio OR 0·83 95% CI 0·70 to 0·99, p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days 95% CI −2·71 to −2·15, p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 95% CI 0·57 to 0·82, p<0·0001).
Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance.
National Institute for Health Research.
Many astrophysical events, such as novae and X-ray bursts, are powered by reactions with radioactive nuclei. Studying the properties of these nuclei in the laboratory can therefore further our ...understanding of these astrophysical explosions. The TwinSol separator at the University of Notre Dame has recently been used to produce intense (∼106 pps) beams of 17F. In this article, some of the first measurements with these beams are discussed.
Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker ...for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship.
The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017.
We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment.
Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis.
From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results.
This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.
The general transcription factor TFIID is a multiprotein complex containing the TATA-binding protein and several associated factors (TAFs), some of which may function as coactivators that are ...essential for activated, but not basal, transcription. Here we describe the isolation and characterization of the first gene encoding a TAF protein. The deduced amino acid sequence of TAF110 revealed the presence of several glutamine- and serine/threonine-rich regions reminiscent of the protein-protein interaction domains of the regulatory transcription factor Sp1 that are involved in transcription activation and multimerization. In both Drosophila cells and yeast, TAF110 specifically interacts with the glutamine-rich activation domains of Sp1. Moreover, purified Sp1 selectively binds recombinant TAF110 in vitro. These findings taken together suggest that TAF110 may function as a coactivator by serving as a site of protein-protein contact between activators like Sp1 and the TFIID complex.
Background
Symptomatic prolonged sinus pauses on termination of atrial fibrillation (AF) are an accepted indication for pacemaker implantation. We evaluated the outcome of AF ablation in patients ...with paroxysmal AF‐related tachycardia‐bradycardia syndrome and compared the efficacy of catheter ablation with permanent pacing plus antiarrhythmic drugs (AADs).
Methods and Results
Patients with prolonged symptomatic sinus pauses on termination of AF were retrospectively analyzed. Forty‐three consecutive patients who underwent catheter ablation (ABL group) were compared to 57 patients who underwent permanent pacing plus AADs (PM group). All 43 patients in the ABL group fulfilled Class I indication for pacemaker implantation at baseline but they actually underwent AF ablation. Reevaluation after 20.1 ± 9.6 months of follow‐up showed that 41 patients (95.3%) did no longer need a pacemaker (Class III indication). Total cardiac‐related rehospitalization was not significantly different between the two groups (P = 0.921). Tachycardia‐related hospitalization was significantly higher in the PM group than the ABL group (14.0% and 0%, P = 0.029). More patients in the PM group were on AADs (PM 40.4%, ABL 4.7%, P < 0.001) while sinus rhythm maintenance was remarkably higher in the ABL group at the end of follow‐up (83.7% vs 21.1% in PM group, P < 0.001).
Conclusions
In patients with paroxysmal AF‐related tachycardia‐bradycardia syndrome, AF ablation seems to be superior to a strategy of pacing plus AAD. Pacemaker implantation can be waived in the majority of patients after a successful ablation.
Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available ...from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics.
A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions.
A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4–12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively.
Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
•The efficacy of immunotherapy for melanoma in-transit metastases is unknown.•An international multicenter retrospective cohort study.•Systemic immunotherapy is an effective treatment for melanoma in-transit metastases.
We study of the role of galaxy-galaxy interactions and disk instabilities in producing starburst activity in galaxies out to z=4. For this, we use a sample of 387 galaxies with robust total star ...formation rate measurements from Herschel, gas masses from ALMA, stellar masses and redshifts from multi-band photometry, and JWST/NIRCam rest-frame optical imaging. Using mass-controlled samples, we find an increased fraction of interacting galaxies in the starburst regime at all redshifts out to z=4. This increase correlates with star formation efficiency (SFE), but not with gas fraction. However, the correlation is weak (and only significant out to z=2), which could be explained by the short duration of SFE increase during interaction. In addition, we find that isolated disk galaxies make up a significant fraction of the starburst population. The fraction of such galaxies with star-forming clumps ("clumpy disks") is significantly increased compared to the main-sequence disk population. Furthermore, this fraction directly correlates with SFE. This is direct observational evidence for a long-term increase of SFE maintained due to disk instabilities, contributing to the majority of starburst galaxies in our sample and hence to substantial mass growth in these systems. This result could also be of importance for explaining the growth of the most massive galaxies at z>6.
The high degree of microbial diversity found in soils is attributed to the highly heterogeneous pore space and the dynamic aqueous microenvironments. Previous studies have shown that spatial and ...temporal variations in aqueous diffusion pathways play an important role in shaping microbial habitats and biological activity in unsaturated porous media. A new modeling framework was developed for the quantitative description of diffusion-dominated microbial interactions focusing on competitive growth of two microbial species inhabiting partially saturated rough surfaces. Surface heterogeneity was represented by patches with different porosities and water retention properties, yielding heterogeneous distribution of water contents that varies with changes in relative humidity or soil matric potential. Nutrient diffusion and microbial growth on the variably hydrated and heterogeneous surface was modeled using a hybrid method that combines a reaction diffusion method for nutrient field with individual based model for microbial growth and expansion. The model elucidated the effects of hydration dynamics and heterogeneity on nutrient fluxes and mobility affecting microbial population growth, expansion, and coexistence at the microscale. In contrast with single species dominance under wet conditions, results demonstrated prolonged coexistence of two competing species under drier conditions where nutrient diffusion and microbial movement were both limited. The uneven distribution of resources and diffusion pathways in heterogeneous surfaces highlighted the importance of position in the landscape for survival that may compensate for competitive disadvantages conferred by physiological traits. Increased motility was beneficial for expansion and survival. Temporal variations in hydration conditions resulted in fluctuations in microbial growth rate and population size. Population growth dynamics of the dominant species under wet-dry cycles were similar to growth under average value of diffusion coefficients for dry and wet conditions, respectively, suggesting that the time-averaged diffusion coefficient could serve as a useful indicator for estimation of microbial activities in a highly dynamic system such as that found in soils.
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