An Analysis of Infectious Failures in Acute Cholangitis

To determine the factors responsible for therapeutic failures in acute cholangitis, a series of 127 patients was analyzed. There were 64 females and 63 males whose mean age was 57.2 years. Ninetyfour (74.0%) of these patients were clinically cured with initial measures, whereas 33 patients (26%) failed initial therapy for an infectious reason. No differences were observed between the two groups in regard to age and gender. However, more patients in the group that failed had a malignant cause for their bile duct obstruction (72.7% vs. 42.6%, p < 0.01) and had a pretreatment positive blood culture (45.5% vs. 13.8%, p < 0.01). Patients who failed had a higher mean total bilirubin level (9.7 mg/dl vs. 5.5 mg/dl, p < 0.005) and more of them had a level greater than 2.2 mg/dl (97% vs. 69.9%, p < 0.001). Also, more bile cultures were initially positive (93.9% vs. 76.6%, p < 0.05) and more organisms were isolated per culture (3.88 vs. 2.86, p < 0.03) in the patients who failed. In addition, more patients failed who had two or more organisms in the bile (33% vs. 8.3%, p < 0.02). Patients in whom Candida, or any panresistant organism was isolated also tended to fail. Multivariant analysis showed that malignancy, bacteremia, bilirubin ≥ 2.2 mg/dl, ≥ 2 organisms in the bile and a panresistant organism were the best predictors of treatment failure with a serum bilirubin level ≥ 2.2 mg/dl being the variable that increases a patient's log-odds ratio of failure the greatest. In conclusion, patients with acute cholangitis who have an increased chance to fail initial therapy can be identified, and treatment altered accordingly

Anatomy and phylogenetic relationships of Temnodontosaurus zetlandicus (Reptilia: Ichthyosauria)

peer reviewedParvipelvia is a major clade of ichthyosaurians that diversified during the Triassic-Jurassic transition. The interrelationships of early parvipelvians remain unclear and many genera are loosely diagnosed, such as Temnodontosaurus, an ecologically important genus from the Early Jurassic of Western Europe. One taxon concentrates many taxonomic issues: ‘Ichthyosaurus’ acutirostris was previously assigned to Temnodontosaurus and for which ‘Ichthyosaurus’ zetlandicus represents a junior synonym. We redescribe the holotype of ‘Ichthyosaurus’ zetlandicus (CAMSM J35176) and a new specimen probably attributable to this taxon (MNHNL TU885) from the Toarcian of Luxembourg. We find that Temnodontosaurus zetlandicus comb. nov. is a valid species that should be referred to the genus Temnodontosaurus, sharing a number of traits with Temnodontosaurus nuertingensis and Temnodontosaurus trigonodon, despite having a distinct cranial architecture. Our phylogenetic analyses under both implied weighting maximum parsimony and Bayesian inference recover T. zetlandicus as closely related to several species currently assigned to Temnodontosaurus. Species included in Temnodontosaurus form a polyphyletic yet well-clustered group among basal neoichthyosaurians, demonstrating that the monophyly of this genus needs to be thoroughly investigated

Two-axis accelerometer based on multicore fibre Bragg gratings

We report an accelerometer based upon a simple fibre cantilever constructed from a short length of multicore fibre(MCF) containing fibre Bragg gratings (FBGs). Two-axis measurement is demonstrated up to 3 kHz

Dynamic two-axis curvature measurement using multicore fiber Bragg gratings interrogated by arrayed waveguide gratings

We describe the use of arrayed waveguide gratings (AWGs) in the interrogation of fiber Bragg gratings (FBGs) for dynamic strain measurement. The ratiometric AWG output was calibrated in a static deflection experiment over a ±200 με range. Dynamic strain measurement was demonstrated with a FBG in a conventional single-mode fiber mounted on the surface of a vibrating cantilever and on a piezoelectric actuator, giving a resolution of 0.5 με at 2.4 kHz. We present results of this technique extended to measure the dynamic differential strain between two FBG pairs within a multicore fiber. An arbitrary cantilever oscillation of the multicore fiber was determined from curvature measurements in two orthogonal axes at 1125 Hz with a resolution of 0.05 m-1. © 2006 Optical Society of America

Assessing the influence of watershed characteristics on chlorophyll a in water bodies at global and regional scales

Prediction of primary production of lentic water bodies (i.e., lakes and reservoirs) is valuable to researchers and resource managers alike, but is very rarely done at the global scale.&nbsp; With the development of remote sensing technologies, it is now feasible to gather large amounts of data across the world, including understudied and remote regions. To determine which factors were most important in explaining the variation of chlorophyll a (Chl-a), an indicator of primary production in water bodies, at global and regional scales, we first developed a geospatial database of 227 water bodies and watersheds with corresponding Chl-a,&nbsp;nutrient, hydrogeomorphic, and climate data. Then we used a generalized additive modeling approach and developed model selection criteria to select models that most parsimoniously related Chl-a to predictor variables for all 227 water bodies and for 51 lakes in the Laurentian Great Lakes region in the data set. Our best global model contained two hydrogeomorphic variables (water body surface area and the ratio of watershed to water body surface area) and a climate variable (average temperature in the warmest model selection criteria to select models that most parsimoniously related Chl-a to predictor variables quarter) and explained ~ 30% of variation in Chl-a.&nbsp;Our regional model contained one hydrogeomorphic variable (flow accumulation) and the same climate variable, but explained substantially more variation (58%). Our results indicate that a regional approach to watershed modeling may be more informative to predicting Chl-a,&nbsp;and that nearly a third of global variability in Chl-a may be explained using hydrogeomorphic and climate variables

Lateral opening in the intact β-barrel assembly machinery captured by cryo-EM

The β-barrel assembly machinery (BAM) is a ~203 kDa complex of five proteins (BamA-E) which is essential for viability in E. coli. BAM promotes the folding and insertion of β-barrel proteins into the outer membrane via a poorly understood mechanism. Several current models suggest that BAM functions through a ‘lateral gating’ motion of the β-barrel of BamA. Here we present a cryo-EM structure of the BamABCDE complex, at 4.9 Å resolution. The structure is in a laterally open conformation showing that gating is independent of BamB binding. We describe conformational changes throughout the complex, and interactions between BamA, B, D, and E and the detergent micelle that suggest communication between BAM and the lipid bilayer. Finally, using an enhanced reconstitution protocol and functional assays, we show that for the outer membrane protein OmpT, efficient folding in vitro requires lateral gating in BAM

Outer membrane protein folding from an energy landscape perspective

The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. How OMPs fold into this crowded environment remains an open question. Here, we review current knowledge about OFMP folding mechanisms in vitro and discuss how the need to fold to a stable native state has shaped their folding energy landscapes. We also highlight the role of chaperones and the β-barrel assembly machinery (BAM) in assisting OMP folding in vivo and discuss proposed mechanisms by which this fascinating machinery may catalyse OMP folding

Effects of Periplasmic Chaperones and Membrane Thickness on BamA-Catalyzed Outer-Membrane Protein Folding

The biogenesis of outer-membrane proteins (OMPs) in gram-negative bacteria involves delivery by periplasmic chaperones to the β-barrel assembly machinery (BAM), which catalyzes OMP insertion into the outer membrane. Here, we examine the effects of membrane thickness, the Escherichia coli periplasmic chaperones Skp and SurA, and BamA, the central subunit of the BAM complex, on the folding kinetics of a model OMP (tOmpA) using fluorescence spectroscopy, native mass spectrometry, and molecular dynamics simulations. We show that prefolded BamA promotes the release of tOmpA from Skp despite the nM affinity of the Skp:tOmpA complex. This activity is located in the BamA β-barrel domain, but is greater when full-length BamA is present, indicating that both the β-barrel and polypeptide transport-associated (POTRA) domains are required for maximal activity. By contrast, SurA is unable to release tOmpA from Skp, providing direct evidence against a sequential chaperone model. By varying lipid acyl chain length in synthetic liposomes we show that BamA has a greater catalytic effect on tOmpA folding in thicker bilayers, suggesting that BAM catalysis involves lowering of the kinetic barrier imposed by the hydrophobic thickness of the membrane. Consistent with this, molecular dynamics simulations reveal that increases in membrane thinning/disorder by the transmembrane domain of BamA is greatest in thicker bilayers. Finally, we demonstrate that cross-linking of the BamA barrel does not affect tOmpA folding kinetics in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes, suggesting that lateral gating of the BamA barrel and/or hybrid barrel formation is not required, at least for the assembly of a small 8-stranded OMP in vitro

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population