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Background PBPs are involved in the construction of peptidoglycan, which is the major constituent of bacterial cell walls and the target of β-lactam antibiotics. There is little published research analysing the relationship between β-lactams with differing bacterial PBP targets and how they can be manipulated in combinations with respect to clinical or microbiological (e.g. resistance) outcomes (i.e. does expanded PBP activity via a combination lead to better in vitro/in vivo outcomes). Objectives To systematically explore the relationship between double β-lactam therapy (with and without at least one partner being a β-lactamase inhibitor antibiotic such as co-amoxiclav) and in vitro activity against susceptible Escherichia coli strains. Methods We systematically explored the relationship between double β-lactam therapy combinations against seven E. coli strains of variable resistance in vitro. This included fully susceptible isolates, ESBL producers and carbapenemase producers (CPEs). For each of 10 antibiotics, the MIC was determined individually, and subsequently in combination with 9 further antibiotics, using the MTS™ ‘cross’ synergy method (Liofilchem, 2012). Results Overall, 86/630 (13.6%) of all combinations tested showed synergy and 408/630 (64.8%) were additive; 136/630 (21.6%) combinations showed indifference. Of the 86 ‘bug–drug’ combinations that showed synergy, 42/86 (49%) included ceftazidime/avibactam, representing 42/126 (33%) of all ceftazidime/avibactam-based combinations tested, and 56/86 (65%) of synergistic combinations covered PBP2. Synergy was most commonly detected in ESBL producers (58/86; 67% of combinations) and less frequently seen in CPEs (2/86; 2% of combinations) and fully susceptible isolates (8/86; 9% of combinations). Additive effects were seen in 92/180 (51%) combinations versus ESBLs, compared with 18/90 (20%) in CPEs, versus 154/180 (86%) in fully susceptible isolates. No antagonism was identified with any antibiotic combination. Conclusions In the combinations tested, synergy or additive effects were common (78%); similar to our previous work with fosfomycin/β-lactam combinations (89%), but higher than we found with fosfomycin/non-β-lactam combinations (28%). Many of the synergistic bug–drug combinations identified contained a β-lactam inhibitor as a partner and/or provided PBP2 activity. This provisionally suggests a role for PBP2 (also targeted by avibactam) in synergy, although the presence of a β-lactamase inhibitor may also be important. Confirmation using an alternative method and mechanistic elucidation is required. The clinical/microbiological importance of such effects remains unclear.

This study investigated concurrent talar dome injuries associated with tibial pilon fractures, mapping their distribution across the proximal talar dome articular surface. It compared the two main mechanisms of injury (MOI), falling from a height and motor vehicle accident (MVA), and whether the fractures were open or closed.From a previously compiled database of acute distal tibial pilon fractures (AO/OTA 43B/C) in adults of 105 cases, 53 cases were identified with a concurrent injury to the talar dome with a known mechanism of injury and in 44 it was known if the fracture was open or closed. Case specific 2D injury maps were created using a 1×1mm grid, which were overlayed in an Excel document to allow for comparative analyses. A two-way ANOVA was conducted that examined the effect of both MOI and if the fracture was open or closed on what percentage of the talar dome surface was injured.There was a statistically-significant difference between the average percentage of injured squares on the talar dome by both whether the fracture was open or closed (f(1)=5.27, p= .027) and the mechanism of injury (f(1)=8.08, p= .007), though the interaction between these was not significant (p= .156). Open injuries and injuries that occurred during an MVA were more likely to increase the surface area of the talar dome injuries.We have identified both MOI and if the fracture was either open or closed impacts the size of the injury present on the talar dome. Future research will investigate the aetiology of the differences noted, highlighting the clinical implications.Surgeons treating tibial pilon fractures caused by either a MVA or an open fracture, should be aware of an increased risk of large injuries to the surface of the talar dome.

Tibial pilon fractures are typically the result of high-energy axial loads, with complex intra- articular fractures that are often difficult to reconstruct anatomically. Only nine simultaneous pilon and talus fractures have been published previously, but we hypothesised the chondral surface of the dome is affected more frequently.Data was acquired prospectively from 154 acute distal tibial pilon fractures (AO/OTA 43B/C) in adults. Radiographs, photographs, and intra-operative drawings of each case were utilised to document the presence of any macroscopic injuries of the talus. Detailed 1x1mm maps were created of the injuries in each case and transposed onto a statistical shape model of a talus; this enables the cumulative data to be analysed in Excel. Data was analysed using a Chi-squared test.From 154 cases, 104 were considered at risk and their talar domes were inspected; of these, macroscopic injuries were identified in 55 (52.4%). The prevalence of talar dome injury was greater with B-type fractures (53.5%) than C-type fractures (31.5%) (ρ = .01). Injuries were more common in men than women and presented with different distribution of injuries (ρ = .032). A significant difference in the distribution of injuries was also identified when comparing falls and motor vehicle accidents (ρ = .007).Concomitant injuries to the articular surface of the dome of the talus are relatively common, and this perhaps explains the discordance between the post-operative appearance following internal fixation and the clinical outcomes observed. These injuries were focused on the lateral third of the dome in men and MVAs, whereas women and fall mechanism were more evenly distributed.Surgeons who operatively manage high-energy pilon fractures should consider routine inspection of the talar dome to assess the possibility of associated macroscopic osteochondral injuries.

Polygonal impact craters (PICs) are supposed to form as a result of impacts into structure systems within the target. The structure systems are an umbrella term which encompass faults, joints, fractures, lithographic boundaries, and other planes of weakness. These impact craters are defined as having at least two linear rim segments with a recognizable angle between the segments. PICs have been reported on both rocky and icy bodies including Ceres. Using a near-global Cerean crater database, PICs were categorized into four different categories: (1) polygonal craters not related to visible structure systems (PICNVS), (2) polygonal craters related to visible structure systems outside of the crater (PICVSO), (3) polygonal craters related to visible structure systems inside of the crater (PICVSI), and (4) polygonal craters related to visible structure systems inside and outside of the crater (PICVSIO). Measurements of the number of linear rim segments, the angle between linear rim segments, mean angle between linear rim segments for the crater, length of linear rim segments, and the mean length of the linear rim segments for the crater were reported for each category. Additionally, the angle between nearby structure systems and the linear rim segments are determined, along with the crater's cardinal direction with relation to the structure system. The most frequent type of PIC is those not related to structure systems. Hexagonal craters are the most prominent polygon shape observed, which is consistent with the observed shape of PICs throughout the solar system. The visible structure systems which displayed the highest number of PICs related to them were the Junina and Samhain Catenae. The average angle between linear rim segments for PICs on Ceres is 121.99° ± 0.25° which is similar to the average angle between linear rim segments reported for PICs on Rhea and Dione. Polygonal craters are found in different degradation states, indicating structure systems have influenced the formation of PICs throughout much of Ceres' history. The observation of greater concentrations of PICs in the northern hemisphere may indicate target strength differences and support the idea of crustal heterogeneity across Ceres; however, the lack of PICs in the southern hemisphere may be due to the younger and larger impact basins (Urvara and Yalode) erasing these craters creating an observational bias.

We report on the first results of a large-scale comparison study of central pit craters throughout the solar system, focused on Mars, Mercury, Ganymede, Rhea, Dione, and Tethys. We have identified 10 more central pit craters on Rhea, Dione, and Tethys than have previously been reported. We see a general trend that the median ratio of the pit to crater diameter (Dp/Dc) decreases with increasing gravity and decreasing volatile content of the crust. Floor pits are more common on volatile-rich bodies while summit pits become more common as crustal volatile content decreases. Uplifted bedrock from below the crater floor occurs in the central peak upon which summit pits are found and in rims around floor pits, which may or may not break the surface. Peaks on which summit pits are found on Mars and Mercury share similar characteristics to those of nonpitted central peaks, indicating that some normal central peaks undergo an additional process to create summit pits. Martian floor pits do not appear to be the result of a central peak collapse as the median ratio of the peak to crater diameter (Dpk/Dc) is about twice as high for central peaks/summit pits than Dp/Dc values for floor pits. Median Dpk/Dc is twice as high for Mars as for Mercury, reflecting differing crustal strength between the two bodies. Results indicate that a complicated interplay of crustal volatiles, target strength, surface gravity, and impactor energy along with both uplift and collapse are involved in central pit formation. Multiple formation models may be required to explain the range of central pits seen throughout the solar system.

BackgroundGenetic studies have strongly linked autophagy to Crohn’s disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process.MethodsAutophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by polymerase chain reaction (PCR) array with changes in signaling pathways examined by immunoblot and quantitative reverse transcription PCR (RT-qPCR). Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) were evaluated by gentamicin protection assays and RT-qPCR, respectively. The marker LC3 was analyzed in peripheral blood mononuclear cells (PBMCs) from pediatric patients by flow cytometry.ResultsAzathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNFα. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy.ConclusionsModulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic efficacy of azathioprine in IBD.

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed. Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved

Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.

Impact crater databases are one of the first data products produced from images acquired by planetary spacecraft missions and are used in a variety of studies investigating the formation ages and geologic histories of surface units. Martian crater databases have been compiled since the first global images of the planet were acquired by the Mariner 9 mission and today include a variety of morphologic and morphometric data about each crater. Three of the most widely used Martian crater databases are described in this contribution.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. The etiology involves a combination of genetic and environmental factors resulting in abnormal immune responses to intestinal microbiota. Genetic studies have strongly linked genes involved in autophagy to CD, and genes involved in the unfolded protein response (UPR) to IBD. The UPR is triggered in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), and autophagy plays a key role in relieving ER stress and restoring homeostasis. This review summarizes the known interactions between autophagy and the UPR and discusses the impact of these converging pathways on IBD pathogenesis. With a paucity of effective long-term treatments for IBD, targeting of synergistic pathways may provide novel and more effective therapeutic options.

The Martian obliquity cycle is predominately influenced by Solar and Jovian tidal forces. The present-day axial tilt of Mars (25 degrees) is predicted to cycle between 0 degrees and 60 degrees (Mischna & Richardson 2005) with excursions up to 80 degrees(Laskar et al. 2004). We focused on Arabia Terra, a region especially well-suited for studying glacial migration due to its location in the northern mid-latitude (20-40 degrees North, 0-30 degrees East) zone, and its heavily cratered terrain. We created glacial and fluvial morphology distribution maps with the ESRI Aeronautical Reconnaissance Coverage Geographic Information System (ArcGIS). We determined the ages of our craters in order to establish a time-domain link between the Martian obliquity cycle and glacial migration; we found the average crater age to be roughly 2 billion years old.

The Society of Toxicologic Pathology formed a working group in collaboration with the American Society for Veterinary Clinical Pathology to provide recommendations for the appropriate inclusion of clinical pathology evaluation in recovery arms of nonclinical toxicity studies but not on when to perform recovery studies. Evaluation of the recovery of clinical pathology findings is not required routinely but provides useful information on risk assessment in nonclinical toxicity studies and is recommended when the ability of the organ to recover is uncertain. The study design generally requires inclusion of concurrent controls to separate procedure-related changes from test article–related changes, but return of clinical pathology values toward baseline may be sufficient in some cases. Evaluation of either a select or full panel of standard hematology, coagulation, and serum and urine chemistry biomarkers can be scientifically justified. It is also acceptable to redesignate dosing phase animals to the recovery phase or vice versa to optimize data interpretation. Assessment of delayed toxicity during the recovery phase is not required but may be appropriate in development programs with unique concerns. Evaluation of the recovery of clinical pathology data for vaccine development is required and, for efficacy markers, is recommended if it furthers pharmacologic understanding.

Osteomyelitis of the hand is uncommon, but if not adequately and promptly treated the detrimental effects on hand function can be devastating. The majority of literature on osteomyelitis relates to the lower limb, but the principles of management are applicable to the hand, with good surgical debridement and culture-guided antimicrobial therapy. For osteomyelitis in general, antibiotic therapy of 4–6 weeks’ duration (intravenous and/or oral) is typically recommended. In the hand, length and mode of antibiotic administration are still under study. Level of Evidence: V

Impact cratering is the one geologic process which is common to all solar system objects. Impact craters form by the resulting explosion between a solar system body and hypervelocity objects. Comparison with craters formed by chemical and nuclear explosions reveals that crater diameter is related to other morphometric characteristics of the crater, such as depth and rim height. These relationships allow scientists to use impact craters to probe the subsurface structure within the upper few kilometer of a planetary surface and to estimate the amounts and types of degradational processes which have affected the planet since crater formation. Crater size–frequency distribution analysis provides the primary mechanism for determining ages of planetary terrains and constraining the timing of resurfacing episodes. Thus, impact craters provide many important insights into the evolution of planetary surfaces.

Human rhinoviruses are the primary etiological agent of the common cold. This infection can be mild and self-limiting in immunocompetent hosts, but can be associated with bronchiolitis in infants, pneumonia in the immunosuppressed and exacerbations of pre-existing pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Many of these conditions can place significant economic costs upon healthcare infrastructure. There is currently no licensed vaccine for rhinovirus, as the large variety of rhinovirus serotypes has posed significant challenges for research. In this review, we discuss current knowledge around antiviral drugs and small molecule inhibitors of rhinovirus infection, as well as antiviral host defense peptides as exciting prospects to approach the development of novel therapeutics which target human rhinovirus.

Low-aspect ratio layered ejecta (LARLE) craters are one of the most enigmatic types of martian layered ejecta craters. We propose that the extensive outer layer of these craters is produced through the same base surge mechanism as that which produced the base surge deposits generated by near-surface, buried nuclear and high-explosive detonations. However, the LARLE layers have higher aspect ratios compared with base surge deposits from explosion craters, a result of differences in thicknesses of these layers. This characteristics is probably caused by the addition of large amounts of small particles of dust and ice derived from climate-related mantles of snow, ice and dust in the areas where LARLE craters form. These deposits are likely to be quickly stabilized (order of a few days to a few years) from eolian erosion by formation of duricrust produced by diffusion of water vapor out of the deposits.

Highlights • The host defence peptide LL-37 can reduce Human Rhinovirus 1B (HRV1B) replication in airway epithelial cells. • The antiviral activity of LL-37 is sequence specific. • LL-37 reduces the metabolic activity of cells infected with HRV1B without inducing substantial apoptotic or necrotic cell death. • The antiviral activity of cathelicidin peptides towards HRV1B is conserved in peptides from other mammalian species including pig and sheep., Human rhinoviruses (HRVs) are the most common cause of viral respiratory tract infections, and are associated with significant morbidity and mortality in immunocompromised individuals and patients with pre-existing pulmonary conditions. The therapeutic options available are extremely limited and therefore novel therapeutics for HRV infections are of significant interest. Cathelicidins have been shown to have potent antiviral activity against a range of pathogens and are known to be key immunomodulatory mediators during infection. We therefore assessed the antiviral potential of cathelicidins from humans and other mammalian species against HRV, together with the potential for the human cathelicidin to modulate apoptotic pathways and alter cell viability during HRV infection. We demonstrate that LL-37, the porcine cathelicidin Protegrin-1, and the ovine cathelicidin SMAP-29 display potent antiviral activity towards HRV and that this activity is visible when either the virus is exposed to the peptides prior to cell infection or after cells have been infected. We further demonstrate that, in contrast to established findings with bacterial infection models, LL-37 does not induce apoptosis or necrosis in HRV-infected lung epithelial cells at physiological or superphysiological concentrations, but does reduce the metabolic activity of infected cells compared to uninfected cells treated with similar peptide concentrations. Collectively, the findings from this study demonstrate that the mechanism of action of cathelicidins against rhinovirus is by directly affecting the virus and we propose that the delivery of exogenous cathelicidins, or novel synthetic analogues, represent an exciting and novel therapeutic strategy for rhinovirus infection.