Glucocorticoid with cyclophosphamide for paraquat-induced lung fibrosis.

Paraquat is an effective and widely used herbicide but is also a lethal poison. In many developing countries paraquat is widely available and inexpensive, making poisoning prevention difficult. However most of the people who become poisoned from paraquat have taken it as a means of suicide.Standard treatment for paraquat poisoning both prevents further absorption and reduces the load of paraquat in the blood through haemoperfusion or haemodialysis. The effectiveness of standard treatments is extremely limited.The immune system plays an important role in exacerbating paraquat-induced lung fibrosis. Immunosuppressive treatment using glucocorticoid and cyclophosphamide in combination is being developed and studied. To assess the effects of glucocorticoid with cyclophosphamide on mortality in patients with paraquat-induced lung fibrosis. The most recent search was run on the 15th April 2014. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (Ovid), ISI WOS (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), trials registries, Chinese databases (, , ) and reference lists. RCTs were included in this review. All patients were to receive standard care, plus the intervention or control. The intervention was glucocorticoid with cyclophosphamide in combination versus a control of a placebo, standard care alone or any other therapy in addition to standard care. The mortality risk ratio (RR) and 95% confidence interval (CI) was calculated for each study on an intention-to-treat basis. Data for all-cause mortality at final follow-up were summarised in a meta-analysis using a fixed-effect model. This systematic review includes three trials with a combined total of 164 participants who had moderate to severe paraquat poisoning. Patients who received glucocorticoid with cyclophosphamide in addition to standard care had a lower risk of death at final follow-up than those receiving standard care only (RR 0.72; 95% CI 0.59 to 0.89). Based on the findings of three small RCTs of moderate to severely poisoned patients, glucocorticoid with cyclophosphamide in addition to standard care may be a beneficial treatment for patients with paraquat-induced lung fibrosis. To enable further study of the effects of glucocorticoid with cyclophosphamide for patients with moderate to severe paraquat poisoning, hospitals may provide this treatment as part of an RCT with allocation concealment

Urban blue space renovation and local resident and visitor well-being:A case study from Plymouth, UK

Observational studies have suggested that people with better access to attractive, safe, and inclusive blue spaces enjoy higher psychological well-being, with particular benefits for those living in deprived urban areas. However, intervention studies are scarce. To help bridge this gap we conducted a repeat cross-sectional study exploring local resident and visitor well-being before and after a small-scale intervention aimed at improving the quality of an urban beach area in a deprived neighbourhood in Plymouth, United Kingdom. Physical alterations were co-created with local stakeholders and residents, and accompanied by a series of on-site community events. Key outcomes were self-reported psychological well-being, satisfaction with personal safety and community belonging, and perceptions of site quality. Adjusted linear models showed that positive well-being (B = 7.42; 95% CI = 4.18–10.67) and life satisfaction (B = 0.40; 95% CI = 0.11–0.70) were both higher after the intervention compared to before, with associations for life satisfaction stronger among those who visited the site in the last four weeks. Associations with positive well-being were partially mediated by greater satisfaction with community belonging; and associations with life satisfaction were partially and independently mediated by greater satisfaction with personal safety and community belonging. Although caution needs to be taken due to the repeat cross-sectional design and the sampling of site visitors as well as local residents, the findings support the idea that environmental improvements to urban blue spaces can foster better psychological well-being, and underline the importance of community involvement in the process

Therapeutic Hypothermia Reduces Intracranial Pressure and Partial Brain Oxygen Tension in Patients with Severe Traumatic Brain Injury:Preliminary Data from the Eurotherm3235 Trial

Traumatic brain injury (TBI) is a significant cause of disability and death and a huge economic burden throughout the world. Much of the morbidity associated with TBI is attributed to secondary brain injuries resulting in hypoxia and ischemia after the initial trauma. Intracranial hypertension and decreased partial brain oxygen tension (P(bt)O(2)) are targeted as potentially avoidable causes of morbidity. Therapeutic hypothermia (TH) may be an effective intervention to reduce intracranial pressure (ICP), but could also affect cerebral blood flow (CBF). This is a retrospective analysis of prospectively collected data from 17 patients admitted to the Western General Hospital, Edinburgh. Patients with an ICP >20 mmHg refractory to initial therapy were randomized to standard care or standard care and TH (intervention group) titrated between 32°C and 35°C to reduce ICP. ICP and P(bt)O(2) were measured using the Licox system and core temperature was recorded through rectal thermometer. Data were analyzed at the hour before cooling, the first hour at target temperature, 2 consecutive hours at target temperature, and after 6 hours of hypothermia. There was a mean decrease in ICP of 4.3±1.6 mmHg (p<0.04) from 15.7 to 11.4 mmHg, from precooling to the first epoch of hypothermia in the intervention group (n=9) that was not seen in the control group (n=8). A decrease in ICP was maintained throughout all time periods. There was a mean decrease in P(bt)O(2) of 7.8±3.1 mmHg (p<0.05) from 30.2 to 22.4 mmHg, from precooling to stable hypothermia, which was not seen in the control group. This research supports others in demonstrating a decrease in ICP with temperature, which could facilitate a reduction in the use of hyperosmolar agents or other stage II interventions. The decrease in P(bt)O(2) is not below the suggested treatment threshold of 20 mmHg, but might indicate a decrease in CBF

Mechanical model of the ultra-fast underwater trap of Utricularia

The underwater traps of the carnivorous plants of the Utricularia species catch their preys through the repetition of an "active slow deflation / passive fast suction" sequence. In this paper, we propose a mechanical model that describes both phases and strongly supports the hypothesis that the trap door acts as a flexible valve that buckles under the combined effects of pressure forces and the mechanical stimulation of trigger hairs, and not as a panel articulated on hinges. This model combines two different approaches, namely (i) the description of thin membranes as triangle meshes with strain and curvature energy, and (ii) the molecular dynamics approach, which consists in computing the time evolution of the position of each vertex of the mesh according to Langevin equations. The only free parameter in the expression of the elastic energy is the Young's modulus E of the membranes. The values for this parameter are unequivocally obtained by requiring that the trap model fires, like real traps, when the pressure difference between the outside and the inside of the trap reaches about 15 kPa. Among other results, our simulations show that, for a pressure difference slightly larger than the critical one, the door buckles, slides on the threshold and finally swings wide open, in excellent agreement with the sequence observed in high-speed videos.Comment: Accepted for publication in Physical Review

Spontaneous Firings of Carnivorous Aquatic Utricularia Traps: Temporal Patterns and Mechanical Oscillations

Aquatic species of Utricularia are carnivorous plants living in environments poor in nutrients. Their trapping mechanism has fascinated generations of scientists and is still debated today. It was reported recently that Utricularia traps can fire spontaneously. We show here that these spontaneous firings follow an unexpected diversity of temporal patterns, from “metronomic” traps which fire at fixed time intervals to “random” patterns, displaying more scattered firing times. Some “bursting” traps even combine both aspects, with groups of fast regular firings separated by a variable amount of time. We propose a physical model to understand these very particular behaviors, showing that a trap of Utricularia accomplishes mechanical oscillations, based on continuous pumping and sudden opening of the trap door (buckling). We isolate the key parameters governing these oscillations and discuss the effect of their fluctuations

Components of SurA Required for Outer Membrane Biogenesis in Uropathogenic Escherichia coli

Background: SurA is a periplasmic peptidyl-prolyl isomerase (PPIase) and chaperone of Escherichia coli and other Gramnegative bacteria. In contrast to other PPIases, SurA appears to have a distinct role in chaperoning newly synthesized porins destined for insertion into the outer membrane. Previous studies have indicated that the chaperone activity of SurA rests in its ‘‘core module’ ’ (the N- plus C-terminal domains), based on in vivo envelope phenotypes and in vitro binding and protection of non-native substrates. Methodology/Principal Findings: In this study, we determined the components of SurA required for chaperone activity using in vivo phenotypes relevant to disease causation by uropathogenic E. coli (UPEC), namely membrane resistance to permeation by antimicrobials and maturation of the type 1 pilus usher FimD. FimD is a SurA-dependent, integral outer membrane protein through which heteropolymeric type 1 pili, which confer bladder epithelial binding and invasion capacity upon uropathogenic E. coli, are assembled and extruded. Consistent with prior results, the in vivo chaperone activity of SurA in UPEC rested primarily in the core module. However, the PPIase domains I and II were not expendable for wild-type resistance to novobiocin in broth culture. Steady-state levels of FimD were substantially restored in the UPEC surA mutant complemented with the SurA N- plus C-terminal domains. The addition of PPIase domain I augmented FimD maturation into the outer membrane, consistent with a model in which domain I enhances stability of and/or substrat

Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. INTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUNDING: National Institute for Health Research Health Technology Assessment Programme

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions

This research is funded by the NIHR Research for Patient Benefit programme (NIHR203568). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.Peer reviewe