Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: When we recorded LFPs in S1-M1 of awake mice we again observed large synchronised seizure-like potentials occuring following 100 μM (10 min incubation) SR101 application (Fig. 2d). Note that movement artefacts were not removed from the LFP trace shown in Fig. 2d. This seizure-like activity was correlated with a drop in low-frequency power (1–4 Hz) and an increase in higher-frequency power (12–30 Hz) (Fig. 2d and Supplementary Fig. S1) similar to seen in Fig. 1b and previous epilepsy publications13,17. The individual seizure-like events in awake mice exhibited an average amplitude of 1. 4 ± 0. 82 mV and average event intervals of 0. 83 ± 0. 75 s (Fig. 2e). Thus, the average seizure-like event amplitude was 0. 24 mV smaller (Unpaired Welch’s t-test, t = 1. 632 df = 8. 605, P = 0. 1387) and the event interval 0. 16 s shorter (Unpaired Welch’s t-test, t = 2. 181 df = 9. 934, P = 0. 0543) than in anaesthetized mice. Overall, this experiment expands the finding that SR101 evoke seizure-like cortical activity to awake animals, potentially making it useful as an epileptogenic agent for future in vivo experiments investigating cortical epilepsy, conditioned that SR101’s mechanism of action will be revealed in future experiments. Figure 2SR101 can induce seizure-like activity in awake mice. (a) Experimental setup. (b) LFP recordings from the same mouse during ketamine/xylazine (KX) anaesthesia and wakefulness. (c) Frequency-domain spectra showing change in power distribution between KX anaesthesia and awake LFP from (b). (d) Upper, LFP recording showing development of seizure-like activity in primary sensori-motor cortex following 100 μM SR101 loading (10 min incubation). Note that movement artefacts have not been removed from the LFP. Lower, frequency power spectrograms from period 1 and 2 from LFP above. (e) Histograms showing individual seizure-like activity event amplitudes and intervals.

Output: pass


Input: Claim: Personalized medicine can help reduce adverse drug reactions. [SEP] Text: Academy of Enter your Email address: Subscribe to eTOC Home >. . . the 7, 2006 —As drug reimbursement under D becomes a reality, medical groups are grappling not only with how to get the right drugs to all Medicare beneficiaries who need them, but also with how to make sure all patients takes their medications without adverse drug reactions or interactions. At a meeting here in November on drug discovery, development, and translation convened by the Institute of Medicine (IOM), invited speakers addressed the role of health-care professionals and consumers in reducing adverse drug events. The IOM Forum was held shortly after the FDA announced on Nov. 2 its requirement that drug makers submit prescription drug label information to the agency in a new electronic formatwas held shortly before the Nov. 8 announcement that the Institute for Practices, headquartered in Huntingdon, PA, is partnering with the FDA on an educational campaign to eliminate potentially harmful, error-prone medical abbreviations such as HCT for hydrocortisone, which could be mistaken for hydrochlorothiazide. The new joint educational campaign will be launched in the first half of 2006. speakers cited statistics from the 1999 IOM report, Is Human, that estimated that up to 98,000 Americans die each year from medical errors, many from adverse drug reactions and drug-drug interactions. Those statistics, they said, were good reason for establishing a national database that would include drug-drug interactions, adverse drug reactions, as well as misuse and underuse. “Drug databases have focused on misuse in the past, but I think we're going to see more drug databases that address drug underuse based on evidence-based practices,” said Scott Weingarten, MD, President and CEO of Zynx Health, citing the failure to prescribe long-term aspirin therapy after a heart attack. Dr. Weingarten is also of Medicine at the University of California-School of Medicine and Director of Research at Cedars-SystemSidney N. of Pharmacovigilance & Inc, a Huntington Valley, PA-based firm that provides advice on drug safety and risk assessment to the pharmaceutical industry, said that drug labeling is now little more than a “laundry list” of adverse drug reactions. “You end up with screen after screen of information, but what does it tell the clinician to do? ” asked Dr. Kahn. “There is limited information useful to prescribers.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: 6 m above mean sea level (Ollila, 2002), several new town areas were planned and built below this level, after the publication of the guidelines in flood-prone areas, within the Area (Schmidt-Thomé & Klein, 2011). These developments continued until the Gudrun hit Helsinki in January 2005, flooding several newly built houses. This extreme event contributed to the further development and implementation of the climate change adaptation strategies mentioned above. A newer guide, by Parjanne and Huokuna (2014), raises the minimum elevation to 2. 8 m. Nonetheless, in 2014, houses continued to be built on the Area shorelines, often less than 1 m above sea level. According to the architects responsible for issuing building permits, the investors building close to sea level were informed that these buildings are located in flood-prone areas. Despite these guidelines, and knowing that they were building in a flood prone area, private investors perceived that the benefit of living on the shoreline outweighed the risks to which they exposed their assets. The cooperation of the private sector in developing and implementing climate change adaptation strategies in urban areas Finland is rather weak (Klein, Mäntysalo, & Juhola, 2015). According to Finnish insurance companies, many wealthy persons do not mind that their flood prone assets are not insurable. In the case of flood events, assets are protected with sand bags. Afterwards, the flood damages are repaired at the owner’s expense. In some cases, repairs are necessary annually, but the fact of living close to the sea outweighs risks and costs. Per definition, extreme events occur only seldom (from a human perspective). Still, their impacts are often disastrous. The problems, obstacles, and/or negligence in adapting to such events lead to the conclusion that it should be feasible to discuss (mal-)adaptation to the (current) climate and its extremes first, before heading straightforward into climate change adaptation. The message on climate change conveyed by IPCC’s summary for policy makers (IPCC, 2007b, 2014) is that hydro-meteorological natural hazards will, with high confidence, increase on nearly all continents, in both intensities and frequencies. Therefore the statement above might also be asked the other way round: in the Words: by Nowadays?

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: Full size imageLower concentrations or shorter incubation time does not evoke abnormal cortical LFP activityThe original publication by Nimmerjahn and colleagues, showing the ability of SR101 to label cortical astrocytes in vivo, recommended using 25–100 μM SR101 and incubation for one to five minutes8. However, from S1 provided in the supplementary material, it appears that a large fraction of publications use concentrations higher than this (see S1). 1 and 2 we show that topical loading of 100 μM and 250 μM SR101 (10 min incubation) may induce abnormal cortical neuronal activity, an effect that ideally is undesireable. Thus, in the final experiment we tested the effect of lower concentrations, i. e. 25 μM and 50 μM, of SR101 and concentrations of 100 μM and 250 μM incubated for one minute on cortical neuronal activity. We observed bright labelling of cortical astrocytes using either 100 μM (1 min incubation) or 50 μM (10 min incubation) SR101 (Fig. 3b,d). Contrary to the previous experiments, we did not observe any abnormal LFP activity in the anaesthetised cortex following loading, despite leaving the SR101 on for 30 min and 20 min for 25 μM and 50 μM, respectively (Fig. 3c–d and Supplementary S5). Non-filtered recordings displaying the application and wash out induced artefacts, together with power spectrograms, are provided in Supplementary Fig. S5. Thus, from these experiments it appears that concentrations of 50 μM, or less, SR101 does not induce abnormal cortical neuronal activity, but still sufficiently labels astrocytes (summarised in Fig. 3d). Figure 3Lower SR101 concentrations or shorter incubation time does not evoke abnormal cortical LFP activity. (a) Experimental setup. (b) Astrocytic SR101 uptake following cortical 100 μM (1 min incubation) or 50 μM (10 min incubation) SR101 application (images acquired 60 min following loading). (c) Left, LFP recordings following 25 μM (30 min incubation), 50 μM (20 min incubation), 100 μM (1 min incubation) or 250 μM (1 min incubation) SR101 application. Right, close-up of LFPs shown on the left. (d) Summary table showing main findings.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Since the discovery of the causative gene, our understanding of the structure and function of CFTR and the impact of different mutations has increased and allowed pharmaceutical companies to design new mutation‐specific therapies targeting the underlying molecular defect. Therapies targeting mutation classes III and IV (CFTR potentiators) aim to normalise airway surface liquid and help re‐establish mucociliary clearance, which then has a beneficial impact on the chronic infection and inflammation that characterizes lung disease in people with cystic fibrosis. These therapies may also affect other mutations. evaluate the effects of CFTR potentiators on clinically important outcomes in children and adults with cystic fibrosis. Search methods We searched the Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant 2015. We searched the EU Register, clinicaltrials. gov (US Register) and the Platform (ICTRP). Last search of clinical trial registries: 06 February 2014. Selection criteria Randomised controlled trials of parallel design comparing CFTR potentiators to placebo in people with cystic fibrosis. In a post hoc change we excluded trials combining CFTR potentiators with other mutation‐specific therapies. These will be considered in a separate review. Data collection and analysis The authors independently extracted data and assessed the risk of bias in included trials; they contacted trial authors for additional data. Meta‐analyses were undertaken on outcomes at a number of time points. Main results We included four randomised controlled trials (n = 378), lasting from 28 days to 48 weeks, comparing the potentiator ivacaftor to placebo. Trials differed in terms of design and participant eligibility criteria, which limited the meta‐analyses. The phase 2 trial (n = 19) and two phase 3 trials (adult trial (n = 167), paediatric trial (n = 52)), recruited participants with the G551D mutation (class III). The fourth trial (n = 140) enrolled participants homozygous for the ΔF508 mutation (class II). Risks of bias in the trials were moderate. Random sequence generation, allocation concealment and blinding of trial personnel were well‐documented. Participant blinding was less clear throughout all trials; in three trials, some participant data were excluded from the analysis. Selective outcome reporting was apparent in three trials. All trials were sponsored by industry and supported by other non‐pharmaceutical funding bodies.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: Since many societies are obviously unwilling or unable to adjust properly to the current climate and its extremes, why would they suddenly be willing or able to adjust to potential changes that might occur in the future? Instead of arguing about the potential climate change impacts, much can be learned from current mal-adaptation practices. Vulnerabilities and risks are often neglected despite better knowledge and because of perceived benefits that outweigh the risks. Humans have always settled in areas affected by natural hazards. When disasters hit, settlements were rebuilt, often on the very same spot. There are virtually no examples of any larger city that was given up or relocated due to risks related to hydro-meteorological hazards. Adopted protective measures, whether engineering solutions such as dams, or regulative one’s such as zoning, cannot mitigate all risks. People accept risks because the perceived benefits of locations outnumber the potential risks. The nature of extreme events, and their rare occurrences, often catches societies off guard and cause substantial disasters. Several overlaying factors can determine the extent of disasters. For example, certain flood heights have never been recorded in human history, or they have simply been forgotten. Upstream changes in river catchments, such as deforestation, sand mining, and riverbed straightening, change flood patterns. When hazards (floods, droughts, etc. ) do not occur for a longer time frame (from a human perspective), development does take place in hazardous areas. When disasters do occur, the search for someone (or something) to blame starts. Because people perceive great benefits from settling in potentially hazardous areas, and because they accept the risks rather than avoiding them, a feasible solution would be to minimize the risks while allowing maximum benefits. Valuable input on the debate on adaptation concepts can be derived from the coastal reconstruction along the after the tsunami in 2004. A meeting of international experts in the aftermath of the 2004 tsunami in Bangkok, Thailand counted with the presence of the then Minister and the Minister for Tourism. One group of geoscientists pledged that, because of the tsunami hazard, the tourism industry should not be allowed to rebuild damaged installations on the coast but only in higher, flood-proof areas. Such a relocation of tourist industries would lead to substantial losses from this important source of income for Thailand, especially since Malaysia had already announced that it would not retreat from beach resorts.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: Full size imageDiscussionHere we report that SR101, a widely used fluorescent dye for specific labelling of astrocytes, possess potent bioactive effects able to change cortical neuronal activity in vivo following topical loading. Currently the mechanism for how SR101 triggers the observed change in cortical neuronal activity is unknown. The two most likely hypotheses may be that: (1) SR101 has a direct effect on cortical neurones, or (2) SR101 has an indirect effect on neuronal activity via an astrocyte-mediated mechanism. We have previously shown, that in hippocampal slices SR101 induces a direct effect on pyramidal neurone membrane structures, leading to a reduction in action potential firing threshold and a long-term increase in neuronal excitability and synaptic efficacy9. This finding is in agreement with a similar experiment performed in hippocampal slices10. Here the authors showed that SR101 markedly increased the excitability of pyramidal neurones as well as induced monosynaptic long-term potentiation of synaptic efficacy in hippocampal area CA1. These effects developed already after five minutes following 100 μM or 25 μM SR101 bath application10. This time course agrees with our finding that SR101-induced seizure-like LFP activity develops within five to ten minutes following topical loading, depending on the applied concentration (Fig. 1). This rather rapid time course favours a direct SR101-mediated effect on neurones. We observed that cortical astrocytes starts to appear bright under the 2-photon microscope within ten to twenty minutes following 100 μM SR101 application (Fig. 1), similar to what Nimmerjahn and colleagues reported in the original publication8. If the SR101-triggered effect on neuronal LFP activity was via an astrocyte-dependent intra-cellular mechanism, one might expect that SR101 uptake into cortical astrocytes preceded that of LFP changes; this did not seem to be the case. Thus, it appears more likely that SR101 has a direct effect on neurones while the concentration is still relatively high in the extracellular environment. This may also be supported by the striking similarity between the seizure-like LFP activity presented here (Fig. 1) and previously published epileptiform activity induced in vivo by application of the compound 4-AP, targeting neuronal potassium channels15.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Evidence suggests that ivacaftor is an effective treatment for people (over six years of age) with cystic fibrosis and the G551D mutation, but not for those with the ΔF508 mutation. Trials of ivacaftor in people with different genetic mutations are underway. Quality of the evidence In most of the trials, the volunteers were put into different treatment groups completely at random, so we were satisfied that those taking part had an equal chance of being in either group (placebo or ivacaftor). We are also satisfied that in most trials no one could work out which group the next volunteer would be put into, so that healthier people did not receive the treatment and make the results seem better. We could not be sure whether the people taking part in the trial or the clinicians running the trial knew who was receiving which treatments and what effect this knowledge might have on the results. Unfortunately, none of the trials reported all their results clearly; sometimes they did not report them in a way that we could use in the review and sometimes they did not report the data at all. This affected the certainty with which we judged the overall results. trials were sponsored by Incorporated. Institute of Health (NIH), the Foundation (CFF) and other non‐pharmaceutical funding bodies also supported the trials. Visual summary Authors' conclusions available in English Español Implications for practice The two G551D phase 3 trials demonstrated a clinically relevant impact of ivacaftor on outcomes at 24 and 48 weeks, providing evidence for the use of ivacaftor in children (over six years of age) and adults with CF and the G551D mutation (Davies 2013; Ramsey 2011). The ΔF508 trial demonstrated no evidence to support the use of ivacaftor in those with the ΔF508 mutation (Flume 2011). This conclusion is based on results from a single trial which we judged to have a moderate to high risk of bias; and therefore this conclusion should be interpreted with some caution. Implications for research Ivacaftor is the first intervention that corrects the underlying molecular defect in CF. It has demonstrated effectiveness in people with a class III mutation (G551D) and has the potential to be used for other class III mutations. Further trials examining the use of ivacaftor in class III to IV mutations (e. g.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: After a hefty debate, the expert group agreed on the proposal to regulate the land use in such a way that tourist installations remain on the beaches remain, but that rescue and other vital infrastructures would be located on higher grounds. Local people would be trained on the tsunami hazard, evacuation routes would be planned and installed, and a tsunami early warning system would be set up. The tsunami hazard land use and emergency regulations follow those of Hawaii (Johnston & Dudley, 2009). The former for Tourism was satisfied with this proposal and accepted it. In the meantime, said regulations have been implemented in Thailand (Johnston & Dudley 2009). It would be advisable to follow such examples of disaster risk reduction and carefully consider financial and other benefits for local economies implementing climate change adaptation practices. This tsunami-related disaster risk management also serves as a good example of the potential to build synergies with mutual benefits between the two concepts of disaster risk management (DRR) and climate change adaptation (CCA) (IPCC, 2012; Pollner, Kryspin-Watson, & Nieuwejaar, 2008; Solecki, Leichenko, & O’Brien, 2011). can climate change adaptation measures be implemented successfully and sustainably? Strategies and regulations on climate change adaptation will only be accepted and implemented if a majority of the involved and affected persons perceive these as beneficial to them and do not perceive them as a financial burden. Only a broad understanding of the need for and usefulness of climate change adaptation measures will lead to a successful and sustainable implementation. Raising of institutional awareness and the development of regulations are necessary. International bodies, such as the IPCC, contribute valuable knowledge and overall frameworks. Institutions like the EU Commission contribute guidelines. Acts and decrees are developed on a national level and implemented on the local level. Local stakeholders, decision makers, and the private sector need to understand uncertainties and agree on local vulnerabilities and resulting risk patterns, to be able to develop tailored and acceptable solutions (Schmidt-Thomé & Kaulbarsz, 2008). To be successful, implemented measures must fit into local cultural and political settings and be financially bearable. The development of climate change solutions should follow and respect local legislations, regulations, cultures, and interests. The implemented measures will be sustainable only if they are perceived as beneficial to the local socio-economic and cultural settings, because local people will ensure their maintenance.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: However, recent work have suggested astrocyte involvement in the development of epileptic activity15,27,28 and it is conceivable that SR101-induced astrocyte signalling occurs following uptake and contributes to the observed seizure-like LFP activity. Similar, a possible oligodendrocyte-mediated effect cannot be excluded, based on the recent finding that SR101 labels oligodendrocytes in vivo6 and the intimate proximity between neuronal axon initial segments and myelin sheathes29. Overall, the current knowledge of SR101-evoked changes of neuronal excitability and its uptake time course leads us to suggest, for now, that the most likely mechanism of action is via a direct effect on neurones, but future experiments should aim to answer this question in more detail. The main purpose of applying SR101 to the cortical surface before initiating 2-photon microscopy experiments, is to label astrocytes in order to unambiguously distinguishing between neuronal and astrocytic signaling in vivo1,4,10,30. Thus, any interference with normal brain physiology mediated by SR101 is in that context strongly undesirable. Although, we have not explored the after-effects of SR101-induced seizure-like LFP activity and its influence on subsequent experiments, other studies indicate that some long-term effects could be expected. In our earlier work we showed that ten minutes of SR101 bath application evoke long-term potentiation of synaptic efficacy lasting 80 minutes following exposure in hippocampal slices9. Similar results have been reported by Garaschuk showing increased population spike amplitude 50 minutes following SR101 exposure10. Overall this suggests, that the exposure of the neuronal tissue to SR101 can cause long-term changes in synaptic efficacy of excitatory transmission. In addition, previous observations show that epileptic seizure activity can induce long-term synaptic plasticity31,32, as well as increase the expression of the synaptic plasticity-associated immediate-early gene c-Fos33,34. Finally, recent work shows that spontaneous interictal epileptiform discharges can impair memory consolidation18. Hence, it is a possiblity that the observed 30–40 minutes of abnormal cortical LFP activity (Figs 1 and 2) cause similar changes in synaptic plasticity and impacts subsequent physiological recordings, such as experiments investigating synaptic plasticity in vivo.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: III G551D CFTR is produced and embedded in the cell membrane, but the chloride channel does not respond (‘switch on’) to normal stimulation from the cell. This means there is no significant ion transport across the protein. Individuals have some residual CFTR function. IV R347P CFTR is transported to the outer cell membrane, and responds to normal stimulation, but functions at a low level because chloride ions do not cross the channel appropriately. Individuals have some residual CFTR function. V A455is produced, but the amount of protein is reduced. Individuals have some residual CFTR function. CFTR: cystic fibrosis transmembrane conductance regulator Description of the intervention Understanding how the mutations, which are described in the additional tables (Table 1), affect the production, structure, and function of CFTR has led to the concept of mutation‐specific therapies. One strategy, relating mainly to mutations classes III to V but also to class II, is to improve the function of CFTR that has reached the cell membrane, but whose function is compromised (McKone 2004). Drugs that improve CFTR function in the cell membrane are called potentiators and have the potential to correct the abnormal salt transport that characterises CF. Potentiators can be administered orally, or as an inhaled preparation. Two distinct approaches have resulted in the recognition of candidate drugs with this mode of action (Amaral 2007): testing of compounds known to affect CFTR or other ion‐channels (either pharmaceutical drugs or chemicals which occur naturally in plants, herbs, fruits or food components); high throughput screening, which involves testing large numbers of diverse chemicals, on laboratory cell lines, to identify which of these may stimulate CFTR; In addition to potentiators, other drugs which aim to correct defects of the CFTR are also under investigation in clinical trials. These include correctors (which increase the amount of CFTR in the cell membrane by preventing early degradation ‐ class II mutations) and 'stop‐codon therapies' which act to prevent structural abnormalities of CFTR that occur when premature stop codons terminate protein synthesis too early ‐ class I mutations). A Cochrane review of trials assessing correctors is ongoing (Sinha 2014) and one assessing stop codon therapies has just been registered. How the intervention might work Ivacaftor, a CFTR potentiator was identified through high throughput screening by Incorporated.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: It has been proven that so-called no-regret measures present the most feasible solutions, even though IPCC (2014) criticizes this as non-sufficient for climate change adaptation. No-regret measures are of benefit immediately after their installation, even in the absence of climate change impacts. Such measures can, for example, protect areas from current floods and from future, potentially higher floods (e. g. , Petersell, Suuroja, All, & Shtokalenko, 2013). Some flood retention areas are designed multi-functionally, as a recreational park, for instance, which raises the overall value of the entire neighborhood (e. g. , Rimkus, Kažys, Stonevičius, & Valiuškevičius, 2013). No-regret measures to protect from current and potential future urban flood patterns can be designed to improving local living environments (Jarva et al. , 2014). No-regret measures are thus win-win solutions that are best achieved by interdisciplinary communication. Experience has shown that it is easier for decision makers to invest in adaption measures to current problems, such as extreme event patterns, rather than investing in adaption measures to climate change effects that might take place in 50 years or more. While investing to protect from current hazard patterns, it is possible also to take potential climate change impacts into account. Ideally, climate change adaptation measures have social acceptance right from the start. If local climate change adaption measures also protect from current hazard patterns and if living conditions improve, decision makers can easily justify investments and achieve two goals at the same time. Once climate change impacts to hazard patterns become visible and start to affect livelihoods, these protective measures can be re-designed gradually. The analysis of sea level rise impacts on shallow groundwater aquifers in the City of Hanko (Finland) yielded the results that the current water intakes are vulnerable to sea level rise and consequent salinization (Luoma, Klein, & Backman, 2013). An analysis with local waterworks did not lead to the immediate decision to relocate groundwater intakes merely because of potential future risks. Part of the discussion took into account the future socio-economic and population trends of this city: How will local industries develop, will water demand grow or decrease, and how many people will live in this city in a couple of decades? Currently no decisions or investments on relocating water intakes have been taken.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: In agreement with this consideration is previous work discussing spontaneous Ca2+ transients in visual cortex before and after injection of 100 μM SR101 (described in)10. Here the authors described that SR101 injection initially caused an increase in the frequency of Ca2+ transients, supporting our LFP observations (Figs 1 and 2). However, 40 minutes after the SR101 injection spontaneous Ca2+ transients were significantly reduced compared to baseline, suggestive of long-term depression. Thus, overall, SR101 is able to change cortical synaptic efficacy, on a time scale that impact experimental data obtained in vivo. SR101 was originally discovered to selectively label cortical astrocytes in 20048. Thus, the question arises why the potent effects of SR101 concentrations ≥100 μM on cortical LFP activity have not been reported until now. As previously described, the main purpose of SR101 application is to label astrocytes to distinguish between neuronal- and astrocytic Ca2+ transients. For measuring Ca2+ signals organic Ca2+ indicator dyes, such as 488 BAPTA-1 AM, has been widely used1,4,8,30. This Ca2+ indicator dye require ~1 hour following loading to reach a stable maximal fluorescence level in stained cells30. In our experiments, we observed that SR101-triggered seizure-like LFP activity ceased after 30–40 minutes, depending on the SR101 concentration used (Fig. 1). Thus, if SR101 is applied together with an organic Ca2+ indicator dye and the subsequent experiment is not initiated until 1 hour following loading, the abnormal neuronal activity is likely not seen. Furthermore, in our experiments, we applied SR101 onto S1-M1 cortical areas, allowing us to observe behavioural outputs, i. e. contra-lateral hindlimb muscle contractions, during SR101-induced seizure-like LFP activity (Fig. 1, Supplementary Fig. S4 and S1–3). However, if SR101 is applied to non-motor cortical areas, e. g. visual- or auditory cortex, no such obvious behavioural outputs might develop, again masking the abnormal neuronal activity from the experimenter. In summary, we here show that commonly used loading concentrations of the astrocyte-specific indicator SR101, i. e.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: 1 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 1 CFQ‐R score (respiratory domain, child version) ‐ adjusted change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 1. 2 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 2 CFQ‐R score (respiratory domain score, parent/caregiver version) ‐ adjusted change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 1. 3 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 3 CFQ‐R score (respiratory domain score, pooled) ‐ absolute change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 1. 4 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 4 FEV1 ‐ mean relative change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 1. 5 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 5 Adverse events occurring in greater than or equal to 5% of trial participants. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 1. 6 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 6 All adverse events. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 1. 7 Comparison 1 Ivacaftor (VX‐770) versus placebo in people with at least one G551D CFTR mutation, Outcome 7 Severity of adverse effects of therapy with regards to study drug interruption (moderate) or discontinuation (severe).

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: This example shows that it is valuable to conduct both vulnerability and risk analysis under climate change scenarios, but to also keep in mind future uncertainties, in terms of socio-economic developments, before making decisions hastily that might lead to futile investments. Timescales strongly affect the points of view of stakeholders and are important for decision making. Some geo-hazards and related geo-risks may never occur during a human lifespan, others might occur rather frequently. The periodicity, geological processes, and impact delays are, therefore, very important issues in the communication of geosciences. It is often forgotten that climate change is a slow, ongoing process, and its impact occurs steadily, not suddenly at the end of the 21st century. Human impacts on the living environment and the exploitation of natural resources are often stronger than climate change signals and occur more quickly than climate change impacts. It is certainly possible that climate change contributes adverse impacts, but it is also possible that these might never occur. Climate change impacts might end up being completely different than currently estimated, due to uncertainties of models and due to human impacts. It is very important, therefore, to keep timescales and changes to land use and socio-economical and political frameworks in mind. For example, some investments that yield short term revenues might never be affected by climate change—and if they were affected, they might as well be decommissioned. It is one important part of climate change adaptation to keep the time-scales of anthropogenic and geological processes in mind. There are possibilities to decrease the effect of uncertainties in climate change adaptation measures by developing adaptation measures at community levels. Such adaptation measures do not decrease the uncertainties in climate change models per se, but the focus on local vulnerability patterns leads to improvements of adaptive capacities and to improvements in local resilience (van Aalst, Cannon, & Burton, 2008). Optimally, such analyses of vulnerability focus on disaster potential caused by extreme events, as these are most commonly remembered, and the potential impacts are based on real experiences. Derived disaster risk management options can then be used to further develop protective or adaptive measures to cope with changing climatic patterns (intensifying cloudbursts, longer dry spells, etc. ) (Schmidt-Thomé, Nguyen, Pham, Jarva, & Nuottimäki, 2014).

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: 100 μM and 250 μM, can induce seizure-like activity in S1-M1 five to ten minutes following topical loading, when incubated for ten minutes. This SR101-induced synchronized cortical activity can evoke motor outputs and muscle contractions even in anaesthetised mice. Finally we show, that 25 μM and 50 μM SR101 does not appear to cause abnormal LFP activity following loading, but still labels cortical astrocytes. Overall, our observations may call into question the widespread usage of 100–300 μM SR101 for topical loading of cortical astrocytes, given its potent bioactive effects on cortical tissue when incubated for ten minutes. We advocate that SR101 concentrations no higher than 50 μM should be used for in vivo experiments, to avoid the risk of evoking abnormal cortical neuronal activity. MethodsAnimal preparationAll experiments carried out in Rochester were in compliance with the of for the Care and Use of and in accordance with guidelines approved by the institute ethics committee for the care and use of animals. All experiments performed at the University of Copenhagen were approved by the Committee (Permission No. 2012-15-2934-00719 and 2015-15-0201-00535) and was in accordance with Regulations. Mouse preparation was modified from previously published protocol35. Wild-type mice of either sex, 6–12 weeks old (N = 30), were anaesthetised with an intraperitoneal injection of ketamine (120 mg kg–1) and xylazine (10 mg kg–1) (KX) dissolved in saline. Depth of anaesthesia was monitored by pinch withdrawal reflex throughout the experiment. We supplied half the initial dose of KX to the anaesthesia every 60 minutes. If the mouse responded to pinch stimulation additional KX anaesthesia was given immediately. Core body temperature was monitored by a rectal probe and maintained at 37 ± 0. 5 °C by a heating blanket (BS4, Harvard Apparatus). Eyes were protected with eye ointment (). A custom-made metal plate was glued to the exposed and cleaned skull with cyanoacrylate. A craniotomy (2–3 mm in diameter), with the centre 0. 5 mm posterior to bregma and 3.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: This means there is no significant ion transport across the protein. Patients have minimal CFTR function. IV R347P CFTR is transported to the outer cell membrane, and responds to normal stimulation, but functions at a low level because chloride ions do not cross the channel appropriately. Patients have some residual CFTR function. V A455is produced, but the amount of protein is reduced. Patients have some residual CFTR function. CFTR: cystic fibrosis transmembrane regulator Description of the intervention Understanding how the mutations, which are described in the additional tables (Table 1), affect the production, structure, and function of CFTR has led to the concept of mutation‐specific therapies. For class II mutations a full length of protein is produced; however, it is structurally abnormal because the protein is folded incorrectly. It is recognised as abnormal by the cell and degraded before reaching the cell membrane. This is called a defect in intracellular trafficking. Scientists have recognised that certain manoeuvres can affect this process, for example reducing cell temperature, and the trafficking defect can be overcome (Colledge 1995). In such circumstances the protein may reach the cell membrane and function as a salt transporter. This has lead to the search for molecules that can overcome the trafficking defect. These molecules have been called 'correctors'. Two distinct approaches have resulted in the recognition of candidate drugs with this mode of action (Amaral 2007): testing of compounds known to affect CFTR or other ion channels (either pharmaceutical drugs or chemicals which occur naturally in plants, herbs, fruits or food components); high throughput screening, which involves testing large numbers of diverse chemicals, on laboratory cell lines, to identify which of these may overcome the intracellular trafficking defect. These approaches have resulted in the identification of small molecules that may be taken orally, and have been examined in phase 1 and phase 2 clinical trials (Rubenstein 1997; 2011). How the intervention might work In the airways of the lung, correction of the basic defect could lead to normalisation of airway surface liquid, and the resulting re‐establishment of mucociliary clearance, which would then have a beneficial impact on the chronic infection and inflammation that characterizes CF lung disease. In addition to correctors, other drugs which aim to treat defects of the CFTR are also under investigation in clinical studies.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: In this way, mutual benefits and cross-feeding between political and institutional demands can accomplish disaster risk management and climate change adaptation (e. g. , IPCC, 2012; Pollner et al. , 2008; 2012). There are numerous examples of successful adaptation practices from the community level. In such so-called bottom-up approaches (vs. top-down approaches), local people evaluate the vulnerabilities of their local environments and socio-economic settings to climate change impacts. Such community-based climate change adaptation practices usually use participatory approaches to develop tailored adaptation measures (van Aalst et al. , 2008). for the Development and Implementation of Adaptation MeasuresParticipatory approaches focus on governance issues, as the involvement of citizens in decision-making practices is becoming more important from a basic democratic and social justice perspective. By involving various interest groups, a more complex understanding of the issues at stake may be achieved, and socially accepted solutions to problems may be found by taking into account the various interests, motivations, and expertise. Early integration of manifold expertise and interests minimizes the risk of costly adjustments at a later stage, even though it might seem time consuming and challenging (Slocum, 2003; Wollenberg, 2000). In addition, the integration of relevant stakeholders reduces the amount of potential resistance and leads overall to a faster implementation of measures (e. g. , Rimkus et al. , 2013; Petersell et al. , 2013). The integration of local stakeholders and interdisciplinary approaches in participatory tools have proven effective in successfully developing and implementing climate change adaptation measures (Hinkel, Bisaro, & Swart, 2015) and may lead the way to mainstreaming climate change adaptation in practice. Decision making under changing climatic conditions often requires weighing different adaptation options to reach an agreement on a best-fit and socio-economically viable solution. There are many participatory approaches for weighing non-mathematical variables and options, for example the Delphi Method, Cost-(CBA), and the (MCDA). Experience has shown that these have been applied to several decision-making processes, involving different options and the opinions of various stakeholders, decision makers, and local people. Many of these tools do not necessarily require an immediate interaction between the persons involved and can be conducted online. To reach agreements acceptable to all involved, experience has shown that the endorsement of communication and fostering of the interaction of different interest groups can be most valuable.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: 5 mm lateral from the midline, was prepared over the right or left primary sensori-motor area (S1-M1) of the cortex and the dura carefully removed while necessary care was taken to avoid damage the cortical tissue (Fig. 1a). The cortical surface was kept moist by topical Ringer solution application (in mM: 126 NaCl, 3. 5 KCl, 1. 24 NaH2PO4, 26 NaHCO3, 10 glucose, 2 CaCl2 and 1 MgSO4 at pH 7. 4). In a subset of experiments, the contra-lateral sciatic nerve was exposed and dissected free from the surrounding tissues (similar to)36, cut distally and then mounted on a custom-made hook-electrode (Fig. 1a). We used this arrangement for recording of compound action potentials in the motor axons projecting to skeletal muscles of the distal hindlimb, providing us a measure of the timing of cortical output compared with the peripheral motor activity. The skin surrounding the exposed muscles and nerves of the hindlimb was sewed to a metal frame forming a bath that was filled with warm paraffin oil to reduce current shunting to the bathing media. For the experiments in awake mice (Fig. 2a) we adapted a published protocol23. Briefly, mice were anaesthetised using KX, head restrained with a custom-made mini-frame glued to the skull with cyanoacrylate and habituated to the restraint over two days, with a total training duration of 3–4 hours. On the day of the experiment a craniotomy was prepared as described above in isoflurane anesthesia and the mice were allowed to recover from the anaesthesia for 1 hour prior to conducting the experiments in order to avoid any after-effects on cortical activity. The mice were during recordings placed in a behavioural tube to minimise movement and to comfort the mice (Fig. 2a)23 and the room was kept dark and quiet. Body temperature was maintained as described above. ElectrophysiologyWe recorded primary sensori-motor cortical layer II (100–150 μm below the pial surface) local field potentials (LFP) continuously using a NaCl-filled glass micro-electrode (Resistance 2–5 MΩ) connected to a DP-311 differential amplifier (). Filters were set at 0.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: These include potentiators (which increase the amount of CFTR in the cell membrane by preventing early degradation ‐ class III to V mutations) and 'stop‐codon therapies' which act to prevent structural abnormalities of CFTR that occur when premature stop codons terminate protein synthesis too early ‐ class I mutations). Cochrane reviews of studies assessing each of these interventions are in progress. Due to the underlying defects of the Phe508del mutation as mentioned in the additional tables (Table 1), it is possible that correctors may need to be combined with potentiators to achieve a clinical benefit. Why it is important to do this review Since CFTR correctors are novel therapies, it is important that randomised controlled trials (RCTs) testing these chemicals are critically appraised. This will enable examination of the evidence relating to the benefits and harms of CFTR correctors. It is important that funding bodies have a clear evidence base on which to assess new therapies for CF that aim to correct the basic defect. In addition, critical appraisal of included studies will help inform future study design. Phe508del (also known as F508del) is the most common CFTR mutation that causes CF, being found in up to 80% of people with CF. Phe508del is a class II mutation and a therapy that can correct this mutation will have a positive impact on a significant proportion of the CF population (Southern 1997); therefore, due to the number of patients who will be prescribed this treatment, it is likely that these therapies will represent a significant healthcare cost. This review aims to collate evidence from RCTs that have evaluated the benefits and harms of CFTR correctors for patients with CF. evaluate the effects of CFTR correctors on clinically important outcomes in children and adults with CF. The clinically important outcomes will include both benefits and harms that participants may experience. for considering studies for this review Types of studies We will include RCTs of parallel design (published or unpublished). We will not include quasi‐randomised studies. Additionally, we will not include cross‐over studies as we do not feel this study design is appropriate given that the intervention aims to correct the underlying defect. Types of participants We will include studies involving children or adults with CF, as confirmed either by the presence of two disease‐causing mutations, or by a combination of positive sweat test and recognised clinical features of CF.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: Sustainable climate change adaptation solutions can be reached by achieving a generally accepted understanding, by all involved interest groups and stakeholders, of the necessity to adapt to changing climatic conditions in any given area or place. This acceptance can be reached by the joint evaluation of options and their respective pros and cons. Among the great variety of participatory tools, scenario workshops have proven to be successful at providing a tool that supports communication among stakeholders, scientists, and decision makers. According to Slocum (2003), scenario workshops are useful when dealing with uncertainties related to climate change as they focus on and support long-term decision making by developing alternative options for future developments. Scenario workshops develop long-term story lines of possible future developments and are suitable to integrate natural hazards and climate change impacts into land-use planning. (Schmidt-Thomé et al. , 2014). ConclusionsClimate change adaptation largely takes place in an environment characterized by inherent uncertainties of climate models. It has proven most successful to use current extreme event patterns to analyze local vulnerabilities and resulting risks to achieve an understanding of adaptation needs, challenges, and potentials. The future is and will remain uncertain, no matter how sophisticated models might be one day. It is virtually impossible to foresee economic or climatic developments and their variances over longer time spans, though general trends and their impacts can be estimated. These estimates can serve as valuable sources to derive climate (change) adaptation policies and measures. Since climate change adaptation measures are implemented mainly at the local level, it will always remain crucial to tailor the measures according to current and short term socio-economic interests and demands. Adaptation measures have to respect local conditions and should support local development; otherwise, they might become socio-economically unbearable. If adaptation measures are too costly, they might be counter-productive, leading to economic downturns and making themselves obsolete. There are many potential futures that do not depend only on climate change. Local politics and economics, as well as social decision making are shaping factors for the future. Climate change models are valuable tools, but communication is the most important factor in making decisions on climate change adaptation measures. To achieve the implementation of sustainable climate change adaptation measures, the integration of large numbers of stakeholders, decision makers, and the private sector is key. Solutions should be structured in a way that climate change adaptation measures are not investments into a distant future.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: 1 Hz high-pass and 100 Hz low-pass and sampled at 10 kHz using a power1401 digitiser (Design, UK) and Spike2 version 6 (CED, UK) or pCLAMP 9. 2 software (). The electroneurogram (ENG) was recorded with a custom-made hook-electrode (Fig. 1a) connected to a DP-311 differential amplifier (Warner instruments, Hamden, USA) and high-pass and low-pass filtered at 1 Hz and 1 kHz, respectively. The ENG signal was digitised and sampled at 2 kHz using a power1401 digitizer (Design, UK) and Spike2 version 6 software (CED, UK). 2-photon in vivo microscopyFor visualising sulforhodamine 101 (SR101) uptake into cortical astrocytes in vivo (Figs 1b and 3b) we used 2-photon microscopy as previously described23. We used a custom-built (modified 300) microscope (Olympus software Fluoview 300) with a 20× water-immersion objective (NA 0. 95, 20XW, Olympus), linked to a Ti:sapphire laser (Mai Tai, Spectra-Physics). Excitation wavelength was set at 800 nm. The emitted light was separated with an emission filter (ET595/60 Chroma). The laser power going into the cortical tissue was in the range of 20–30 mW37. Dye applicationSR101 (Molecular Probes, S359) was dissolved in Ringer solution to concentrations of 25 μM, 50 μM, 100 μM or 250 μM, all within the range for what is used in the litterature4,15,19,20 (see S1). In some experiments we tested (Dextran, Molecular Probes, D1863), a tissue fixable analog of SR101, at concentrations of 100 μM or 500 μM. The dissolved dye was topically applied to the exposed dura-free cortical surface. Right before application of the dye, the Ringer solution bathing the craniotomy was carefully absorbed. The dye solution was then applied using a pipette onto the exposed cortex to cover the cranial window.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Skip to Our site uses cookies to improve your experience. You can find out more about our use of cookies in About Cookies, including instructions on how to turn off cookies if you wish to do so. By continuing to browse this site you agree to us using cookies as described in About Cookies. I accept evidence. Informed decisions. Better health. search Open menu language : language : Review language Select your preferred language for and other content. Sections without translation will be in English. Español فارسی Français हिन्दी Indonesia 日本語 한국어 ês Русский Română தமிழ் ภาษาไทย 繁體中文 简体中文 Website language Select your preferred language for the website. English Español (CDSR) for trials What's new (search and ) is created Search help quick guides Search FApublications in the of Editorial policies Information for authors translations What's new Data reuse options Permissions and reprints Media information Contact us Terms and conditions Known issues content content and plain language summary only and plain language summary only Cite this 0 language summary Authors' conclusions Summary of findings and tables 10. 1002/14651858. CD009841. pub3 Collapse all Expand all Abstract available in English Español فارسی Français 简体中文 fibrosis (CF) is the commonest inherited life‐shortening illness in white populations, caused by a mutation in the gene that codes for the cystic fibrosis transmembrane regulator protein (CFTR), which functions as a salt transporter. This mutation mainly affects the airways where excess salt absorption dehydrates the airway lining leading to impaired mucociliary clearance. Consequently, thick, sticky mucus accumulates making the airway prone to chronic infection and progressive inflammation; respiratory failure often ensues. Other complications include malnutrition, diabetes and subfertility. Increased understanding of the condition has allowed pharmaceutical companies to design mutation‐specific therapies targeting the underlying molecular defect.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: Where feasible, close cooperation with natural hazard mitigation and disaster risk management will support the justification of climate change adaptation measures, such as land use restrictions, investments in protective measures, and many others. Immediate benefits should be palpable, despite potential climate change impacts (e. g. , Schmidt-Thomé, Ivanona, & Schäfer, 2013; Schmidt-Thomé et al. , 2014) and ideally, no-regret measures that serve and improve current living conditions are generally perceived as beneficial to the living environment of an area. 86. Adger, W. N. , Barnett, J. , Brown, K. , Marshall, N. , & O’Brien, K. (2013). Cultural dimensions of climate change impacts and adaptation. Change, 3(2), 112–117. Adger, W. N. , Dessai S. , Goulden, M. , Hulme, M. , Lorenzoni, I. , Nelson, D. R. , et al. (2009). Are there social limits to adaptation to climate change? Climatic Change, 93, 335–354. Archer, D. , & Brovkin, V. (2008). The millennial atmospheric lifetime of anthropogenic CO2. Climatic Change, 90, 283–297. Barredo J. I. (2009). Normalised flood losses in Europe: 1970−2006. Sciences, 9, 97–104. Barredo J. I. (2010). No upward trend in normalised windstorm losses in Europe: 1970−2008. Sciences, 10, 97–104. Berkhout, F. (2012). Adaptation to climate change by organizations. Reviews: Climate Change, 3(1), 91–106. & Kabat, P. (2013). On the nature of barriers to climate change adaptation. Change, 13(5), 1119–1129. Burton, I. (2009). Deconstructing adaptation … & reconstructing. In E. L. F. Schipper & I. Burton (Eds. ), Reader on Adaptation (2010. Environmental Development, 6, 69–79. City of Helsinki. (2010). Helsingin kaupungin tulvastrategia [The strategy for flood management in the city of Helsinki].

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: The SR101 was kept on the cortical surface for 1, 10, 20 or 30 min, depending on the concentration used, all incubation durations were within the range for what is used in the literature (see S1) and carefully washed away using Ringer solution (see Supplementary Fig. S3). Only one SR101 concentration was used in each experiment. In four experiments we pressure ejected the SR101 (1 min pulse, 120–200 mbar; 100 μM SR101) onto the cortical surface under agarose (1. 5%, Sigma) and a glass coverslip. This approach enabled us to image the time course of astrocytic SR101 uptake using 2-photon microscopy (Fig. 1b). To eliminate the possibility that our experimental observations resulted from a contaminated batch of SR101 we used several different SR101 batches over the course of many months, all were bought from Molecular Probes. LFP analysisPower measurementsLFP processing and analysis was performed using (2015a, ). First, any 50 Hz or 60 Hz line noise were removed from the recording using the rmlinesc function, available from the Chronux 2. 0, an open-source, -based, data analysis toolbox available at The de-noised LFP was then down sampled to 1kHz using the resample function in. LFP traces chosen for power spectral analysis was then normalized to the z-score18 by subtracting the mean and dividing by the standard deviation of the LFP during the entire LFP recording. For exploring the frequency-domain dynamics in LFPs we used the mtspectrumc function, a multitaper method implemented in the Chronux 2. 0 toolbox38. For this analysis we used a padding factor of -1, time-bandwidth product of 3 and 5 tapers. For the frequency-domain graphs (Fig. 2c and Supplementary Fig. S1) a moving average and moving standard deviation with a window size of 50 was applied afterwards. Fig. S7 no moving average or moving standard deviation was applied, in order to show the raw frequency-domain dyamics. Fig. S1f the average power (in decibel) was determined for delta (1–4 Hz) and beta (12–30 Hz) LFP bands within period 1 (i. e. baseline) and period 2 (i. e.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Plain language summary available in English Español فارسی Français 简体中文 Ivacaftor (marketed as Kalydeco®), a new specific therapy for cystic fibrosis Review question How does ivacaftor affect clinical outcomes (survival, quality of life and lung function) in people with cystic fibrosis (CF)? people with CF, airway surfaces do not have enough water because of an abnormal protein; this makes it difficult to clear thick and sticky mucus, which leads to lung infections. Ivacaftor works on the abnormal protein in people with some mutations to allow the airways retain more water and better clear mucus, so fewer lung infections develop. Ivacaftor was aimed at people with class III and IV mutations, and has been studied in people with G551D (class III), R117H (class IV) and F508del (class II) mutations. Trial characteristics We included five trials (447 participants) comparing ivacaftor to placebo (dummy treatment with no active medication) lasting between four and 48 weeks. Three trials enrolled a total of 238 people with at least one copy of the G551D mutation, one trial enrolled 140 people with two copies of the F508del mutation and one enrolled 69 people with at least one copy of the R117H mutation. The evidence is up to date as of 21 November 2018. Key results F508del mutation The trial did not report any deaths or show improvements in lung function, quality of life scores or weight. Cough and pulmonary exacerbations (flare ups of lung disease) were the most reported adverse events when taking both ivacaftor and placebo; there were a similar number of flare ups for both groups. Sweat chloride concentrations were reduced with ivacaftor. G551D mutation No deaths were reported. Both children and adults taking ivacaftor showed improvements in lung function, but only adults reported higher quality of life scores. People given placebo reported more coughing and experienced more episodes of decreased lung function; more adults taking ivacaftor reported episodes of dizziness. Similar numbers of people taking ivacaftor and placebo delayed the course of medication, or withdrew from the trial altogether, due to side effects (e. g. psychological issues, liver disease, severe breathing problems). There were more serious pulmonary exacerbations whilst taking placebo compared to ivacaftor.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: Gerstengarbe, F. -W. , & Werner, P. C. (2009). A short update on Koeppen climate shifts in Europe between 1901 and 2003. Climatic Change, 92, 99–107. Grothmann, T. , & Patt, A. (2005). Adaptive capacity and human cognition: the process of individual adaptation to climate change. Change, 15(3), 199–213. Guemas, V. , Doblas-Reyes, F. J. , Andreu-Burillo, I. , & Asif, M. (2013). Retrospective prediction of the global warming slowdown in the past decade. Change, 3, 649–653. Hinkel, J. , Bisaro, A. , & Swart, B. (2015). Towards a diagnostic adaptation science. Change, 16, 1–5. Hitz, S. , & Smith, J. (2004) Estimating global impacts from climate change. Change, 14, 201–218. HSY (Authority). (2013). . Helsinki, Finland. IPCC (1990). Climate Change. . . IPCC. (2000). Special report on Emission Scenarios. Cambridge, U. K. : Press. IPCC. (2001). 2001. II: Impacts, Adaptation and Vulnerability. Annex B. Glossary of Terms. . IPCC. (2007a). 2007: Impacts, Adaptation and Vulnerability. Contribution of II to the Report of the on Climate Change. IPCC. (2007b). 2007: Synthesis Report. . IPCC (2012). Managing the Risks of and Disasters to Change Adaptation. A of I and II of the on Climate Change. IPCC (2014). 2014. Impacts, Adaptation, and Vulnerability. II Contribution to the Report of the on Climate Change. Jarva, J. , Nuottimäki, K. , Kankaanpää, S. , Tarvainen, P. , Schmidt-Thomé, P. , Kesäniemi, O. , Pusa, M. , Rautio, K. , Lampinen, H. , & Keskisaari, K. (2014). Climate-proof living environment.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: SR101-induced LFP activity) for both anaesthetised and awake recordings. The relative change in power density (i. e. period 2 vs period 1, reported in % of baseline) was then determined for both anaesthetised and awake recording. Time-frequency spectrograms were constructed using the multitaper method implemented in the mtspecgramc function in the Chronux 2. 0 toolbox38. For this analysis we used a padding factor of −1, a moving window of 2. 5 s in duration with a slide of 50 ms along the time axis and time-bandwidth product of 3 and 5 tapers. All power measurements are reported in units of decibel (dB) unless otherwise stated. Event detectionFor determining the individual event amplitude and event intervals for the synchronized cortical seizure-like activity (Figs 1d and 2e) we used custom-made procedures in. First a threshold was determined as 4 standard deviations (S. D. ) more negative than the mean LFP during baseline (first 5 min of recording) and synchronized cortical seizure-like events were located using this threshold. Next the amplitude and event interval was determined for all of the events in the recording. Amplitudes and event intervals across experiments were pooled and histograms produced using the histogram function with 40 bins in. We determined the synchronized cortical seizure-like activity onset and cessation relative to topical application of either 100 μM or 250 μM SR101 (Fig. 1e and Supplementary Fig. S2) using custom-made procedures in. For this we determined time-points for the first and last seizure-like event in a recording using a threshold determined as 4 standard deviations more negative than the mean LFP during baseline (first 5 min of recording) and calculated the delta times from the time-point of SR101 application. Correlation between LFP and ENG eventsFor determining the correlation between seizure-like events and ENG compound action potential events (Fig. 1f and Supplementary Fig. S4) we first determined the time-points for all the seizure-like events in a recording and converted the LFP recording into binaries, i. e. 0 if no seizure-like event and 1 if seizure-like event was present, using a threshold determined as 4 S. D. more negative than the mean LFP during baseline (first 5 min of recording).

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Adults taking ivacaftor were admitted to hospital less often and had fewer courses of intravenous antibiotics for exacerbations. Both children and adults and children increased their weight with ivacaftor. There was a drop in sweat chloride concentrations with ivacaftor. R117H mutation No deaths occurred in this trial. While quality of life scores improved with ivacaftor, lung function did not. Cough and pulmonary exacerbations (flare ups of lung disease) were the most reported adverse events when taking both ivacaftor and placebo; there were a similar number of flare ups for both groups. There was no difference in weight; but as for other mutations there was a reduction in sweat chloride concentration with ivacaftor. Evidence suggests that ivacaftor is an effective treatment for people (over six years of age) with cystic fibrosis and the G551D mutation, but not for those with the F508del or R117H mutations. Quality of the evidence In most trials, individuals were put into different treatment groups at random with equal chances of being given either placebo or ivacaftor; no one could work out which treatment the next person would receive, so that healthier people did not receive ivacaftor and make the results seem better. We were not sure whether anyone involved in the trial knew who was receiving which treatment and how this might affect results. No trials reported all results clearly; sometimes they did not report them in a way that we could use in the review and sometimes they did not report the data at all. This affected our certainty regarding the overall results. Information about some side effects was limited as not many people experienced them, therefore, it is difficult to judge whether there was a difference between treatment groups We judged the evidence in this review to be moderate to low quality. Trial funding sources All trials were sponsored by Incorporated. Institute of Health (NIH), the Foundation (CFF) and other non‐pharmaceutical funding bodies also supported the trials. Visual summary Authors' conclusions Implications for practice The F508del trial demonstrated no evidence to support the use of ivacaftor in those with the F508del mutation (2011). The two G551D phase 3 trials demonstrated a clinically relevant impact of ivacaftor on outcomes at 24 and 48 weeks in children (over six years of age) and adults with cystic fibrosis (CF) and the G551D mutation (2013; 2011).

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: Methodologies, tools, and practical recommendations for climate change adaptation in the Kymenlaakso and Uusimaa regions and the Area. Special report (GTK). of Finland, Espoo. Johnston, J. B. , & Dudly, W. C. (2009). Pacific island tsunami resilience planning guide. Tsunami hazard mitigation and disaster management. Solutions. Karl, T. R. , Arguez, A. , Huang, B. , (2015). Possible artifacts of data biases in the recent global surface warming hiatus. Science, 348(6242), 1469–1472. Keatinge W. , Donaldson G. , Cordioli E. , Martinelli M. , Kunst A. , Mackenbach J. , et al. (2000). Heat related mortality in warm and cold regions of Europe: Observational study. BMJ, 321, 670–673. Klein, J. , Mäntysalo, R. , & Juhola, S. (2015). Legitimacy of urban climate change adaptation: A case in Helsinki. Change, 16(3), 815–826. Knieling, J. , & Schaerffer, M. (2013). Climate adaptation in metropolis Hamburg: Paradigm shift in urban planning and water management towards “living with water”? In P. Schmidt-Thomé & J. Klein (Eds. ), Climate change adaptation in practice: From strategy development to implementation (836. Levina, E. , & Tirpak, D. (2006). Adaptation to climate change: Key terms. Paris: OECD/IEA. Luoma, S. , Klein, J. , & Backman, B. (2013). Climate change and groundwater: Impacts and adaptation in shallow coastal aquifer in Hanko, South Finland. In P. Schmidt-Thomé & J. Klein (Eds. ), Climate change adaptation in practice: From strategy development to implementation (2300. Climate Change, 109, 213–241. Commission. (2013). Glossary of terms and definitions on climate change and adaptation. . Ministerium für Bau, Landesentwicklung und Umwelt Mecklenburg-Vorpommern. (1993).

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: Next we screened the ENG recording for the presence of compound action potentials, using a threshold as 4 S. D. from the mean ENG during baseline (first 5 min of recording), in the time windows corresponding to where the binary LFP was 1. If ENG compound action potentials were present in the time window, that window was assigned 1 and if no compound action potentials were present assigned 0. Afterwards, we plotted the cumulative number of seizure-like LFP events versus the cumulative number of ENG compound action potential events at those time points and calculated the linear correlation using a Pearsons’s correlation test (Fig. 1f). StatisticsOur preliminary experiments suggested the existence of very large LFP changes from topical SR101 application. We therefore used the smallest number of mice that is neccesary to compare statistically based on power analysis considering that all mice exposed to 100 μM and 250 μM SR101 for 10 min developed seizure-like activity, which was not observed in any control experiments (see Supplementary Fig. S2). Statistical comparison between relative onsets- and cessation of seizure-like activity between 100 μM and 250 μM SR101 was assessed using a two-sided Welch’s t-test (Fig. 1d). This test was chosen due to the violation of the Student’s t-test assumptions, i. e. equal variances and sample sizes39. Statistical comparision for power spectral density in 1–4 Hz and 12–30 Hz LFP bands during baseline compared to during SR101-induced seizure-like activity was assessed using a paired Student’s t-test. We considered significant tests with P < 0. 05. Exact P-values are reported unless smaller than 0. 0001. For calculating the linear correlation between the cumulative number of seizure-like LFP events versus the cumulative number of ENG compound action potential events we used the Pearsons’s correlation test and reported the R2-value (Fig. 1e). Data is plotted as mean ± S. D. where appropriate. Figures were created with Illustrator CC 19. 2. 1 (Adobe, USA). Additional InformationHow to cite this 10. 1038/srep30433 (2016). 10. 1038/ncomms6422 (2014). 10. 1126/science. aaa7945 (2015). 10. 1038/nn. 4013 (2015). 10.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: The second most common mutation in the UK is the G551D mutation (class III mutation). This mutation exists in 514 (5. 84%) people with CF in the UK. The R117H mutation (class IV mutation) is the third most common mutation, present in 398 (4. 52%) people with CF in the UK (2013). Open in table viewerTable 1. Classes of mutations affecting CFTR production, structure, and function mutation Impact on CFTR structure and function I G542X Synthesis of CFTR is critically impaired, and no functional protein is produced. This is due to the presence of a premature stop codon in the nucleotide sequence. Individuals have minimal CFTR function. II ΔF508 A full length of CFTR is produced, but this is structurally abnormal and destroyed by the cell before it reaches the cell membrane. This is called a defect in the intracellular trafficking pathway. Minimal amounts of CFTR can escape being destroyed and be transported to the cell membrane. However here, class products display defective ion transport. Individuals have minimal CFTR function. III G551D CFTR is produced and embedded in the cell membrane, but the chloride channel does not respond (‘switch on’) to normal stimulation from the cell. This means there is no significant ion transport across the protein. Individuals have some residual CFTR function. IV R347P CFTR is transported to the outer cell membrane, and responds to normal stimulation, but functions at a low level because chloride ions do not cross the channel appropriately. Individuals have some residual CFTR function. V A455is produced, but the amount of protein is reduced. Individuals have some residual CFTR function. CFTR: cystic fibrosis transmembrane conductance regulator Description of the intervention Understanding how the mutations, which are described in the additional tables (Table 1), affect the production, structure, and function of CFTR has led to the concept of mutation‐specific therapies. One strategy, relating mainly to mutations classes III to V but also to class II, is to improve the function of CFTR that has reached the cell membrane, but whose function is compromised (McKone 2004). Drugs that improve CFTR function in the cell membrane are called potentiators and have the potential to correct the abnormal salt transport that characterises CF. Potentiators can be administered orally, or as an inhaled preparation.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: Generalplan Küsten- und Hochwasserschutz Mecklenburg-Vorpommern. Germany: Schwerin. Ministry of Agriculture and Forestry. (2005). Finland’s national strategy for adaptation to climate change. Publication 1a/2005. Helsinki, Finland. Ministry of Agriculture and Forestry. (2009). Evaluation of the implementation of Finland’s national strategy for adaptation to climate change. Ministry of Agriculture and Forestry 4a/2009. Helsinki, Finland. Ministry of Agriculture and Forestry. (2013). Ilmastonmuutoksen kansallisen sopeutumisstrategian arviointi. (Evaluation of Finland’s national strategy for adaptation to climate change). Project group memo 2013:5. Helsinki, Finland. Ministry of Agriculture and Forestry. (2014). Ilmastonmuutoksen kansallinen sopeutumisstrategia 2022. (National climate change adaptation strategy 2022). Draft 7. 3. 2014. Helsinki, Finland. Moser, S. C. , & Ekstrom, J. A. (2010). A framework to diagnose barriers to climate change adaptation. Proceedings of the of Sciences, 107(51), 22026–22031. Mundaca, L. T. , Markandya, A. , & Nørgaard, J. (2013). Walking away from a low‐carbon economy? Recent and historical trends using a regional decomposition analysis. Energy Policy, 61, 1471–1480. Munich Re. (2015). Topics Geo. Natural catastrophes 2014. Analyses, assessments, positions. Munich, Germany. Initiative for Rebuilding and Resiliency (2013). PlaNYC: A stronger, more resilient New York. New York. Ollila, M. (Ed. ). (2002). Ylimmät vedenkorkeudet ja sortumariskit ranta-alueille rakennettaessa. Suositus alimmista rakentamiskorkeuksista. (Highest water levels and risk of landslide when building on shores; Recommendations for the minimum permissible building heights). 52. Parjanne, A. , & Huokuna, M. (Eds. ).

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: 1016/j. neuron. 2009. 03. 019 (2009). 10. 1073/pnas. 1514209112 (2015). 101. Nat. Methods 11, 1081–1082, doi: 10. 1038/nmeth. 3140 (2014). 10. 1007/s00429-013-0645-0 (2013). 10. 1038/nmeth706 (2004). 10. 1016/j. neuroscience. 2010. 06. 020 (2010). 10. 1016/j. expneurol. 2012. 02. 009 (2013). 10. 3389/fnins. 2015. 00025 (2015). 10. 1111/epi. 12406 (2013). 10. 1152/jn. 01040. 2014 (2015). 10. 1007/s10867-011-9216-x (2011). 10. 1038/nm1277 (2005). 10. 1016/j. expneurol. 2013. 05. 004 (2013). 10. 1152/jn. 90770. 2008 (2009). 10. 1038/nm. 4084 (2016). Haiss, F. et al. Improved in vivo two-photon imaging after blood replacement by perfluorocarbon. J. Physiol. 587, 3153–3158, doi: 10. 1113/jphysiol. 2009. 169474 (2009). 10. 1172/JCI82859 (2016). 10. 1038/jcbfm. 2010. 204 (2011). 10. 1101/pdb. prot068155 (2012). 10. 1038/nm. 3400 (2013). 10. 1111/epi. 12247 (2013). 10. 1016/j. neuron. 2014 (2015). 10. 1016/j. neuron. 2014. 12. 059 (2010). 10. 1523/jneurosci. 4980-07. 2008 (2008). 10. 1073/pnas. 1311967110 (2013). 10. 1016/j. neuron. 2012. 01. 007 (2012). 10. 1038/nprot. 2006. 58 (2006). 10. 1016/0166-2236(90)90135-W (1990). 10. 1002/syn. 890140102 (1993). 10.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Two distinct approaches have resulted in the recognition of candidate drugs with this mode of action (Amaral 2007): testing of compounds known to affect CFTR or other ion‐channels (either pharmaceutical drugs or chemicals which occur naturally in plants, herbs, fruits or food components); high throughput screening, which involves testing large numbers of diverse chemicals, on laboratory cell lines, to identify which of these may stimulate CFTR. In addition to potentiators, other drugs which aim to correct defects of the CFTR are also under investigation in clinical trials. These include correctors (which increase the amount of CFTR in the cell membrane by preventing early degradation ‐ class II mutations) and 'stop‐codon therapies' which act to prevent structural abnormalities of CFTR that occur when premature stop codons terminate protein synthesis too early ‐ class I mutations). of trials assessing correctors and one assessing stop codon therapies have been published (Aslam 2017; Southern 2018). How the intervention might work The CFTR potentiator ivacaftor was identified through high‐throughput screening by Incorporated. In cell and animal models, it was able to restore CFTR function for class III mutations and correct the abnormal transmembrane salt transport (2009). However, the precise mechanism of action of ivacaftor is unclear, owing to the limited amount of data. The correction of the basic defect in CF in the airways of the lung could lead to the normalization of airway surface liquid; the resulting re‐establishment of mucociliary clearance, would then have a beneficial impact on the chronic infection and inflammation that characterizes CF lung disease. Why it is important to do this review Since CFTR potentiators are novel therapies, it is important that randomised controlled trials (RCTs) testing these agents are critically appraised. This will enable examination of the evidence relating to the benefits and harms of CFTR potentiators. It is important that funding bodies have a clear evidence base on which to assess new therapies for CF that aim to correct the basic defect, particularly given the large prevalence of people with mutations that might be impacted by CFTR potentiators. It is likely that these therapies will represent a significant healthcare resource. In addition, critical appraisal of included trials will help inform future trial design. This review aims to collate evidence from RCTs that have evaluated the benefits and harms of CFTR potentiators in people with CF.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: (2014). Tulviin varautuminen rakentamisessa. Opas alimpien rakentamiskorkeuksien määrittämiseksi ranta-alueilla. [Flood preparedness in building—guide for determining the lowest building elevations in shore areas]. 2014. Institute: Helsinki, Finland. Petersell, V. , Suuroja, S. , All, T. , & M. Shtokalenko. (2013). Impacts of sea level change to the coastal zone. In P. Schmidt-Thomé & J. Klein (Eds. ), Climate change adaptation in practice: From strategy development to implementation (2005. Review, 9(1), 29–42. Pollner, J. , Kryspin-Watson, J. , & Nieuwejaar, S. (2008). Disaster risk management and climate change adaptation in Europe and Central Asia. GFDRR/World BankRahmstorf, S. , & Schellnhuber, H. J. (2006). Der Klimawandel: Diagnose, Prognose, Therapie. Munich: Germany, C. H. Beck. Raupach, M. R. , Marland, G. , Ciais, P. , Quéré, C. L. , Canadell, J. G. , Klepper, G. , & Field, C. B. (2007). Global and regional drivers of accelerating CO2 emissions. Proceedings of the of Sciences, 104(24), 10288–10293. Rial, J. A. , Pielke, Sr. , R. A. , Beniston, M. , Claussen, M. , Canadell, J. , Cox, P. , et al. (2004). Nonlinearities, feedbacks and critical thresholds within the Earth’s climate system. Climatic Change, 65(1–2), 11–38. Rimkus, E. , Kažys, J. , Stonevičius, E. , & Valiuškevičius, G. (2013). Adaptation to climate change in the Smeltalė River basin, Lithuania. In P. Schmidt-Thomé & J. Klein (Eds.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: This potential toxic effect may even have resulted in accumulation of mutants that grow faster than the originally inoculated strain due to reduced scFv173-2-5-AP production. The maximal expression level is obviously very important in the context of recombinant protein production, and Figure 2 shows that in this respect none of the systems is superior for all proteins. Generally XylS/Pm ML1-17 and LacI/P T7lac tended to produce most recombinant protein in the studies in strain ER2566 (Figure 2, Panels A-C). The mutations in the Pm core region were of vital importance, as XylS/Pm ML1-17 produced between 1. 2- and 4. 0- fold more active protein than the corresponding wild-type system. Note also that AraC/P BAD generated similar amounts of active protein compared to XylS/Pm ML1-17 when the studies were done in an ara negative strain (DH10B; Figure 2, Panels D-F). LacI/P T7lac is generally known to be a very strong system because of the efficient transcription exerted by the T7 RNA polymerase [9, 40], but the comparative analysis demonstrated that this system was not superior to XylS/Pm ML1-17 for the genes studied here. Especially in the higher copy-number plasmids, up to four times more activity was detected in strains harboring XylS/Pm ML1-17. We also noted in this and other related ongoing studies in our laboratory that to get stable expression from the LacI/P T7lac system, ER2566 cells needed to be freshly transformed prior to expression studies, as also recommended by Vethanayagam and Flower [42]. Similar observations were not made for any of the other three systems. Figure 2Maximum expression of three different genes placed under control of different regulator/promoter systems. Data represent relative expression levels under induced conditions where the activity of M1x (gene x under conrol of the Pm wildtype promoter, RK2 replicon) was set to 1. 0. Expression was induced in a way that activity levels were maximized: 2 mM m-toluate for strains harboring XylS/Pm- based constructs, 1 mM IPTG for those with LacI/PT7lac, 0.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: Three trials examined the impact of ivacaftor on people with a class III mutation (G551D) (Accurso 2010; 2013; 2011). One trial enrolled participants with a class II mutation (F508del) (2011) and one enrolled participants with a class IV mutation (R117H) (2015). The trial that evaluated ivacaftor for people with F508del enrolled participants aged 12 years or over (n = 140) for a duration of 16 weeks (2011). The first G551D trial was a phase 2 trial enrolling participants 18 years and over and measuring a number of outcomes at 14 and 28 days (Accurso 2010). This was followed by two phase 3 trials, the first enrolling participants aged 12 years and older (n = 167) (2011) and the second enrolled participants aged 6 to 11 years (n = 52) (2013). These trials reported outcomes at 24 and 48 weeks. The R117H trial enrolled participants over six years of age (n = 69) and measured outcomes at 24 weeks (2015). The primary end points for these trials were safety (Accurso 2010) or change in FEV1 (2013; 2015; 2011) or both (2011). With respect to this review's primary outcomes, there were no deaths reported in any of the trials and the length and size of the trials precluded valid assessment of the impact of ivacaftor on survival. For CFQ‐R scores, no significant difference was reported in the F508del trial (2011). The adults randomised to ivacaftor in the phase 2 G551D trial did not report significantly higher CFQ‐R respiratory domain scores 28 days (Accurso 2010). However, adults in the phase 3 G551D trial reported significantly higher CFQ‐R respiratory scores at 24 weeks, MD 8. 10 (95% CI 4. 63 to 11. 57) and at 48 weeks, MD 8. 70 (95% CI 5. 51 to 11. 89) (Analysis 2. 3). This finding was not reproduced in the paediatric participants (2013). The R117H trial reported significantly higher CFQ‐R scores at 24 weeks in participants randomised to ivacaftor, MD 8. 40 (95% CI 2. 17 to 14. 63) (Analysis 3. 1) (2015).

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: ), Climate change adaptation in practice—From strategy development to implementation (1248. Schmidt-Thomé, K. , & Peltonen, L. (2006). Actors, networks and actor-networks in coping with sea level rise. In P. Schmidt-Thomé (Ed. ), Sea level change affecting the spatial development in the region (41. Espoo, Finland. Schmidt-Thomé, P. , & Kaulbarsz, D. (2008). Communicating uncertainty in climate change adaptation and decision support: Further development of the Gdańsk case study. In D. G. E. Liverman, C. Pereira, & B. Marker (Eds. ), Communicating environmental geoscience (305. London: Geological Society. Schmidt-Thomé, P. , & Klein, J. (2011). Applying climate change adaptation in spatial planning processes. In G. Schernewski, J. Hofstede, & T. Neumann (Eds. ), Global change and Baltic coastal zones (141. Stern, N. (2006). Stern review on the economics of climate change. Report to the and the Chancellor of the Exchequer on the Economics of Climate Change. H. M. Treasury. UNEP. (2014). The adaptation gap report 2014. (UNEP). Nairobi, Kenya. . (2015). Glossary of climate change acronyms. on Climate Change. . (2009). Terminology on disaster risk reduction. for Disaster Reduction. Geneva, Switzerland. . (2012). Disaster risk reduction and climate change adaptation in the Pacific: An institutional and policy analysis. Suva, Fiji. United Nations. (1992). framework convention on climate change. United Nations. United Nations. (2014). World urbanization prospects: The 2014 revision. United Nations. Van Aalst, M. K. , Cannon, T. , & Burton, I. (2008). Community level adaptation to climate change: The potential role of participatory community risk assessment. Change, 18(1), 165–179Van Vuuren, D. P. , Edmonds, J. , Kainuma, M. , Riahi, K. , Thomson, A. , Hibbard, K. , et al. (2011). The representative concentration pathways: An overview.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: In case of luciferase the amount of active protein was highest for XylS/Pm ML1-17 both according to activity measurements (see above) and deduced as soluble protein (Figure 3, Panel A). However, the very high level of transcription in the LacI/P T7lac system resulted in a correspondingly big production of insoluble and inactive luciferase protein, not seen to a comparable extent for any of the other systems. Figure 3Correlation between the accumulated transcript and protein produced after induction. The five proteins (Panels A-E) were expressed in E. coli ER2566 harboring pMB1-based plasmids. Five hours after induction, samples were collected for relative quantification real-time RT-PCR (qRT-PCR) and SDS-PAGE. Accumulated transcript data were correlated to the XylS/Pm system (M2x; gene x under conrol of the Pm wildtype promoter, pMB1 replicon). The total protein fractions were separated into the soluble supernatant and the insoluble pellet fraction after sonication and separated through SDS-PAGE followed by staining with blue. Further information about the naming system can be found in Table 1. Neg: Negative control. Full size imageFor GFP and HGH (and D) production of soluble protein was very effective in both XylS/Pm ML1-17 and LacI/P T7lac and the final outcome at the protein level was more similar for these proteins than for luciferase. Generally, LacI/P T7lac had an apparent advantage by its performance at the transcriptional level, but this potential was often not reflected at the translational level, such that the system often produced a vast amount of transcripts that were either translated into inactive protein or were not translated at all. Note also that the amounts of protein and transcript correlated well for XylS/Pm and XylS/Pm ML1-17 (except for scFv173-2-5-AP, Panel B), probably mainly because the amounts of transcript were generally much lower than for LacI/P T7lac and therefore did not overload the translational machinery.

Output: pass


Input: Claim: Some cancers are treated more effectively with therapies tailored to specific genetic mutations. [SEP] Text: 4 Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 4 Adverse events in > 15% of participants. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 3. 5 Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 5 Summary of pulmonary exacerbations. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 3. 6 Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 6 Time to first pulmonary exacerbation. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 3. 7 Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 7 FEV1 predicted % absolute change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 3. 8 Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 8 BMI absolute change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Figures and Tables - Analysis 3. 9 Comparison 3 Ivacaftor (VX‐770) versus placebo in people with at least one R117H CFTR mutation, Outcome 9 Sweat chloride concentration ‐ change from baseline. Using systematic reviews (free)Navigate to figure in ReviewPrint figureOpen in new tab Summary of findings for the main comparison.

Output: corroborate


Input: Claim: Climate adaptation alone can fully counteract the effects of climate change. [SEP] Text: KeywordsWater resourcesClimate adaptationClimate variability and changeWater supplyHydropowerHydrologyStationarityUtility economicsPublic finance IntroductionThere is international agreement at the about the need for collective action to address the likely impacts of global warming on human societies. One response has been to encourage all sectors of society to identify and implement actions that can help adapt to the emerging impacts of climate change and work to mitigate its drivers. Water resources and the services dependent on them are an integral part of the climate system (Chahine 1992). Because of this, the managers of water resource systems and of the services that depend on them must develop appropriate responses to the potential impacts of climate change (Strzepek et al. 2011). continent is considered to be particularly vulnerable to these impacts both because of their magnitude and because African societies have less physical, financial, and human resources available to address these impacts. A further challenge is that the impacts of climate change on water resources are local, diverse, and not well-characterized. Unlike the general global warming trend, for which there is robust evidence that is consistent with the predicted impact of anthropogenic activities, direct evidence of significant changes in hydrological variables is not nearly as strong and consistent. For example, it appears that at a global level, precipitation is increasing (Adler et al. 2017). However, models predict increases in drought frequency over significant areas due to warming (Ukkola et al. 2020) although empirical evidence in support of this is limited (Hegerl et al. 2019) and predictions are based on various definitions of drought. While warming trends are a direct result of anthropogenically induced atmospheric changes that act through a single dominant mechanism at global level, the impacts on the main hydrological processes – evaporation, precipitation, runoff, and infiltration – are secondary and tertiary effects that are further influenced by a wide variety of mechanisms at a local, regional, and global level. So while there is only a limited increase in global precipitation averages, there are more extensive regional variations and substantial changes in parameters such as rainfall intensity (Trenberth 2011) which, coupled with the impact of warmer temperatures on aridity, lead to changes in tertiary variables such as stream flow. The likely impact of climate change on hydrological processes is generally still too uncertain to make it possible for water resource planners and managers to identify locally specific adaptive measures.

Output: contrast


Input: Claim: Chassis organisms like E. coli are commonly used for synthetic gene construction. [SEP] Text: It is also interesting to note that, in terms of both active and total protein produced, XylS/Pm ML1-17 and LacI/P T7lac generally performed best. For scFv173-2-5-AP (Figure 3, Panel B) a more complex picture was observed, but this could be mainly related to the effects of toxic protein production on host growth or variability among the systems in the kinetics of induction [46]. Uninduced expression levels are highest for LacI/P trc and lowest for AraC/P BAD The tightness of the different regulator/promoter systems is another important feature, particularly for production of host-toxic proteins [47]. We studied this with the same set-up as for induced conditions, using luciferase, scFv173-2-5-AP and GFP, and as expected the background increased for all systems when the higher copy number vectors were used. The increase was in most cases approximately proportional to that of the plasmid copy number. Therefore, only findings collected from strains harboring pMB1-based plasmids are presented (Figure 4). Figure 4Investigation of the tightness of different regulator/promoter systems in combination with the pMB1 replicon. Protein activity was determined in parallel with induced cultures at the time point corresponding to five hours after induction. The data presented are from independet biological replica. The following E. coli strains were used as expression hosts. Panels A-C: ER2566. Panels D-E: DH10B. The capital letters represent the regulator/ promoter systems according to Table 1. Uninduced expression of GFP in DH10B was very close to the detection limit in LB medium and was left out. Full size imageGenerally, LacI/P trc tended to be the leakiest system producing 3. 8 to 8. 2 times more active protein than XylS/Pm under uninduced conditions. Similarly, XylS/Pm ML1-17 displayed 2. 8- to 5. 8-fold higher background expression than the wild-type system. AraC/P BAD appeared to be, as expected, the tightest system giving rise to 0. 1 and 0. 4 times the background level for luciferase and scFv173-2-5-AP, respectively.

Output: pass