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Objective To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care. Methods PROVE was a retrospective, non‐interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure‐freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment‐emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme‐inducing antiseizure medications (EIASMs). Results Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24‐month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent. Significance In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

Background House dust mite (HDM) allergens constitute the most frequent cause of persistent allergic rhinitis and asthma. The symptoms vary throughout the year but typically peak in spring, autumn and (to a lesser extent) mid-winter. Methods We performed a 13-month, observational, multicentre survey of adult patients with a self-reported history of moderate-to-severe, poorly controlled, physician-diagnosed HDM respiratory allergy in three European countries (France, Italy and Spain). After screening and inclusion, 28 detailed, fortnightly telephone interviews were used to gather extensive data on the participants’ symptom prevalence and intensity, medical consultations, disease burden and medication use from late May 2012 to early July 2013. This report focuses on the disease burden. Results Of the 22,995 screened participants, 313 met the inclusion criteria and completed the post-inclusion questionnaire ( n  = 114 in Italy, 92 in France and 107 in Spain). The median time since the first symptoms of HDM allergy was ≥ 13 years in each country. A relevant minority of the participants suffered from symptoms of HDM allergy every day or almost every day of the year (14% in Italy, 46% in France and 37% in Spain). According to the fortnightly telephone interviews, the most frequently impacted disease burden variables were sleep, daytime tiredness and irritability, with the highest values in spring 2012, autumn 2012 and spring 2013 (mirroring symptom intensities). Professional activities were more affected than social activities. The burden data were heterogeneous: around a quarter of participants were strongly or very strongly affected but most of the remaining participants were only rarely bothered or not bothered. Conclusions In a 13-month, fortnightly survey of patients in France, Italy and Spain with a self-reported history of moderate-to-severe, poorly controlled, HDM-induced allergic rhinitis and asthma, we found that a relevant minority of participants regularly reported a severe or very severe impact of their allergy on tiredness, sleep and professional activities (including time off work). The disease burden peaked in autumn and late spring.

Eurasian watermilfoil (Myriophyllum spicatum) is a non‐native and invasive aquatic macrophyte with a broad North American distribution. It can have significant negative effects on invaded waterbodies, including decreased native macrophyte diversity, formation of recreational nuisances, and lowered lakefront property values. Previous research suggests that M. spicatum decreases in response to herbicide treatment, but most studies are spatially and temporally limited, usually focusing on a single waterbody for a single year. The long‐term effects of herbicides remain relatively unknown. Here, we share the results of an 11‐yr observational study of aquatic macrophyte diversity, dynamics, and response to herbicide treatment on 28 Wisconsin lakes (15 of which were adaptively managed with herbicide for M. spicatum and 13 of which acted as unmanaged reference lakes). We found that overall, adaptive management decreases M. spicatum abundance over time, but that the efficacy of individual herbicide treatments can vary. We also found that lakes with relatively new M. spicatum populations (discovered within the last decade) treated smaller areas with lower frequency than lakes with established populations, and were able to maintain lower M. spicatum abundance. This suggests that using adaptive, science‐based aquatic plant management strategies, including early detection and response, may increase invasive species management success. Finally, we show that the effect of herbicide treatment on native macrophytes is variable and can be significant. Overall, our results suggest that while herbicide treatment can be an effective adaptive management tool, particularly in lakes with relatively recent M. spicatum invasions, the specific effects of individual treatments can be unpredictable. This study allows lake stakeholders to better understand the efficacy of herbicide treatment, in addition to the possible non‐target effects on native macrophyte species.

The Collective Clemency Bill passed by the Italian Parliament in July 2006 represents a natural experiment to analyze the behavioral response of individuals to an exogenous manipulation of prison sentences. On the basis of a unique data set on the postrelease behavior of former inmates, we find that 1 month less time served in prison commuted into 1 month more in expected sentence for future crimes reduces the probability of recidivism by 0.16 percentage points. From this result we estimate an elasticity of average recidivism with respect to the expected punishment equal to −0.74 for a 7‐month period.

Background: Multiple sclerosis (MS) is a chronic disease that may require decades of ongoing treatment. Therefore, the long-term safety and efficacy of disease-modifying therapies is an important consideration. Methods: The LONGTERMS study evaluated the safety and efficacy of fingolimod in patients with relapsing MS (RMS) with up to 14 years of exposure. This phase IIIb, open-label extension study included patients aged ⩾ 18 years with confirmed RMS diagnosis who completed previous phase II/III/IIIb core/extension studies of fingolimod. Patients received fingolimod 0.5 mg orally once daily; safety and efficacy (clinical and magnetic resonance imaging) were the main outcomes. Results: Of 4086 patients from the core studies who entered LONGTERMS, 3480 (85.2%) completed the study. The median age (range) was 38 (17–65) years and median fingolimod exposure was 944.5 (range 75–4777) days. Overall, 85.5% of patients experienced at least one adverse event (AE); most common AEs (⩾10%) were viral upper respiratory tract infection (17.3%), headache (13.3%), hypertension (11.0%) and lymphopenia (10.7%). Among patients with serious AEs (12.6%), basal cell carcinoma and MS relapse (0.9% each) were most frequently reported. The aggregate annualized relapse rate decreased from 0.22 (in years 0–2) to 0.17 (years 0–10); 45.5% of patients remained relapse free after 10 years. At year 10, 63.2% of patients were free from 6-month confirmed disability worsening. Conclusion: This long-term observational study of patients treated for up to 14 years with fingolimod confirmed its established safety profile with no new safety concerns. Patients with RMS receiving fingolimod had sustained low levels of disease activity and progression. Trial Registration: ClinicalTrials.gov identifier: NCT01201356.

The literature on causal discovery has focused on interventions that involve randomly assigning values to a single variable. But such a randomized intervention is not the only possibility, nor is it always optimal. In some cases it is impossible or it would be unethical to perform such an intervention. We provide an account of ‘hard’ and ‘soft’ interventions and discuss what they can contribute to causal discovery. We also describe how the choice of the optimal intervention(s) depends heavily on the particular experimental setup and the assumptions that can be made.

In 1995, Crawford and Ostrom proposed a grammatical syntax for examining institutional statements (i.e., rules, norms, and strategies) as part of the institutional analysis and development framework. This article constitutes the first attempt at applying the grammatical syntax to code institutional statements using two pieces of U.S. legislation. The authors illustrate how the grammatical syntax can serve as a basis for collecting, presenting, and analyzing data in a way that is reliable and conveys valid and substantive meaning for the researcher. The article concludes by describing some implementation challenges and ideas for future theoretical and field research.

Objective To evaluate the relation of symptom onset to balloon time and door to balloon time with long term clinical outcome in patients with ST segment elevation myocardial infarction (STEMI) having primary percutaneous coronary intervention.Design Observation of large cohort of patients with acute myocardial infarction.Setting 26 tertiary hospitals in Japan.Participants 3391 patients with STEMI who had primary percutaneous coronary intervention within 24 hours of symptom onset.Main outcome measures Composite of death and congestive heart failure, compared by onset to balloon time and door to balloon time.Results Compared with an onset to balloon time greater than 3 hours, a time of less than 3 hours was associated with a lower incidence of a composite of death and congestive heart failure (13.5% (123/964) v 19.2% (429/2427), P<0.001; relative risk reduction 29.7%). After adjustment for confounders, a short onset to balloon time was independently associated with a lower risk of the composite endpoint (adjusted hazard ratio 0.70, 95% confidence interval 0.56 to 0.88; P=0.002). However, no significant difference was found in the incidence of a composite of death and congestive heart failure between the two groups of patients with short (≤90 minutes) and long (>90 minutes) door to balloon time (16.7% (270/1671) v 18.4% (282/1720), P=0.54; relative risk reduction 9.2%). After adjustment for confounders, no significant difference was seen in the risk of the composite endpoint between the two groups of patients with short and long door to balloon time (adjusted hazard ratio: 0.98, 0.78 to 1.24: P=0.87). A door to balloon time of less than 90 minutes was associated with a lower incidence of a composite of death and congestive heart failure in patients who presented within 2 hours of symptom onset (11.9% (74/883) v 18.1% (147/655), P=0.01; relative risk reduction 34.3%) but not in patients who presented later (19.7% (196/788) v 18.7% (135/1065), P=0.44; −5.3%). Short door to balloon time was independently associated with a lower risk of a composite of death and congestive heart failure in patients with early presentation (adjusted hazard ratio 0.58, 0.38 to 0.87; P=0.009) but not in patients with delayed presentation (1.57, 1.12 to 2.18; P=0.008). A significant interaction was seen between door to balloon time and time to presentation (interaction P=0.01).Conclusions Short onset to balloon time was associated with better 3 year clinical outcome in patients with STEMI having primary percutaneous coronary intervention, whereas the benefit of short door to balloon time was limited to patients who presented early. Efforts to minimise onset to balloon time, including reduction of patient related delay, should be recommended to improve clinical outcome in STEMI patients.

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms.

The impact of a biological invasion on native communities is expected to be uneven across invaded landscapes due to differences in local abiotic conditions, invader abundance, and traits and composition of the native community. One way to improve predictive ability about the impact of an invasive species given variable conditions is to exploit known mechanisms driving invasive species' success. Invasive plants frequently exhibit allelopathic traits, which can be directly toxic to plants or indirectly impact them via disruption of root symbionts, including mycorrhizal fungi. The indirect mechanism – mutualism disruption – is predicted to impact plants that rely on mycorrhizas but not affect non‐mycorrhizal plant species. To assess whether invader‐driven mutualism disruption explains observed changes in native plant communities, we analyzed long‐term (1998–2018) plant cover data from forest plots across the state of Illinois. We evaluated native plant communities experiencing a range of abundance of invasive allelopathic garlic mustard Alliaria petiolata and varying environmental conditions. Consistent with the mutualism disruption hypothesis, we showed that as garlic mustard abundance increased over time in 0.25 m2 sampling quadrats, the abundance of mycorrhizal plant species decreased, but non‐mycorrhizal plant species did not. Over space and time, garlic mustard abundance predicted plant abundances and diversity at the quadrat level, but this relationship was not present at a larger scale when quadrats were aggregated within sites. Garlic mustard's impact on the plant community was highly localized, yet it was as important as abiotic variables for predicting local plant diversity. We showed that garlic mustard abundance was a key predictor of patterns of plant diversity across invasion intensity and environmental heterogeneity in a way that is consistent with mutualism disruption. Our work indicates that the mutualism disruption hypothesis can provide generalizable predictions of the impacts of allelopathic invasive plants that are evident at a broad spatial scale.