| 1. |
- Arance, Ana, et al.
(författare)
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Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination.
- 2023
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 41:1, s. 75-85
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Tidskriftsartikel (refereegranskat)abstract
- Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
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| 2. |
- Ascierto, Paolo A, et al.
(författare)
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Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial.
- 2019
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Ingår i: JAMA oncology. - : American Medical Association (AMA). - 2374-2445 .- 2374-2437. ; 5:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors.To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation.Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks).Overall survival.At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P<.001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects.Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.ClinicalTrials.gov identifier: NCT01721772.
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| 3. |
- Falster, Daniel, et al.
(författare)
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AusTraits, a curated plant trait database for the Australian flora
- 2021
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Ingår i: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge.
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| 4. |
- Forouzanfar, Mohammad H, et al.
(författare)
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Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013.
- 2015
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
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| 5. |
- Gauld, Jethro G., et al.
(författare)
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Hotspots in the grid : Avian sensitivity and vulnerability to collision risk from energy infrastructure interactions in Europe and North Africa
- 2022
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Ingår i: Journal of Applied Ecology. - : John Wiley & Sons. - 0021-8901 .- 1365-2664. ; 59:6, s. 1496-1512
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Tidskriftsartikel (refereegranskat)abstract
- Wind turbines and power lines can cause bird mortality due to collision or electrocution. The biodiversity impacts of energy infrastructure (EI) can be minimised through effective landscape-scale planning and mitigation. The identification of high-vulnerability areas is urgently needed to assess potential cumulative impacts of EI while supporting the transition to zero carbon energy. We collected GPS location data from 1,454 birds from 27 species susceptible to collision within Europe and North Africa and identified areas where tracked birds are most at risk of colliding with existing EI. Sensitivity to EI development was estimated for wind turbines and power lines by calculating the proportion of GPS flight locations at heights where birds were at risk of collision and accounting for species' specific susceptibility to collision. We mapped the maximum collision sensitivity value obtained across all species, in each 5 x 5 km grid cell, across Europe and North Africa. Vulnerability to collision was obtained by overlaying the sensitivity surfaces with density of wind turbines and transmission power lines. Results: Exposure to risk varied across the 27 species, with some species flying consistently at heights where they risk collision. For areas with sufficient tracking data within Europe and North Africa, 13.6% of the area was classified as high sensitivity to wind turbines and 9.4% was classified as high sensitivity to transmission power lines. Sensitive areas were concentrated within important migratory corridors and along coastlines. Hotspots of vulnerability to collision with wind turbines and transmission power lines (2018 data) were scattered across the study region with highest concentrations occurring in central Europe, near the strait of Gibraltar and the Bosporus in Turkey. Synthesis and applications. We identify the areas of Europe and North Africa that are most sensitive for the specific populations of birds for which sufficient GPS tracking data at high spatial resolution were available. We also map vulnerability hotspots where mitigation at existing EI should be prioritised to reduce collision risks. As tracking data availability improves our method could be applied to more species and areas to help reduce bird-EI conflicts.
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| 6. |
- Reilly, Colin, 1977, et al.
(författare)
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Academic achievement in school-aged children with active epilepsy: A population-based study.
- 2014
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Ingår i: Epilepsia. - : Wiley. - 1528-1167 .- 0013-9580. ; 55:12, s. 1910-1917
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To provide population-based data on the performance of school-aged children with epilepsy on measures of academic achievement and factors associated with this performance after controlling for IQ. METHODS: Eighty-five (74%) of 115 children with "active" epilepsy (experienced a seizure in the past year and/or on antiepileptic drugs [AEDs]) underwent psychological assessment including measures of IQ, aspects of working memory and processing speed. Sixty-five of the 85 were able to complete subtests on the Wide Range Achievement Test-Fourth Edition (WRAT-4). Paired sample t-tests were conducted to compare subtest scores. Factors associated with academic performance after controlling for IQ were examined using linear regression. RESULTS: Seventy-two percent of the children, who could complete subtests on the WRAT-4, displayed "low achievement" (1 standard deviation [SD] below test mean) and 42% displayed "underachievement" (1 SD below assessed IQ) on at least one of the four WRAT-4 subtests. The mean scores on the Math Computation subtest and Sentence Comprehension subtest were significantly lower than scores on the Word Reading (p < 0.05) and Spelling (p < 0.001) subtests. Younger age at seizure onset was associated (p < 0.05) with decreased scores on three of the four WRAT-4 subtests after controlling for IQ. Difficulties with auditory working memory were associated with difficulties on reading comprehension (p < 0.05), and parent-reported difficulties with school attendance were associated with decreased scores on the Spelling and Word Reading subtests after controlling for IQ (p < 0.05). SIGNIFICANCE: Difficulties with academic achievement are common in school-aged children with "active" epilepsy. Much of the difficulties can be attributed to lowered global cognition. However, specific cognitive deficits, younger onset of first seizure, and school attendance difficulties may contribute to difficulties independent of global cognition. There is a need to screen all children with "active" epilepsy for difficulties in school achievement, to identify contributory factors and to identify efficacious interventions for ameliorating such difficulties.
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| 7. |
- Reilly, Colin, 1977, et al.
(författare)
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Cognition in school-aged children with "active" epilepsy: A population-based study.
- 2015
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Ingår i: Journal of clinical and experimental neuropsychology. - : Informa UK Limited. - 1744-411X .- 1380-3395. ; 37:4, s. 429-438
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: There is a lack of population-based data on specific cognitive profiles in childhood epilepsy. This study sought to determine the frequency of impairments in global cognition and aspects of working memory and processing speed in a population-based sample of children with "active" epilepsy (on antiepileptic Drugs (AEDs), and/or had a seizure in the last year). Factors significantly associated with global and specific difficulties in cognition were also identified. METHOD: A total of 85 (74% of eligible population) school-aged children (5-15 years) with "active" epilepsy underwent comprehensive psychological assessment including assessment of global cognition, working memory, and processing speed. Scores on cognitive subtests were compared via paired-samples t tests. The factors associated with cognitive difficulties were analyzed via linear regression. RESULTS: A total of 24% of children were functioning below IQ 50, and 40% had IQ scores below 70. Scores on the Processing Speed Index were significantly lower than scores on the Verbal or Performance indexes on Wechsler instruments. The Coding subtest was a significant weakness compared with the other Wechsler subtests. A total of 58% of children displayed "memory underachievement" (memory score 1 SD below assessed IQ) on at least one of the four administered working memory subtests. Factors significantly associated with globally impaired cognition included being on polytherapy (β = -13.0; 95% CI [-19.3, -6.6], p = .000) and having attention-deficit/hyperactivity disorder (ADHD; β = -11.1, 95% CI [-3.0, -19.3], p = .008). Being on polytherapy was also associated with lower scores on the working memory and processing speed composite scores. Having developmental coordination disorder (DCD) was associated with a lower score on the processing speed composite. CONCLUSIONS: There is a high rate of global and specific cognitive difficulties in childhood epilepsy. Difficulties are most pronounced in aspects of working memory and processing speed. Predictors of cognitive impairment in childhood epilepsy include epilepsy-related and behavioral factors, which may differ depending on the domain of cognition assessed.
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| 8. |
- Reilly, Colin, 1977, et al.
(författare)
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Factors associated with quality of life in active childhood epilepsy: A population-based study.
- 2015
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Ingår i: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. - : Elsevier BV. - 1532-2130. ; 19:3, s. 308-313
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Improving health-related quality of life (HRQOL), rather than just reducing seizures, should be the principal goal in comprehensive management of childhood epilepsy. There is a lack of population-based data on predictors of HRQOL in childhood epilepsy. METHODS: The Children with Epilepsy in Sussex Schools (CHESS) study is a prospective, population-based study involving school-aged children (5-15 years) with active epilepsy (on one or more AED and/or had a seizure in the last year) in a defined geographical area in the UK. Eighty-five of 115 (74% of eligible population) children underwent comprehensive psychological assessment including measures of cognition, behaviour, and motor functioning. Parents of the children completed the Quality of Life in Childhood Epilepsy (QOLCE).Clinical data on eligible children was extracted using a standardised pro forma. Linear regression analysis was undertaken to identify factors significantly associated with total Quality of Life in this population. RESULTS: Factors independently significantly associated (p < .05) with total QOLCE scores were seizures before 24 months, cognitive impairment (IQ < 85), anxiety, and parent reported school attendance difficulty. These factors were also significantly associated with total QOLCE when children with IQ < 50 were excluded from analysis. CONCLUSIONS: The majority of factors associated with parent reported HRQOL in active childhood epilepsy are related to neurobehavioural and/or psychosocial aspects of the condition.
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| 9. |
- Reilly, Colin, 1977, et al.
(författare)
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Features of autism spectrum disorder (ASD) in childhood epilepsy: A population-based study.
- 2015
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Ingår i: Epilepsy & behavior : E&B. - : Elsevier BV. - 1525-5069. ; 42C, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- In a defined geographical area in the south of the UK, 115 children with active epilepsy (i.e., children who had seizures in the last year and/or children who are currently taking antiepileptic drugs (AEDs)) were identified via a computerized database and liaison with local pediatricians. Eighty-five (74%) of the children (5-15years of age) underwent a comprehensive psychological assessment. Twenty-one percent of the children met the DSM-IV-TR criteria for ASD, and 61% of them had another DSM-IV-TR behavioral or motor disorder. The Autism Spectrum Screening Questionnaire (ASSQ) was completed by parents (n=69) and by teachers (n=67) of children with an IQ>34. Only 9% of children on parent ratings and 15% of children on teacher ratings had no features of ASD. Parents reported significantly (p<.05) more features of ASD on the ASSQ compared with teachers. Factors significantly associated with responses on the ASSQ included respondent (parents reported more features), school placement (more features in specialized settings), and respondent by school placement interaction. Effective screening for ASD in children with epilepsy will need a consideration of the impact of informant and school placement on ratings. In conclusion, features of ASD were common in children with epilepsy regardless of cognitive ability. The ASSQ was a useful screening instrument in this population, and combining parent and teacher forms was optimal in terms of screening properties.
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| 10. |
- Reilly, Colin, 1977, et al.
(författare)
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Features of developmental coordination disorder in active childhood epilepsy: a population-based study.
- 2015
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Ingår i: Developmental medicine and child neurology. - : Wiley. - 1469-8749 .- 0012-1622. ; 57:9, s. 829-834
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To provide data on parent-reported features of developmental coordination disorder (DCD) and describe neurobehavioural comorbidity in children with epilepsy and DCD. METHOD: Eighty-five (74% of those eligible) children (44 males, 41 females; age range 5-15y) with active childhood epilepsy (an epileptic seizure in the last year and/or currently taking antiepileptic drugs) in a population-based cohort underwent comprehensive multidisciplinary assessment. The DCD Questionnaire (DCD-Q) was completed by parents (n=69) of children with an IQ>34, of whom 56 did not have cerebral palsy (CP), and were considered for a diagnosis of DCD. RESULTS: Of those considered for a DCD diagnosis, 16 (29%) met DSM-IV-TR criteria whereas 34 (61%) scored in the at-risk range on the DCD-Q. The sensitivity of the DCD-Q was 100% (95% CI 76-100) and specificity was 55% (95% CI 39-70). Significant predictors of higher scores on the DCD-Q included the presence of autism spectrum disorder, CP, and early seizure onset. Increasing age and IQ were independently associated with higher DCD-Q scores. Intellectual disability, attention-deficit-hyperactivity disorder, academic underachievement, and specific memory problems were the most common neurobehavioural difficulties in those with both DCD and epilepsy. INTERPRETATION: Parent-reported symptoms of DCD are very common in childhood epilepsy. The DCD-Q has good sensitivity but lower specificity in this population.
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| 11. |
- Reilly, Colin, 1977, et al.
(författare)
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Neurobehavioral Comorbidities in Children With Active Epilepsy: A Population-Based Study.
- 2014
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Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 133:6
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Tidskriftsartikel (refereegranskat)abstract
- In addition to recurrent epileptic seizures, children with epilepsy can have coexisting cognitive and behavioral difficulties but the spectrum and prevalence of such difficulties are uncertain.METHODS: The Children with Epilepsy in Sussex Schools study is a prospective, community-based study involving school-aged children (5-15 years) with active epilepsy in a defined geographical area in the United Kingdom. Participants underwent comprehensive psychological assessment, including measures of cognition, behavior, and motor functioning. Consensus neurobehavioral diagnoses were made with respect to Diagnostic and Statistical Manual, Fourth Edition-Text Revision (DSM-IV-TR) criteria.RESULTS: A total of 85 children (74% of eligible population) were enrolled; 80% of children with active epilepsy had a DSM-IV-TR behavioral disorder and/or cognitive impairment (IQ <85). Intellectual disability (ID) (IQ <70) (40%), attention-deficit/hyperactivity disorder (ADHD) (33%), and autism spectrum disorder (ASD) (21%) were the most common neurobehavioral diagnoses. Of those who met criteria for a DSM-IV-TR behavioral disorder, only one-third had previously been diagnosed. Logistic regression revealed that seizures in the first 24 months compared with first seizures at 24 to 60 or 61+ months (odds ratio [OR] 13, 95% confidence interval 2.2-76.9; OR 21.3, 3.2-148.9) and polytherapy (OR 7.7, 1.6-36.3) were independently associated with ID and the presence of ID was associated with a diagnosis of ASD (OR 14.1, 2.3-87.1) after Bonferroni adjustment. Epilepsy-related factors did not independently predict the presence of behavioral disorders.CONCLUSIONS: Screening for neurobehavioral comorbidities should be an integral part of management in children with "active" epilepsy. There is a need for research to identify neurobiological mechanisms underpinning neurobehavioral impairments and studies to evaluate possible treatments.
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| 12. |
- Reilly, Colin, 1977, et al.
(författare)
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Parent- and Teacher-Reported Symptoms of ADHD in School-Aged Children With Active Epilepsy: A Population-Based Study.
- 2017
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Ingår i: Journal of attention disorders. - : SAGE Publications. - 1557-1246 .- 1087-0547. ; 21:11, s. 887-897
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Provide data on the distribution of parent- and teacher-reported symptoms of ADHD in childhood epilepsy and describe coexisting cognitive and behavioral disorders in children with both epilepsy and ADHD. METHOD: Eighty-five (74% of those eligible) children (5-15 years) in a population-based sample with active epilepsy underwent psychological assessment. The ADHD Rating Scale-IV (ADHD-RS-IV) scale was completed by parents (n = 69) and teachers (n = 67) of participating children with an IQ > 34. ADHD was diagnosed with respect to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.). RESULTS: Parents reported significantly more symptoms of ADHD than teachers (p < .001). Symptoms of inattention were more commonly reported than symptoms of hyperactivity-impulsivity (p < .001). Neurobehavioral comorbidity was similar in those with ADHD and non-ADHD with the exception of oppositional defiant disorder (ODD) and developmental coordination disorder (DCD), which were more common in those with both epilepsy and ADHD. CONCLUSION: Symptoms of ADHD are very common in childhood epilepsy but prevalence is influenced by informant.
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| 13. |
- Reilly, Colin, 1977, et al.
(författare)
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Screening for mental health disorders in active childhood epilepsy: Population-based data.
- 2014
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Ingår i: Epilepsy research. - : Elsevier BV. - 1872-6844 .- 0920-1211. ; 108:10, s. 1917-26
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Tidskriftsartikel (refereegranskat)abstract
- Children with epilepsy are at increased risk for behavioral and psychiatric disorders and it has been recommended that all children with epilepsy be screened for such conditions. There is thus a need to identify appropriate screening measures in this population.
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| 14. |
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| 15. |
- Robert, Caroline, et al.
(författare)
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Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma.
- 2020
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 38:33, s. 3937-3946
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Tidskriftsartikel (refereegranskat)abstract
- The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein.In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report.Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.
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| 16. |
- Robert, Caroline, et al.
(författare)
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Nivolumab in Previously Untreated Melanoma without BRAF Mutation
- 2015
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 372:4, s. 320-330
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P < 0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P < 0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P < 0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation.
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| 17. |
- Saha, Chayan Kumar, 1988-
(författare)
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Bioinformatics, evolution and revolution in our understanding of toxin-antitoxin systems
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacteria experience a wide range of natural challenges during their life cycles, to which they must respond and adapt to live. Under stressed conditions such as amino acid starvation, bacteria slow down their growth mechanism by producing small alarmone nucleotides guanosine pentaphosphate (pppGpp) and tetraphosphate (ppGpp), collectively referred to as (p)ppGpp. Accumulation of (p)ppGpp results in a comprehensive alteration in cellular metabolism. The alarmone (p)ppGpp is produced and degraded by enzymes belonging to the RelA/SpoT Homologue (RSH) protein family, named for their sequence similarity to the RelA and SpoT enzymes of Escherichia coli. The members of the RSH protein family can be classified into long multi-domain RSHs and short single-domain RSHs. Long RSH enzymes such as RelA and SpoT, carry both the (p)ppGpp hydrolysis (HD) domain and (p)ppGpp synthesis (SYNTH) domain in the N-terminal domain enzymatic region (NTD), in combination with additional domains in the C-terminal domain regulatory region (CTD). Short single-domain RSHs can be divided into small alarmone hydrolases (SAHs) carrying the HD domain, and small alarmone synthetases (SASs) that only have the SYNTH domain. At the beginning of my PhD, I studied the diversity of RSH proteins across the tree of life. I identified 35,615 RSH proteins from analyses of 24,072 genomes. I used large-scale phylogenetic analyses to classify the RSH proteins into 13 long RSHs, 11 SAHs and 30 SASs subfamilies. To address why bacteria often carry multiple SASs in the same genome and predict new functions, I developed a computational tool called FlaGs – standing for Flanking Genes – to analyse the conservation of genomic neighbourhoods in large datasets. I also developed a web-based version of FlaGs, called webFlaGs, that is publicly accessible and is used by biologists all over the world. The application of FlaGs to SAS RSHs led to the discovery that multiple SAS subfamilies are encoded in conserved and frequently overlapping two or three-gene architecture, reminiscent of toxin−antitoxin (TA) systems. Five SAS representatives from the FaRel, FaRel2, PhRel, PhRel2 and CapRel subfamilies were experimentally validated as toxins (toxSASs) that are neutralised by the products of six neighbouring antitoxin genes. The toxSAS enzyme FaRel from Cellulomonas marina is encoded as the central gene of a conserved three-gene architecture and acts through the production of nucleotide alarmone ppGpp and its unusual toxic analogue ppApp, causing a significant depletion of ATP and GTP. FaRel toxicity can be countered by both downstream and upstream cognate antitoxins. The latter contains a SAH domain that neutralises toxicity through degradation of ppGpp as well as ppApp. Combining phylogenetic and FlaGs analyses we have discovered that the DUF4065 domain of unknown function is a widely distributed antitoxin domain in putative TA-like operons with dozens of distinct toxic domains. Nine DUF4065-containing antitoxins and their cognate toxins were experimentally validated as TA pairs using toxicity neutralisation assays. These antitoxins form complexes with their diverse cognate toxins. Given the versatility of DUF4065, we have renamed this domain Panacea. We hypothesise that there are multiple hyperpromiscuous antitoxins like Panacea that can be associated with many non-homologous toxin domains, which may also be hyperpromiscuous. Thus, TA systems across all bacteria can be represented as a network of toxin and antitoxin domain combinations, with hyperpromiscuous domains being hubs in the network. To test this and compute a network, I developed a new, iterative version of FlaGs, called NetFlax (standing for Network-FlaGs for toxins and antitoxins), that can identify TA-like gene architectures in an unsupervised manner and generate a toxin-antitoxin domain interaction network. The results from NetFlax verify our strategy since we have rediscovered multiple previously characterised TAs as well as brand new ones. We find that Panacea is unusual but not unique in its hyperpromiscuity and our network indicates the presence of novel hyperpromiscuous domains still to be explored. Our findings also demonstrate how a core network of TAs is evolutionarily linked to various accessory genome systems, including conjugative transfer and phage defence mechanisms. The existing network can potentially be a framework on which future discoveries of the biological role of TAs can be mapped.
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| 18. |
- Seibt, Henrik, et al.
(författare)
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Elevated levels of VCA0117 in response to external signals activates type VI secretion in Vibrio cholerae A1552
- 2020
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Ingår i: Environmental Microbiology. - : John Wiley & Sons. - 1462-2912 .- 1462-2920. ; 22:10, s. 4409-4423
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The type VI nanomachine is critical for Vibrio cholerae to establish infections and to thrive in niches co‐occupied by competing bacteria. The genes for the type VI structural proteins are encoded in one large and two small auxiliary gene clusters. VCA0117 (VasH) – a σ54‐transcriptional activator – is strictly required for functionality of the type VI secretion system since it controls production of the structural protein Hcp. While some strains constitutively produce a functional system, others do not and require specific growth conditions of low temperature and high osmolarity for expression of the type VI machinery. Here, we trace integration of these regulatory signals to the promoter activity of the large gene cluster in which many components of the machinery and VCA0117 itself are encoded. Using in vivo and in vitro assays and variants of VCA0117, we show that activation of the σ54‐promoters of the auxiliary gene clusters by elevated VCA0117 levels are all that is required to overcome the need for specialized growth conditions. We propose a model in which signal integration via the large operon promoter directs otherwise restrictive levels of VCA0117 that ultimately dictates a sufficient supply of Hcp for completion of a functional type VI secretion system.
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| 19. |
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| 20. |
- Visser, Els, et al.
(författare)
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Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus
- 2018
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Ingår i: Journal of Surgical Oncology. - : WILEY. - 0022-4790 .- 1096-9098. ; 117:8, s. 1687-1696
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. MethodsPatients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. ResultsOf the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P=0.802) or in-hospital mortality (2% vs 0%, P=0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P=0.013), and higher pathological complete response rates (15% vs 5%, P<0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P=0.645) were found. ConclusionIn this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.
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