Summary
Background
Continuous maintenance therapy with infliximab 5 mg kg−1 every 8 weeks is effective for moderate‐to‐severe plaque‐type psoriasis.
Objectives
To evaluate the efficacy and safety of ...continuous vs. intermittent infliximab maintenance therapy.
Methods
RESTORE2 was a long‐term extension of RESTORE1. At baseline of RESTORE2, eligible patients who had received infliximab for 26 weeks and achieved Psoriasis Area and Severity Index (PASI) 75 in RESTORE1 were rerandomized 1 : 1 to continuous therapy (infliximab 5 mg kg−1 every 8 weeks) or intermittent therapy (no infliximab until > 50% loss of PASI improvement). Safety and efficacy assessments occurred throughout the study.
Results
In total, 222 patients were randomized to receive continuous therapy, and 219 to intermittent therapy. More serious infusion‐related reactions occurred with intermittent therapy (8/219 patients, 4%) than with continuous therapy (1/222 patients, < 1%), leading the sponsor to terminate the study. The mean duration of exposure to infliximab was 40·12 weeks (SD 27·55) with a mean of 5·8 infusions (range 0–16) for continuous therapy and 22·78 weeks (SD 22·98) with a mean of 3·4 infusions (range 0–16) for intermittent therapy. Although no formal efficacy analyses were conducted, continuous therapy led to greater PASI 75 at week 52 in the continuous group (81/101, 80%) than in the intermittent group (39/83, 47%); several other efficacy measures demonstrated similar patterns.
Conclusions
For patients with moderate‐to‐severe plaque‐type psoriasis, continuous therapy with infliximab may be more effective than intermittent therapy. The incidence of serious infusion‐related reactions in the intermittent group suggests that clinicians should avoid intermittent therapy in this population.
What's already known about this topic?
Continuous maintenance therapy with infliximab 5 mg kg−1 every 8 weeks is effective for moderate‐to‐severe plaque‐type psoriasis.
What does this study add?
For patients receiving an intermittent infliximab therapy regimen, the incidence of serious infusion‐related reactions was greater than expected during reinduction.
Clinicians should avoid using intermittent therapy in this patient population.
Abstract
High-resolution historical climate grids are readily available and frequently used as inputs for a wide range of regional management and risk assessments including water supply, ecological ...processes, and as baseline for climate change impact studies that compare them to future projected conditions. Because historical gridded climates are produced using various methods, their portrayal of landscape conditions differ, which becomes a source of uncertainty when they are applied to subsequent analyses. Here we tested the range of values from five gridded climate datasets. We compared their values to observations from 1,231 weather stations, first using each dataset’s native scale, and then after each was rescaled to 270-meter resolution. We inputted the downscaled grids to a mechanistic hydrology model and assessed the spatial results of six hydrological variables across California, in 10 ecoregions and 11 large watersheds in the Sierra Nevada. PRISM was most accurate for precipitation, ClimateNA for maximum temperature, and TopoWx for minimum temperature. The single most accurate dataset overall was PRISM due to the best performance for precipitation and low air temperature errors. Hydrological differences ranged up to 70% of the average monthly streamflow with an average of 35% disagreement for all months derived from different historical climate maps. Large differences in minimum air temperature data produced differences in modeled actual evapotranspiration, snowpack, and streamflow. Areas with the highest variability in climate data, including the Sierra Nevada and Klamath Mountains ecoregions, also had the largest spread for Snow Water Equivalent (SWE), recharge and runoff.
Populations are locally adapted when they exhibit higher fitness than foreign populations in their native habitat. Maize landrace adaptations to highland and lowland conditions are of interest to ...researchers and breeders. To determine the prevalence and strength of local adaptation in maize landraces, we performed a reciprocal transplant experiment across an elevational gradient in Mexico. We grew 120 landraces, grouped into four populations (Mexican Highland, Mexican Lowland, South American Highland, South American Lowland), in Mexican highland and lowland common gardens and collected phenotypes relevant to fitness and known highland‐adaptive traits such as anthocyanin pigmentation and macrohair density. 67k DArTseq markers were generated from field specimens to allow comparisons between phenotypic patterns and population genetic structure. We found phenotypic patterns consistent with local adaptation, though these patterns differ between the Mexican and South American populations. Quantitative trait differentiation (QST) was greater than neutral allele frequency differentiation (FST) for many traits, signaling directional selection between pairs of populations. All populations exhibited higher fitness metric values when grown at their native elevation, and Mexican landraces had higher fitness than South American landraces when grown in these Mexican sites. As environmental distance between landraces’ native collection sites and common garden sites increased, fitness values dropped, suggesting landraces are adapted to environmental conditions at their natal sites. Correlations between fitness and anthocyanin pigmentation and macrohair traits were stronger in the highland site than the lowland site, supporting their status as highland‐adaptive. These results give substance to the long‐held presumption of local adaptation of New World maize landraces to elevation and other environmental variables across North and South America.
Bacteria that colonize the mammalian intestine collectively possess a far larger repertoire of degradative enzymes and metabolic capabilities than their hosts. Microbial fermentation of complex ...non-digestible dietary carbohydrates and host-derived glycans in the human intestine has important consequences for health. Certain dominant species, notably among the Bacteroidetes, are known to possess very large numbers of genes that encode carbohydrate active enzymes and can switch readily between different energy sources in the gut depending on availability. Nevertheless, more nutritionally specialized bacteria appear to play critical roles in the community by initiating the degradation of complex substrates such as plant cell walls, starch particles and mucin. Examples are emerging from the Firmicutes, Actinobacteria and Verrucomicrobium phyla, but more information is needed on these little studied groups. The impact of dietary carbohydrates, including prebiotics, on human health requires understanding of the complex relationship between diet composition, the gut microbiota and metabolic outputs.
Spontaneous closure of the ductus arteriosus depends on gestational age (GA) and might be delayed in preterm infants, resulting in patent ductus arteriosus (PDA). Ibuprofen can be administered to ...enhance closure, but the exposure‐response relationship between ibuprofen and the closure of PDA remains uncertain. We investigated the influence of patient characteristics and ibuprofen exposure on ductus closure. A cohort of preterm infants with PDA and treated with ibuprofen was analyzed. Ibuprofen exposure was based on a previously developed population pharmacokinetic study that was in part based on the same study population. Logistic regression analyses were performed with ductus closure (yes/no) as outcome, to analyze the contribution of ibuprofen exposure and patient characteristics. In our cohort of 263 preterm infants (median GA 26.1 (range: 23.7–30.0) weeks, birthweight 840 (365–1,470) g) receiving ibuprofen treatment consisting of 3 doses that was initiated at a median postnatal age (PNAstart) of 5 (1–32) days, PDA was closed in 55 (21%) patients. Exposure to ibuprofen strongly decreased with PNAstart. Overall, the probability of ductus closure decreased with PNAstart (odds ratio (OR): 0.7, 95% CI: 0.6–0.8) and Z‐score for birthweight (ZBirthweight‐for‐GA; OR: 0.8, 95% CI: 0.6‐1.0), and increased with GA (OR: 1.5, 95% CI: 1.1–1.9). For patients with PNAstart < 1 week, concentrations of ibuprofen, GA, and ZBirthweight‐for‐GA predicted probability of ductus closure. During a window of opportunity for ductus closure within the first days of life, probability of closure depends on GA, ZBirthweight‐for‐GA, and ibuprofen exposure. Increased, yet unstudied dosages might increase the effectivity of ibuprofen beyond the first week of life.
Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive ...heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log
Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
•Most patients remained neuropsychologically stable post-surgery in all domains.•Evidence for increased material-specific memory deficits based on resection side.•Lower pre-surgical ability ...associated with more positive cognitive outcome.•Limitations of retrieved papers suggest more substantial evidence needed.•Agreement on core outcome measures would permit higher quality evidence.
The systematic review aimed to assess the neuropsychological outcomes of temporal lobe resections for epilepsy in children. Additional objectives included determining whether earlier age at surgery leads to better neuropsychological outcomes; the relationships between and predictors of these outcomes.
Using advanced search terms, a systematic review of electronic databases was conducted, comprising MEDLINE, Embase, PsycINFO, Global Health, Web of Science and CINAHL. Included studies reported on outcome following neurosurgical treatment for epilepsy. Specifically, studies were included if they reported neuropsychological outcomes and were concerned only with temporal lobe resection.
73 studies met inclusion criteria. For reported neuropsychological outcomes, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level.
Retrieved evidence highlights the need for improvements to quality of methodology and reporting. Appropriately designed prospective multicentre trials should be conducted with adequate follow-up for long-term outcomes to be measured. Core outcome measures should be agreed between centres. This would permit higher quality evidence so that clinicians, young people and their families may make better informed decisions about whether or not to proceed with surgery and likely post-operative profile.
The microbial community of the human colon contains many bacteria that produce lactic acid, but lactate is normally detected only at low concentrations (<5 mM) in feces from healthy individuals. It ...is not clear, however, which bacteria are mainly responsible for lactate utilization in the human colon. Here, bacteria able to utilize lactate and produce butyrate were identified among isolates obtained from 10(-8) dilutions of fecal samples from five different subjects. Out of nine such strains identified, four were found to be related to Eubacterium hallii and two to Anaerostipes caccae, while the remaining three represent a new species within clostridial cluster XIVa based on their 16S rRNA sequences. Significant ability to utilize lactate was not detected in the butyrate-producing species Roseburia intestinalis, Eubacterium rectale, or Faecalibacterium prausnitzii. Whereas E. hallii and A. caccae strains used both D- and L-lactate, the remaining strains used only the D form. Addition of glucose to batch cultures prevented lactate utilization until the glucose became exhausted. However, when two E. hallii strains and one A. caccae strain were grown in separate cocultures with a starch-utilizing Bifidobacterium adolescentis isolate, with starch as the carbohydrate energy source, the L-lactate produced by B. adolescentis became undetectable and butyrate was formed. Such cross-feeding may help to explain the reported butyrogenic effect of certain dietary substrates, including resistant starch. The abundance of E. hallii in particular in the colonic ecosystem suggests that these bacteria play important roles in preventing lactate accumulation.
Dietary fibre and the gut microbiota Scott, K.P; Duncan, S.H; Flint, H.J
Nutrition bulletin,
September 2008, Letnik:
33, Številka:
3
Journal Article
Recenzirano
The complex human colonic microbiota plays a key role in gut health, and both the composition and metabolism of the gut microbiota are strongly diet related. Controlled dietary intake studies in ...obese individuals demonstrated that consumption of low-carbohydrate diets results in low faecal butyrate concentrations together with a low abundance of the major butyrate-producing bacteria, Roseburia spp. and Eubacterium rectale group. Resistant dietary carbohydrates, including pre-biotics, escape digestion in the upper gastrointestinal tract and are fermented to short-chain fatty acids (SCFAs) by bacteria in the colon. The main SCFAs formed are acetate, propionate and butyrate. Model colonic fermentor systems employed to determine which bacterial groups utilise specific substrates indicated that the bacterial composition and production of SCFAs is substrate dependent. The bacterial colonisers of specific substrates were identified using 16S rRNA sequence analysis. Sequences recovered from bran were most closely related to Roseburia spp., E. rectale and Clostridium hathewayi, while on resistant starch, sequences were most closely related to Ruminococcus bromii and Bifidobacterium adolescentis. Differing intakes of dietary carbohydrate also impact on other factors in the colon such as transit and pH. In continuous fermentor systems, a slightly acidic pH (5.5) representative of the proximal colon gave fourfold higher butyrate concentrations than at the higher pH of 6.5, which is more representative of the distal colon. Bacteroidetes dominated the fermentor at pH 6.5, while the major butyrate-producing bacterial groups competed more effectively for carbohydrate substrates when the pH was mildly acidic (5.5). In in vitro studies in which pH values were even lower, pH 5.2, lactate and acetate accumulated. In contrast, lactate was not detected at pH 6.4 although stable isotope studies revealed that lactate was actively produced. Lactate accumulation at low pH appears to be as a result of the loss of lactate-utilising bacteria including Eubacterium hallii. It is clear that the composition of the colonic microbiota and the balance of its metabolic products is strongly influenced by diet and, in particular, by the intake of resistant carbohydrates and dietary fibre.
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