Abstract Context The prevalence of neuropathic pain in patients with cancer pain has been estimated to be around 40%. Neuropathic pain may be caused by tumor invasion and is considered as mixed ...nociceptive-neuropathic pain, or caused by an anticancer treatment and considered as purely neuropathic pain. The use of adjuvant analgesics in patients with cancer is usually extrapolated from their efficacy in nononcological neuropathic pain syndromes. Objectives In this systematic review, we sought to evaluate the evidence for the beneficial and adverse effects of pharmacologic treatment of neuropathic cancer pain. Methods A systematic review of the literature in PubMed and Embase was performed. Primary outcome measures were absolute risk benefit (ARB), defined as the number of patients with a defined degree of pain relief divided by the total number of patients in the treatment group, and absolute risk harm (ARH), defined as the fraction of patients who dropped out as a result of adverse effects. Results We identified 30 articles that fulfilled our inclusion criteria. Overall, ARB of antidepressants, anticonvulsants, other adjuvant analgesics, or opioids greatly outweighed ARH. There were no significant differences in ARB or ARH between the four groups of medication or between patients with mixed vs. purely neuropathic pain. Because of the low methodological quality of the studies, we could not draw conclusions about the true treatment effect size of the four groups of medications. Conclusion Once a diagnosis of neuropathic pain has been established in patients with cancer, antidepressants, anticonvulsants, or other adjuvant analgesics should be considered in addition to or instead of opioids.
To compare the effect on cognition of carotid artery stenting (CAS) and carotid endarterectomy (CEA) for symptomatic carotid artery stenosis.
Patients randomized to CAS or CEA in the International ...Carotid Stenting Study (ICSS; ISRCTN25337470) at 2 participating centers underwent detailed neuropsychological examinations (NPE) before and 6 months after revascularization. Ischemic brain lesions were assessed with diffusion-weighted imaging before and within 3 days after revascularization. Cognitive test results were standardized into z scores, from which a cognitive sumscore was calculated. The primary outcome was the change in cognitive sumscore between baseline and follow-up.
Of the 1,713 patients included in ICSS, 177 were enrolled in the 2 centers during the substudy period, of whom 140 had an NPE at baseline and 120 at follow-up. One patient with an unreliable baseline NPE was excluded. CAS was associated with a larger decrease in cognition than CEA, but the between-group difference was not statistically significant: -0.17 (95% CI -0.38 to 0.03; p = 0.092). Eighty-nine patients had a pretreatment MRI and 64 within 3 days after revascularization. New ischemic lesions were found twice as often after CAS than after CEA (relative risk 2.1; 95% CI 1.0 to 4.4; p = 0.041).
Differences between CAS and CEA in effect on cognition were not statistically significant, despite a substantially higher rate of new ischemic lesions after CAS than after CEA.
This study provides Class III evidence that any difference between the effects of CAS and CEA on cognition at 6 months after revascularization is small.
Melanoma brain metastasis (MBM) is associated with poor outcome, but targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) have revolutionized treatment over the past decade. We assessed ...the impact of these treatments in a real-world setting.
A single-center cohort study was performed at a large, tertiary referral center for melanoma (Erasmus MC, Rotterdam, the Netherlands). Overall survival (OS) was assessed before and after 2015, after which TTs and ICIs were increasingly prescribed.
There were 430 patients with MBM included; 152 pre-2015 and 278 post-2015. Median OS improved from 4.4 to 6.9 months (HR 0.67,
< 0.001) after 2015. TTs and ICIs prior to MBM diagnosis were associated with poorer median OS as compared to no prior systemic treatment (TTs: 2.0 vs. 10.9 and ICIs: 4.2 vs. 7.9 months,
< 0.001). ICIs directly after MBM diagnosis were associated with improved median OS as compared to no direct ICIs (21.5 vs. 4.2 months,
< 0.001). Stereotactic radiotherapy (SRT; HR 0.49,
= 0.013) and ICIs (HR 0.32,
< 0.001) were independently associated with improved OS.
After 2015, OS significantly improved for patients with MBM, especially with SRT and ICIs. Demonstrating a large survival benefit, ICIs should be considered first after MBM diagnosis, if clinically feasible.
Visuospatial attentional orienting has typically been studied in tasks with low ecological validity. However, real‐life tasks such as driving require allocation of working memory (WM) resources to ...several subtasks over and above orienting in a complex sensory environment. The aims of this study were twofold: firstly, to establish whether electrophysiological signatures of attentional orienting commonly observed under simplified task conditions generalize to a more naturalistic task situation with realistic‐looking stimuli, and, secondly, to assess how these signatures are affected by increased WM load under such conditions. Sixteen healthy participants performed a dual task consisting of a spatial cueing paradigm and a concurrent verbal memory task that simulated aspects of an actual traffic situation. Behaviorally, we observed a load‐induced detriment of sensitivity to targets. In the EEG, we replicated orienting‐related alpha lateralization, the lateralized ERPs ADAN, EDAN, and LDAP, and the P1‐N1 attention effect. When WM load was high (i.e., WM resources were reduced), lateralization of oscillatory activity in the lower alpha band was delayed. In the ERPs, we found that ADAN was also delayed, while EDAN was absent. Later ERP correlates were unaffected by load. Our results show that the findings in highly controlled artificial tasks can be generalized to spatial orienting in ecologically more valid tasks, and further suggest that the initiation of spatial orienting is delayed when WM demands of an unrelated secondary task are high.
► Road outside urban area is cognitively less demanding than inside the urban area. ► Curves decrease mean speed but increase SD acceleration/deceleration and SDLP. ► PDT performance indicated higher ...workload when curves were present. ► Gates locally reduced speed but increased SD of acceleration/deceleration and SDLP. ► Curves and gate constructions can improve traffic safety.
This study examined the impact of traffic calming measures (TCM) on major roads in rural and urban areas. More specifically we investigated the effect of gate constructions located at the entrance of the urban area and horizontal curves within the urban area on driving behavior and workload. Forty-six participants completed a 34km test-drive on a driving simulator with eight thoroughfare configurations, i.e., 2 (curves: present, absent)×2 (gates: present, absent)×2 (peripheral detection task (PDT): present, absent) in a within-subject design.
PDT performance (mean response time (RT) and hit rate) indicated that drivers experienced the road outside the urban area as cognitively less demanding relative to the more complex road environment inside the urban area. Whereas curves induced a speed reduction that was sustained throughout the entire urban area, variability of acceleration/deceleration and lateral position were increased. In addition, PDT performance indicated higher workload when curves were present (versus absent). Gate constructions locally reduced speed (i.e., shortly before and after the entrance) and slightly increased variability of acceleration/deceleration and lateral position nearby the entrance. However, the effects on SDL-A/D and SDLP are too small to expect traffic safety problems.
It can be concluded that both curves and gate constructions can improve traffic safety. Notwithstanding, the decision to implement these measures will depend on contextual factors such as whether the road serves a traffic-, rather than a residential function.
ABSTRACT
A European transect was established, ranging from Sweden to the Azores, to determine the relative influence of geographic factors and agricultural small-scale management on the grassland ...soil microbiome. Within each of five countries (factor ‘Country’), which maximized a range of geographic factors, two differing growth condition regions (factor ‘GCR’) were selected: a favorable region with conditions allowing for high plant biomass production and a contrasting less favorable region with a markedly lower potential. Within each region, grasslands of contrasting management intensities (factor ‘MI’) were defined: intensive and extensive, from which soil samples were collected. Across the transect, ‘MI’ was a strong differentiator of fungal community structure, having a comparable effect to continental scale geographic factors (‘Country’). ‘MI’ was also a highly significant driver of bacterial community structure, but ‘Country’ was clearly the stronger driver. For both, ‘GCR’ was the weakest driver. Also at the regional level, strong effects of MI occurred on various measures of the soil microbiome (i.e. OTU richness, management-associated indicator OTUs), though the effects were largely regional-specific. Our results illustrate the decisive influence of grassland MI on soil microbial community structure, over both regional and continental scales, and, thus, highlight the importance of preserving rare extensive grasslands.
Across a European transect, comprising five countries, we did show that small-scale agricultural grassland management can affect soil fungal community structure as much as continental scale geographic patterns.
Background: Fear-avoidance is one of the factors associated with chronic pain. However, it remains unclear whether the association between fear-avoidance and pain depends on sex. The present study ...aimed to investigate whether the association between fear-avoidance and pain intensity differed between men and women in chronic pain patients. Additionally, the potential confounding effect of affective experiences on the association between fear-avoidance and pain intensity was analyzed. Method: This cohort study included hospital referred chronic pain patients (n = 45). Short momentary assessment questions according to the experience sampling method (ESM) were used to repeatedly assess patients’ pain intensity, level of fear-avoidance and positive as well as negative affect during their daily life. Linear mixed-effects models were applied in the statistical analysis. Unadjusted and adjusted models were made, in which the latter corrected for statistically significant affective experiences and baseline variables, taking the Aikake Information Criterion into account to assess a better model of fit. Results: The results demonstrated an association between fear-avoidance and pain intensity that differed for men and women. In men (n = 13), no association between these variables was found (−0.04 (95% CI: −0.14, 0.06) with a p-value of 0.48), whereas in women (n = 32), an increase in fear-avoidance was associated with a (slight) increase in pain intensity (0.18 (95% CI 0.06, 0.30) with a p-value of 0.003). Affect did not confound the above-mentioned findings. Conclusion: Our data supports previous research highlighting the importance of sex differences in pain experience. These findings may be relevant for clinicians to consider more personalized (i.e., gender specific) pain management in chronic pain patients.
Recently, oversulfated chondroitin sulfate (OSCS) present in certain lots of heparin was identified as the toxic contaminant responsible for severe side effects following intravenous heparin ...administration. The United States Pharmacopeia (USP) and European Pharmacopeia (Eur.Ph.) announced an immediate revision of their monographs for heparin sodium by adding two US Food and Drugs Administration-recommended tests for OSCS based on nuclear magnetic resonance and capillary electrophoresis (CE). However, the proposed CE method provides only partial separation of the OSCS contaminant from heparin, thereby hindering appropriate impurity profiling. Here we present an improved CE method that is especially useful for the reliable quantification of OSCS in heparin samples, but also allows determination of the common impurity dermatan sulfate (DS). Parameters such as type and concentration of background electrolyte, capillary temperature, sample concentration and injection volume were investigated and optimized. Enhancement of the OSCS–heparin separation was achieved by using high concentrations of Tris phosphate (pH 3.0) as background electrolyte. High currents and excessive Joule heating were prevented by employing fused-silica capillaries with an internal diameter of 25
μm. Good separations of OSCS, heparin and DS are obtained within 17
min. The method permits injection of relatively high heparin concentrations (up to 50
mg/ml) and large sample volumes (up to 5% of the capillary volume) allowing OSCS and DS determination in heparin down to the 0.05% and 0.5% (w/w) level, respectively. The CE method is shown to be repeatable and linear (
R
2
>
0.99) for OSCS, heparin and DS. CE analyses of OSCS-contaminated heparin samples and different heparin standards further demonstrate the utility of the method.
Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in ...virtually every patient, but its clinical value for the prediction of relapse has yet to be established.
We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission). End points were 4-year rates of relapse, relapse-free survival, and overall survival.
At least one mutation was detected in 430 out of 482 patients (89.2%). Mutations persisted in 51.4% of those patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which are often present in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate than no detection (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001), as well as with lower rates of relapse-free survival (36.6% vs. 58.1%; hazard ratio for relapse or death, 1.92; P<0.001) and overall survival (41.9% vs. 66.1%; hazard ratio for death, 2.06; P<0.001). Multivariate analysis confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to the rates of relapse (hazard ratio, 1.89; P<0.001), relapse-free survival (hazard ratio for relapse or death, 1.64; P=0.001), and overall survival (hazard ratio for death, 1.64; P=0.003). A comparison of sequencing with flow cytometry for the detection of residual disease showed that sequencing had significant additive prognostic value.
Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.).
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