Endovascular thrombectomy is standard treatment for patients with anterior circulation large vessel occlusion stroke (LVO-a). Prehospital identification of these patients would enable direct routing ...to an endovascular thrombectomy-capable hospital and consequently reduce time-to-endovascular thrombectomy. Electroencephalography (EEG) has previously proven to be promising for LVO-a stroke detection. Fast and reliable electrode application, however, can remain a challenge. A potential alternative is subhairline EEG. We evaluated the diagnostic accuracy of subhairline EEG for LVO-a stroke detection.
We included adult patients with a suspected stroke or known LVO-a stroke and symptom onset time <24 hours. A single 3-minute EEG recording was performed at the emergency department, before endovascular thrombectomy, using 9 self-adhesive electrodes placed on the forehead and behind the ears. We evaluated the diagnostic accuracies of EEG features quantifying frequency band power and brain symmetry (pairwise derived Brain Symmetry Index) for LVO-a stroke detection using receiver operating characteristic analysis. EEG data were of sufficient quality for analysis in 51/52 (98%) included patients. Of these patients, 16 (31%) had an LVO-a stroke, 16 (31%) a non-LVO-a ischemic stroke, 5 (10%) a transient ischemic attack, and 14 (27%) a stroke mimic. Median symptom-onset-to-EEG-time was 266 (interquartile range 130-709) minutes. The highest diagnostic accuracy for LVO-a stroke detection was reached by the pairwise derived Brain Symmetry Index in the theta frequency band (area under the receiver operating characteristic curve 0.90; sensitivity 86%; specificity 83%).
Subhairline EEG could detect LVO-a stroke with high diagnostic accuracy and had high data reliability. These data suggest that subhairline EEG is potentially suitable as a prehospital stroke triage instrument.
Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to ...individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks (‘modules’) using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes.
•This study identified genome-wide DNAm patterns that associated to the general factor of psychopathology after multiple testing correction.•Symptom-specific internalizing and externalizing factors were unrelated to DNAm patterns.•The CpG most strongly driving this association was annotated to FZD1, a gene that has been implicated in neurological processes.•Associations were supported in an independent cohort, as evidenced by significant correlations in effect sizes.
Abstract Background: Patient blood management combines the use of several transfusion alternatives. Integrated use of erythropoietin, cell saver, and/or postoperative drain reinfusion devices on ...allogeneic erythrocyte use was evaluated using a restrictive transfusion threshold. Methods: In a factorial design, adult elective hip- and knee-surgery patients with hemoglobin levels 10 to 13 g/dl (n = 683) were randomized for erythropoietin or not, and subsequently for autologous reinfusion by cell saver or postoperative drain reinfusion devices or for no blood salvage device. Primary outcomes were mean allogeneic intra- and postoperative erythrocyte use and proportion of transfused patients (transfusion rate). Secondary outcome was cost-effectiveness. Results: With erythropoietin (n = 339), mean erythrocyte use was 0.50 units (U)/patient and transfusion rate 16% while without (n = 344), these were 0.71 U/patient and 26%, respectively. Consequently, erythropoietin resulted in a nonsignificant 29% mean erythrocyte reduction (ratio, 0.71; 95% CI, 0.42 to 1.13) and 50% reduction of transfused patients (odds ratio, 0.5; 95% CI, 0.35 to 0.75). Erythropoietin increased costs by €785 per patient (95% CI, 262 to 1,309), that is, €7,300 per avoided transfusion (95% CI, 1,900 to 24,000). With autologous reinfusion, mean erythrocyte use was 0.65 U/patient and transfusion rate was 19% with erythropoietin (n = 214) and 0.76 U/patient and 29% without (n = 206). Compared with controls, autologous blood reinfusion did not result in erythrocyte reduction and increased costs by €537 per patient (95% CI, 45 to 1,030). Conclusions: In hip- and knee-replacement patients (hemoglobin level, 10 to 13 g/dl), even with a restrictive transfusion trigger, erythropoietin significantly avoids transfusion, however, at unacceptably high costs. Autologous blood salvage devices were not effective.
Indication for primary tumour resection (PTR) in asymptomatic metastatic colorectal cancer (mCRC) patients is unclear. Previous retrospective analyses suggest a survival benefit for patients who ...underwent PTR. The aim was to evaluate the prognostic value of PTR in patients with synchronous mCRC by analysis of recent large RCTs including systemic therapy with modern targeted agents.
Individual patient data (IPD) of 3423 patients enrolled into 8 randomised controlled trials (RCTs) with first-line systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analysed.
The number of patients with unresected synchronous mCRC, resected synchronous mCRC and metachronous mCRC was 710 (21%), 1705 (50%) and 1008 (29%), respectively. Adjusting for age, gender, performance status (PS) and prior chemotherapy, the unresected group had a significantly worse median overall survival (16.4 m) compared with the synchronous resected (22.2 m; hazard ratio HR 1.60, 95% CI 1.43–1.78) and metachronous (22.4 m; HR 1.81, 95% CI 1.58–2.07) groups. Similarly, median progression-free survival was significantly worse for the unresected group compared with the synchronous resected (HR 1.31, 95% CI 1.19–1.44) and metachronous (HR 1.47, 95% CI 1.30–1.66) groups. In a multivariate analysis, the observed associations remained significant.
This largest IPD analysis of mCRC trials to date demonstrates an improved survival in synchronous mCRC patients after PTR. These results may be subject to bias since reasons for (non)resection were not available. Until results of ongoing RCTs are available, both upfront PTR followed by systemic treatment and upfront systemic treatment are considered appropriate treatment strategies.
•Data of RCTs regarding primary tumour resection (PTR) in synchronous metastatic colorectal cancer (mCRC) are lacking.•All patients in this analysis of 8 large mCRC trials in the ARCAD database received modern systemic treatment including targeted agents.•Synchronous mCRC patients with upfront PTR have a significant improved survival of almost 6 months compared to unresected mCRC patients.•Results of ongoing RCTs are warranted to obtain a definitive conclusion about the survival benefit of PTR in synchronous mCRC.
This study explored using Big Data, totaling 66 terabytes over 10 years, captured from sensor systems installed in independent living apartments to predict falls from pre-fall changes in residents’ ...Kinect-recorded gait parameters. Over a period of 3 to 48 months, we analyzed gait parameters continuously collected for residents who actually fell (n = 13) and those who did not fall (n = 10). We analyzed associations between participants’ fall events (n = 69) and pre-fall changes in in-home gait speed and stride length (n = 2,070). Preliminary results indicate that a cumulative change in speed over time is associated with the probability of a fall (p < .0001). The odds of a resident falling within 3 weeks after a cumulative change of 2.54 cm/s is 4.22 times the odds of a resident falling within 3 weeks after no change in in-home gait speed. Results demonstrate using sensors to measure in-home gait parameters associated with the occurrence of future falls.
Abstract Purpose The moving rectangle method is used to disentangle the contributions of rectangularization and life span extension to the increase in life expectancy. It requires the choice of an ...endpoint of the survival curve that approaches the maximum age at death. We examined the effect of choosing different end points on the outcomes of this method. Methods For five developed countries, survival curves from age 50 years were constructed per calendar year from 1922 onward. Survival values of 0.1, 0.01, and 0.001 were chosen as end points of the survival curve, and the contributions of rectangularization and life span extension to the increase in life expectancy were calculated using the moving rectangle method. Results The choice of different survival values as end points profoundly influenced the estimated contributions of rectangularization and life span extension to the increase in life expectancy. When choosing 0.001, rectangularization contributed most years, whereas when choosing 0.1, life span extension contributed most years. Conclusions When the moving rectangle method is used to estimate the contributions of rectangularization and life span extension to the increase in life expectancy, its outcomes depend on the choice of the endpoint of the survival curve.
Summary Background The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential ...administration of the same drugs in patients with advanced colorectal cancer. Methods We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. Findings 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16·3 (95% CI 14·3–18·1) months for sequential treatment and 17·4 (15·2–19·2) months for combination treatment (p=0·3281). The hazard ratio for combination versus sequential treatment was 0·92 (95% CI 0·79–1·08; p=0·3281). The frequency of grade 3–4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13% vs 7%; p=0·004). Interpretation Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.
Background
The aim of this study was to evaluate absolute mortality risks and to determine whether changes in mortality risk occurred in patients with intermittent claudication (IC) or critical limb ...ischaemia (CLI) in the Netherlands between 1998 and 2010.
Methods
Data for patients treated between 1998 and 2010 were obtained from Dutch nationwide registers: the Hospital Discharge Register, Population Register and Cause of Death Register. The registers were used to obtain information regarding IC and CLI hospitalizations, co‐morbidities, demographic factors, and date and cause of death. The cohort was split into two time intervals for comparison: 1998–2004 (period 1) and 2005–2010 (period 2). Thirty‐day mortality was excluded to eliminate per‐admission complications. One‐ and 5‐year cardiovascular and all‐cause mortality rates were compared with those of a representative sample of the general Dutch population (28 494 persons) by Cox proportional hazards models.
Results
Some 47 548 patients were included, 34 078 with IC and 13 470 with CLI. In patients with IC, the age‐adjusted 5‐year mortality risk for cardiovascular disease decreased significantly in period 2 (14·1 per cent) compared with that in period 1 (16·1 per cent) in men only (5‐year adjusted hazard ratio (HR) 0·76, 95 per cent c.i. 0·69 to 0·83; P < 0·001). In patients with CLI, the cardiovascular mortality risk decreased significantly only in women, with the 5‐year risk reducing from 31·2 per cent in period 1 to 29·2 per cent in period 2 (adjusted HR 0·84, 0·74 to 0·94; P = 0·004). Compared with the general population, the mortality risk in patients with IC was increased between 1·70 (1·58 to 1·83) and 3·20 (2·69 to 3·81) times, and in those with CLI the risk was increased between 2·24 (2·09 to 2·40) and 5·19 (4·30 to 6·26) times.
Conclusion
The risk of premature death in patients with IC and CLI declined significantly in the Netherlands, in a sex‐specific manner, over the period from 1998 to 2010. The absolute risk of cardiovascular mortality remains high in these patients.
Declining mortality; large burden of cardiovascular deaths
This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our ...previous work, we synthesized a series of d-gluco and l-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (d-gluco and l-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted l-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their d-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.
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