The Impact of Conventional Stroke Risk Factors on Early and Late Onset Ischemic Stroke: a Mendelian Randomization Study.

Objective: Although stroke incidence is decreasing in older ages, it is increasing in young adults. While these divergent trends in stroke incidence are at least partially attributable to diverging prevalence trends in stoke risk factors, age-dependent differences in the impact of stroke risk factors on stroke may also contribute. To address this issue, we utilized Mendelian Randomization (MR) to assess differences in the association of stroke risk factors between early onset ischemic stroke (EOS) and late onset ischemic stroke (LOS). Methods: We employed a two-sample MR design with inverse variance weighting as the primary method of analysis. Using large publicly available genome-wide association summary results, we calculated MR estimates for conventional stroke risk factors (body mass index, total, HDL-and LDL-cholesterol, triglycerides, type 2 diabetes, systolic and diastolic blood pressure, and smoking) in EOS cases (onset 18-59 years, n = 6,728) and controls from the Early Onset Stroke Consortium and in LOS cases (onset ≥ 60 years, n = 9,272) and controls from the Stroke Genetics Network. We then compared odds ratios between EOS and LOS, stratified by TOAST subtypes, to determine if any differences observed between effect sizes could be attributed to differences in the distribution of stroke subtypes. Results: EOS was significantly associated with all risk factors except for total cholesterol levels, and LOS was associated with all risk factors except for triglyceride and total cholesterol levels. The associations of BMI, DBP, SBP, and HDL-cholesterol were significantly stronger in EOS than LOS (all p < 0.004). The differential distribution of stroke subtypes could not explain the difference in effect size observed between EOS and LOS. Conclusion: These results suggest that interventions targeted at lowering body mass index and blood pressure may be particularly important for reducing stroke risk in young adults.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes.

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase the expression of inhibitory immune checkpoint molecules. We conducted the first randomized phase 2 study of azacitidine plus the immune checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 cycles or 75 mg/m² subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment cycles with 73.7% and 65.9%, respectively, completing ≥4 cycles. The overall response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm B (20 of 42; P = .18), and median overall survival was 11.6 months (95% confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased programmed cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining azacitidine with durvalumab in patients with HR-MDS was feasible but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. This trial was registered at www.clinicaltrials.gov as #NCT02775903.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML.

Evidence suggests that combining immunotherapy with hypomethylating agents may enhance antitumor activity. This phase 2 study investigated the activity and safety of durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, combined with azacitidine for patients aged ≥65 years with acute myeloid leukemia (AML), including analyses to identify biomarkers of treatment response. Patients were randomized to first-line therapy with azacitidine 75 mg/m2 on days 1 through 7 with (Arm A, n = 64) or without (Arm B, n = 65) durvalumab 1500 mg on day 1 every 4 weeks. Overall response rate (complete response [CR] + CR with incomplete blood recovery) was similar in both arms (Arm A, 31.3%; Arm B, 35.4%), as were overall survival (Arm A, 13.0 months; Arm B, 14.4 months) and duration of response (Arm A, 24.6 weeks; Arm B, 51.7 weeks; P = .0765). No new safety signals emerged with combination treatment. The most frequently reported treatment-emergent adverse events were constipation (Arm A, 57.8%; Arm B, 53.2%) and thrombocytopenia (Arm A, 42.2%; Arm B, 45.2%). DNA methylation, mutational status, and PD-L1 expression were not associated with response to treatment. In this study, first-line combination therapy with durvalumab and azacitidine in older patients with AML was feasible but did not improve clinical efficacy compared with azacitidine alone. ClinicalTrials.gov: NCT02775903.

Utilization, Utility, and Variability in Usage of Adjunctive Hyperbaric Oxygen Therapy in Spinal Management: A Review of the Literature.

The objective of this review was to understand the clinical utilization, utility, and variability in the usage of adjunctive hyperbaric oxygen therapy (HBOT). Surgical site infection is associated with high morbidity and mortality, increased health care expenditure, and decreased quality of life. With the increasing prevalence of adult spinal deformity and spinal fusion surgery, it is imperative to understand the potential benefits of adjunctive treatments. HBOT is a safe and common procedure indicated to treat various medical conditions. We conducted a literature search across 3 databases for English articles published between December 1, 2019 and December 1, 2000. Thirteen studies were included. HBOT may lessen the duration of antimicrobial therapy and mitigate instrument removal and revision surgery. The current usage indications for HBOT are supported by level III evidence for chronic osteomyelitis and level IV evidence for osteoradionecrosis. However, the same level of evidence exists to support the beneficial use of adjunctive HBOT for noncomplicated spinal infections within 2 months after surgery. When cultured, the most common organisms were Staphylococcus aureus and other low-virulence organisms. The most common treatment protocol consists of 90-minute sessions of 100% Fio2 at 2-3 atmosphere absolute with a mean of 35.3 ± 11.6 sessions for 5.2 ± 1.4 weeks. Adjunctive HBOT should be considered in select high-risk patients. Further improvements in diagnosis and categorization of spinal infections are necessary and will indelibly aid the decision making for the initiation of HBOT.

Quantifying rehabilitation risks for surface-strip coal mines using a soil compaction Bayesian network in South Africa and Australia: To demonstrate the R2 AIN Framework.

Environmental information is acquired and assessed during the environmental impact assessment process for surface-strip coal mine approval. However, integrating these data and quantifying rehabilitation risk using a holistic multidisciplinary approach is seldom undertaken. We present a rehabilitation risk assessment integrated network (R2 AIN™) framework that can be applied using Bayesian networks (BNs) to integrate and quantify such rehabilitation risks. Our framework has 7 steps, including key integration of rehabilitation risk sources and the quantification of undesired rehabilitation risk events to the final application of mitigation. We demonstrate the framework using a soil compaction BN case study in the Witbank Coalfield, South Africa and the Bowen Basin, Australia. Our approach allows for a probabilistic assessment of rehabilitation risk associated with multidisciplines to be integrated and quantified. Using this method, a site's rehabilitation risk profile can be determined before mining activities commence and the effects of manipulating management actions during later mine phases to reduce risk can be gauged, to aid decision making. Integr Environ Assess Manag 2019;15:190-208. © 2019 SETAC.

Accentuated cortico-cortical evoked potentials in neocortical epilepsy in areas of ictal onset.

OBJECTIVE: To determine whether patients with neocortical epilepsy show evidence for increased excitability measured by cortico-cortical evoked potentials (CCEPs) in ictal-onset regions. METHODS: In patients undergoing intracranial recordings with subdural electrodes for epilepsy surgery, we measured amplitudes, latencies, and stimulus thresholds of CCEPs near ictal onset zones (iCCEPs), and compared with adjacent neocortex not associated with ictal EEG (nCCEP). CCEP amplitude and latency measurements were made with each stimulation site, using graded stimulation intensities. RESULTS: Ten patients were included in this study. CCEPs were recorded in eight of 10 patients. The first negative (N1) iCCEP amplitude was higher than that of nCCEP in seven of the eight patients. In the group analysis, this difference was statistically significant. In three of these patients, the difference was individually significant. In one patient, the amplitude was higher in nCCEP than iCCEP and the area selected as nCCEP was within primary eloquent cortex. There was no significant difference seen in latency changes or stimulus threshold. CONCLUSIONS: Accentuated CCEP amplitudes near ictal onset zones could reflect an increased excitability of the cortex associated with the epileptogenic zone in some patients with neocortical epilepsy. The response of the neocortex to low-frequency stimulation may vary depending on the presence or absence of intrinsic epileptogenicity.

Geometric subspace methods and time-delay embedding for EEG artifact removal and classification.

Generalized singular-value decomposition is used to separate multichannel electroencephalogram (EEG) into components found by optimizing a signal-to-noise quotient. These components are used to filter out artifacts. Short-time principal components analysis of time-delay embedded EEG is used to represent windowed EEG data to classify EEG according to which mental task is being performed. Examples are presented of the filtering of various artifacts and results are shown of classification of EEG from five mental tasks using committees of decision trees.

Overexpression and rapid purification of Escherichia coli formamidopyrimidine-DNA glycosylase.

Formamidopyrimidine DNA glycosylase (Fpg) is a DNA glycosylase with an associated AP lyase activity. As a DNA repair enzyme, Fpg excises several modified bases from DNA associated with exposure to oxidizing agents such as free radicals. Experiments in many laboratories have been limited by the availability of the enzyme, and its production required at least a week of work to complete its purification. We have devised a new method that decreases the time and expense of purification of Fpg that should render this protein accessible to any laboratory. Fpg was subcloned into a gamma P(L) promoter-containing vector (pRE) and overproduced in the appropriate Escherichia coli host cells to about 25% of the total cellular protein. Fpg was purified to homogeneity in a simple two-step procedure with a 50% saving in time when compared to the previously known procedure. Comparative studies showed that the excision of 8-hydroxyguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 4,6-diamino-5-formamidopyrimidine, and to a lesser extent, 8-hydroxyadenine was virtually identical for the Fpg purified using this method and for the Fpg purified by the original method. Therefore, this method should prove useful for a large number of laboratories and further research on oxidative DNA damage.