Time domain classification of transient RFI

Since the emergence of radio astronomy as a field, it has been afflicted by radio frequency interference (RFI). RFI continues to present a problem despite increasingly sophisticated countermeasures developed over the decades. Due to technological improvements, radio telescopes have become more sensitive (for example, MeerKAT’s L-band receiver). Existing RFI has become more prominent as a result. At the same time, the prevalence of RFI-generating devices has increased as new technologies have been adopted by society. Many approaches have been developed for mitigating RFI, which are typically used in concert. New telescope arrays are often built far from human habitation in radio-quiet reserves. In South Africa, a radio-quiet reserve has been established in which several world class instruments are under construction. Despite the remote location of the reserve, careful attention is paid to the possibility of RFI. For example, some instruments will begin observations while others are still under construction. The infrastructure and equipment related to the construction work may increase the risk of RFI, especially transient RFI. A number of mitigation strategies have been employed, including the use of fixed and mobile RFI monitoring stations. Such stations operate independently of the main telescope arrays and continuously monitor a wide bandwidth in all directions. They are capable of recording spectra and high resolution time domain captures of transient RFI. Once detected, and if identified, an RFI source can be found and dealt with. The ability to identify the sources of detected RFI would be highly beneficial. Continuous wave intentional transmissions (telecommunication signals for example) are easily identified as they are required to adhere to allocated frequency bands. Transient RFI signals, however, are significantly more challenging to identify since they are generally broadband and highly intermittent. Transient RFI can be generated as a by-product of the normal operation of devices such as relays, AC machines and fluorescent lights, for example. Such devices may be present near radio telescope arrays as part of the infrastructure or equipment involved in the construction of new instruments. Other than contaminating observation data, transient RFI can also appear to have genuine astronomical origins. In one case, transient signals received from a microwave oven exhibited dispersion, suggesting a distant source. Therefore, the ability to identify transient RFI by source would be enormously valuable. Once identified, such sources may be removed or replaced where possible. Despite this need, there is a paucity of work on classifying transient RFI in the literature. This thesis focusses on the problem of identifying transient RFI by source in time domain data of the type captured by remote monitoring stations. Several novel approaches are explored in this thesis. If used with independent RFI monitoring stations, these approaches may aid in tracking down nearby RFI sources at a radio telescope array. They may also be useful for improving RFI flagging in data from radio telescopes themselves. Distinguishing between transient RFI and natural astronomical signals is likely to be an easier prospect than classifying transient RFI by source. Furthermore, these approaches may be better able to avoid excising genuine astronomical transients that nevertheless share some characteristics with RFI signals. The radio telescopes themselves are significantly more sensitive than RFI monitoring stations, and would thus be able to detect RFI sources more easily. However, terrestrial RFI would likely enter via sidelobes, tempering this advantage somewhat. In this thesis, transient RFI is first characterised, prior to classification by source. Labelled time-domain recordings of a number of transient RFI sources are acquired and statistically examined. Second, components analysis techniques are considered for feature selection. Cluster separation is analysed for principal components analysis (PCA) and kernel PCA, the latter proving most suitable. The effect of the supply voltage of certain RFI sources on cluster separation in the principal components domain is also explored. Several na¨ıve classification algorithms are tested, using kernel PCA for feature selection A more sophisticated dictionary-based approach is developed next. While there are variations in repeated recordings of the same RFI source, the signals tend to adhere to a common overarching structure. Full RFI signals are observed to consist of sequences of individual transients. An algorithm is presented to extract individual transients from full recordings, after which they are labelled using unsupervised clustering methods. This procedure results in a dictionary of archetypal transients, from which any full RFI sequence may be represented. Some approaches in Automated Speech Recognition (ASR) are similar: spoken words are divided into individual labelled phonemes. Representing RFI signals as sequences enables the use of hidden Markov models (HMMs) for identification. HMMs are well suited to sequence identification problems, and are known for their robustness to variation. For example, in ASR, HMMs are able to handle the variations in repeated utterances of the same word. When classifying the recorded RFI signals, good accuracy is achieved, improving on the results obtained using the more na¨ıve methods. Finally, a strategy involving deep learning techniques is explored. Recurrent neural networks and convolutional neural networks (CNNs) have shown great promise in a wide variety of classification tasks. Here, a model is developed that includes a pre-trained CNN layer followed by a bidirectional long short-term memory (BLSTM) layer. Special attention is paid to mitigating class imbalance when the model is used with individual transients extracted from full recordings. High classification accuracy is achieved, improving on the dictionary-based approach and the other na¨ıve methods. Recommendations are made for future work on developing these approaches further for practical use with remote monitoring stations. Other possibilities for future research are also discussed, including testing the robustness of the proposed approaches. They may also prove useful for RFI excision in observation data from radio telescopes

Warfarin Anticoagulation Exacerbates the Risk of Hemorrhagic Transformation after rt-PA Treatment in Experimental Stroke: Therapeutic Potential of PCC

Background: Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke. Methods: 62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h. Results: In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001). Conclusion: In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option

Targeting Huntingtin expression in patients with Huntington's disease

Background Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. Methods We conducted a randomized, double-blind, multiple-ascending-dose, phase 1–2a trial involving adults with early Huntington’s disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. Results Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and −20%, −25%, −28%, −42%, and −38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). Conclusions Intrathecal administration of HTTRx to patients with early Huntington’s disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT02519036.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes