Ongoing Activity Research Articles

Harnessing BIM with risk assessment for generating automated safety schedule and developing application for safety training

The construction industry accounts for 24.20% of all accidents in India, resulting in almost 75 accidents daily. Every construction job involves certain risk levels, often resulting in losses such as fatalities, compensation costs, man-hour loss, work delays, and ergonomic disorders in workers. Poor site safety management and hesitation towards adopting new methods and technologies often result in inefficient workflow, accidents, and inferior productivity. All these factors pile up, causing a surge in indirect costs, almost four times direct costs. The Indian construction industry employs 51 million workers but has only 4% formally trained workforce. Safety planning is currently considered a 'secondary' task due to insufficient safety budget, lack of well-defined training modules and modern tools, unawareness about underlying hazards, etc. The current study is an attempt to identify and assess underlying activity-based hazards using the Failure Mode and Effect Analysis (FMEA) approach by harnessing the potential of digital tools such as Building Information Modelling (BIM) and Visual Scripting in Dynamo v.2.10 to facilitate automation in generating 'Safety Schedule' in coordination with the project schedule. This study presents a novel idea of proactive safety planning, enabling workers and managers to foresee possible hazards associated with ongoing activity. Further, a worker training tracker prototype is developed in Microsoft Visual Studio using C# to store and track workers' safety training information. Managers can use this tracker to review workers' competence and ensure that they would have received appropriate role-based safety training. The applicability and effectiveness of the proposed method are demonstrated through a case study project.

VITELLOGENESIS ACTIVITY OF CHANNA MARULIOIDES, BLEEKER, 1851, IMPACT OF FOLICLE STIMULATING HORMONE AS REPRODUCTIVE DOMESTICATION

This study aims to determine the vitelogenesis activity by FSH hormone induction in the early stage of gonadal maturation. The treatament is a differences FSH dose with indicators of vitelogenesis activity were estradiol-17β levels in the blood, Hepatosomatic index (HSI) and Gonadosomatic Index (GSI). The study used a treatment A : Dose FSH at 1.0 ml/kg; B: Dose FSH at 1.25 ml/kg; C : Dose FSH at 1.5 ml/kg; control: nothing induction. The results showed that there was an effect of FSH dose on the estradiol 17β levels, HSI and GSI, there ongoing vitelogenesis activity. The trend of the GSI and HSI has a close correlation to levels of estradiol 17β, with the best dose of the hormone is 1.25 ml/kg resulting levels of esradiol 17β amounting to 63.35 pg / ml and the GSI and HSI are 3.45% and 1.48%. Furthermore, the best treatment successively resulted in increased levels of estradiol 17β, HSI and GSI in treatment C of 41.77 pg/ml, 1.48%, 3.24%; A : 28.01 pg / ml, 1.14 %, 3.42%;. FSH is suitable for reproductive domestication in Channa marulioides.

The Trends and Effects of Flood Occurrences in the Shire River Basin in Chikwawa District of Malawi: A Historical Perspective (1980 - 2019)

Purpose: The purpose of this study was to examine historical trends in flooding in Malawi’s Shire River Basin (SRB). The basin is prone to severe flooding and most affected in the country. For many years, flooding has posed a significant threat to communities in and around the basin. Therefore, the main objective of the study was to document the historical perspective of flood occurrences in terms of frequency and impact in the Shire River Basin of Chikwawa District, Malawi, from 1980 to 2019. 
 Methodology: A mixed survey design was used for the study. Both random and purposive sampling were used to identify participants. A total of 384 respondents took part in the study. The study collected both primary and secondary data. Primary sources of data were collected using household surveys, interviews with key informants, and focus group discussions, while secondary sources of data were collected using documents from both non-governmental and Malawian governmental departments and agencies (MDAs) as well as existing literature. Data from focus group discussions (FGDs), interviews with community elders (CEIs), and key informant interviews (KIIs) were recorded in Chichewa with a voice recorder, transcribed in Chichewa, and then translated into English. Household survey data were processed using Statistical Package for Social Scientists (SPSS) version 25 and secondary data were converted to time series data and then analysed using STATA software to produce charts and graphs. 
 Findings: The results showed that all three hydrometeorological extremes (mean annual temperature, average rainfall and baseflow index) increased, suggesting that both the intensity and frequency of flooding in the Shire River Basin of Chikwawa District were also increasing in absolute terms. People’s perceptions of flooding showed that the Shire River Basin in Chikwawa District experienced excessive flooding every 5 years. This 5-year cycle was, among other factors the result of climate change and forest loss in the study area, leading to an increase in river sedimentation.
 Recommendations: This article found that the local people in the Shire River Basin of Chikwawa District will always live with increasing levels of flooding. Therefore, they should be proactive in flood management and understand the process as an ongoing activity for future risk assessment. Analysing the history of river basin flooding is important as it helps the Malawi's Department of Disaster Management Affairs (DoDMA) officials to be alert and estimate the time frame for the next flood in the Shire River Basin of Chikwawa District to strengthen the flood forecasting accuracy.

Cueing natural event boundaries improves memory in people with post-traumatic stress disorder

People with post-traumatic stress disorder (PTSD) often report difficulty remembering information in their everyday lives. Recent findings suggest that such difficulties may be due to PTSD-related deficits in parsing ongoing activity into discrete events, a process called event segmentation. Here, we investigated the causal relationship between event segmentation and memory by cueing event boundaries and evaluating its effect on subsequent memory in people with PTSD. People with PTSD (n = 38) and trauma-matched controls (n = 36) watched and remembered videos of everyday activities that were either unedited, contained visual and auditory cues at event boundaries, or contained visual and auditory cues at event middles. PTSD symptom severity varied substantial within both the group with a PTSD diagnosis and the control group. Memory performance did not differ significantly between groups, but people with high symptoms of PTSD remembered fewer details from the videos than those with lower symptoms of PTSD. Both those with PTSD and controls remembered more information from the videos in the event boundary cue condition than the middle cue or unedited conditions. This finding has important implications for translational work focusing on addressing everyday memory complaints in people with PTSD.

Cognitive Impairment is Associated with Longitudinal Disability in LGI-1-IgG Encephalitis (S22.007)

<h3>Objective:</h3> To determine predictors of longitudinal clinical outcomes in leucine-rich glioma inactivated-1 immunoglobulin G (LGI-1)-IgG autoimmune encephalitis (AE). <h3>Background:</h3> Longitudinal studies prognosticating outcomes in LGI-1-IgG AE are needed to identify key drivers of disability. We examine disability utilizing modified Rankin Scale (mRS) and an AE specific scale, the clinical assessment scale in AE (CASE). <h3>Design/Methods:</h3> A retrospective observational study of seropositive LGI-1-IgG AE patients was conducted between 2013–2022. Clinical predictors included demographics, clinical and paraclinical data, magnetic resonance imaging (MRI), and Montreal Cognitive Assessment (MoCA). Clinical outcomes included mRS and CASE scores. Logistic and linear regressions were used for modeling mRS and CASE, respectively. Baseline clinical characteristics were included as independent variables in the regression models. <h3>Results:</h3> Thirty patients (60% male, median age=69.5; IQR=63.0–76.0) were included, with a median follow-up time of 8.7 months (IQR=4.3–24.1). Seizures (29, [96.7%]), and cognitive impairment (CI) (30, [100%]) were present in the majority. Median initial MoCA was 23/30 (IQR=21.0–25.0). The majority received acute immunotherapy (27, [90%]), and maintenance immunotherapy, (26 [86.7%]). Baseline mRS (median=2.0, IQR=2.0–3.0) and CASE (mean=4.3, SD=3.7) correlated with each other (<i>r</i>=0.58, <i>P</i>&lt;.001) and with initial MoCA score (mRS <i>r</i>=−0.60, <i>P</i>=.009, CASE <i>r</i>=−0.51, <i>P</i>=.031). After 12 months from symptom onset, mRS (OR=0.88, [CI=0.82–0.94], <i>P</i>&lt;.001) and CASE (β=−0.03, [SE=0.01], <i>P</i>&lt;.001) decreased significantly. Temporal lobe(s) Fluid Attenuation Inversion Recovery (FLAIR) hyperintensity correlated with higher mRS longitudinally (OR=17.49, [CI=2.37, 129.05], <i>P</i>=.005). Higher initial MOCA was associated with lower mRS (OR=0.66, [CI=0.45–0.98], <i>P</i>=.04) and CASE (β=−0.24, [SE=0.13], <i>P</i>=.061) longitudinally. At last follow-up, most patients had ongoing cognitive symptoms (25, [83.3%]), while few had ongoing seizure activity (3, [10%]). <h3>Conclusions:</h3> CI is associated with disability at baseline and long-term follow up, underscoring cognition as an important determinant of disability outcomes in LGI-1-IgG AE. Severity of CI on baseline MoCA may offer prognostic information on long-term disability. <b>Disclosure:</b> Dr. Aboseif has a non-compensated relationship as a AAN Autoimmune Neurology Section -- Education Workgroup with AAN that is relevant to AAN interests or activities. Ms. Li has nothing to disclose. Dr. Amin has nothing to disclose. Brittany Lapin has received personal compensation for serving as an employee of Cleveland Clinic. Brittany Lapin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Quality of Life Research. Brittany Lapin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Anesthesia and Analgeisa. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Abbatemarco has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech . The institution of Dr. Abbatemarco has received research support from Horizon. Dr. Rae-Grant has received publishing royalties from a publication relating to health care. Dr. Rae-Grant has received publishing royalties from a publication relating to health care. Dr. Punia has nothing to disclose. Rachel Galioto has nothing to disclose. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon therapeutics . Dr. Kunchok has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology.

Caspr2 Antibody-Mediated Ataxia, Parkinsonism, and Epilepsy: A Case for Escalating Immunotherapy. (P13-11.007)

<h3>Objective:</h3> To report a rare presentation of anti-Caspr2 syndrome treated successfully with rituximab. <h3>Background:</h3> Anti-Caspr2 syndrome has a variety of clinical phenotypes including encephalopathy, seizure, psychiatric disturbances, respiratory failure, dysautonomia, peripheral nerve dysfunction, as well as ataxia of a constant or episodic nature.¹ In many of the cases with ataxia, there is associated limbic encephalitis.² Anti-Caspr2 syndrome with ataxia, parkinsonism and seizure has only been reported once in the literature.³ This symptomatology can be easily mistaken for an atypical parkinsonism like cerebellar multiple systems atrophy, or spinocerebellar ataxia type 2 but this treatable cause is an important consideration. <h3>Design/Methods:</h3> To report a case of anti-Caspr2 syndrome presenting with pure ataxia, then progressing to parkinsonism, and epilepsy; its successful treatment; and accompanying video examinations. <h3>Results:</h3> A 71 year-old man was referred for 8 months of progressive, generalized ataxia and dysarthria. Immune-mediated ataxia was considered given the subacute course with rapid progression. He was found to have a Caspr2 antibody titer of 1:100. Evaluation for malignancy was unremarkable. Lumbar puncture revealed Caspr2 antibody positivity. The patient was treated with 4 days of intravenous steroids and immunoglobulins with significant improvement. He relapsed four months later with lower extremity weakness and ataxia. Despite maintenance intravenous immunoglobulin, his ataxia continued to progress. He then developed focal seizures with impaired awareness and left sided parkinsonism. He was started on rituximab immunotherapy for ongoing disease activity. His ataxia and parkinsonism significantly improved to near-baseline with continued stability 6 months later. <h3>Conclusions:</h3> This case illustrates an example of an autoimmune-mediated cerebellar ataxia of subacute onset with progression to parkinsonism and epilepsy. Special consideration for anti-Caspr2 syndrome should be taken in cases of progressive ataxia with accompanying neurologic features of parkinsonism and seizure. Escalation to rituximab can be considered for patients who continue to progress despite preliminary immunotherapy. <b>Disclosure:</b> Dr. Sugar has nothing to disclose. Dr. Witek has nothing to disclose.

Morphine and dopamine: Low dose apomorphine can prevent both the induction and expression of morphine locomotor sensitization and conditioning

The disinhibition of dopamine neurons in the VTA by morphine is considered an important contributor to the reward potency of morphine. In this report, three experiments were conducted in which a low dose of apomorphine (0.05 mg/kg) was used as a pretreatment to reduce dopamine activity. Locomotor hyperactivity was used as the behavioral response to morphine (10.0 mg/kg). In the first experiment, five treatments with morphine induced the development of locomotor and conditioned hyperactivity that were prevented by apomorphine given 10 min prior to morphine. Apomorphine before either vehicle or morphine induced equivalent reductions in locomotion. In the second experiment, the apomorphine pretreatment was initiated after induction of a conditioned hyperactivity and apomorphine prevented the expression of the conditioning. To assess the effects of apomorphine on VTA and the nucleus accumbens, ERK measurements were carried out after the induction of locomotor and conditioned hyperactivity. Increased ERK activation was found and these effects were prevented by the apomorphine in both experiments. A third experiment was conducted to assess the effects of acute morphine on ERK before locomotor stimulation was induced by morphine. Acute morphine did not increase locomotion, but a robust ERK response was produced indicating that the morphine-induced ERK activation was not secondary to locomotor stimulation. ERK activation was again prevented by the apomorphine pretreatment. We suggest that contiguity between the ongoing behavioral activity and the morphine activation of the dopamine reward system incentivizes and potentiates the ongoing behavior generating equivalent behavioral sensitization and conditioned effects.

Activity Recognition in Smart Homes via Feature-Rich Visual Extraction of Locomotion Traces

The proliferation of sensors in smart homes makes it possible to monitor human activities, routines, and complex behaviors in an unprecedented way. Hence, human activity recognition has gained increasing attention over the last few years as a tool to improve healthcare and well-being in several applications. However, most existing activity recognition systems rely on cameras or wearable sensors, which may be obtrusive and may invade the user’s privacy, especially at home. Moreover, extracting expressive features from a stream of data provided by heterogeneous smart-home sensors is still an open challenge. In this paper, we investigate a novel method to detect activities of daily living by exploiting unobtrusive smart-home sensors (i.e., passive infrared position sensors and sensors attached to everyday objects) and vision-based deep learning algorithms, without the use of cameras or wearable sensors. Our method relies on depicting the locomotion traces of the user and visual clues about their interaction with objects on a floor plan map of the home, and utilizes pre-trained deep convolutional neural networks to extract features for recognizing ongoing activity. One additional advantage of our method is its seamless extendibility with additional features based on the available sensor data. Extensive experiments with a real-world dataset and a comparison with state-of-the-art approaches demonstrate the effectiveness of our method.

A multi-scale approach to the recent activity of the Stradella thrust in the seismotectonic context of the Emilia Arc (northwestern Italy)

The frontal thrusts and folds of the northern Apennines - Italy - are mainly covered under the alluvial deposits of the Po Plain. Some of these structures show geological evidence of Late Quaternary activity, thus posing the need for an accurate seismic hazard assessment due to widespread housing settlements, industries, lifeline infrastructures, and large towns. We present new morphostructural, geophysical, and seismological data to discuss the recent activity of the Broni-Sarmato fault, an 18 km-long outcropping section of the north-verging Stradella thrust, located 50 km south of Milan, along the Pede-Apennine thrust front (PTF) in the rear of the Emilia Arc thrust system. The new geoelectrical surveys across the fault scarp show deformation of the shallow deposits. The outcropping deformations, with a fault scarp ranging up to 25.8 m, are investigated within the seismotectonic framework of the PTF and the Emilia Arc. The analysis of the associated seismicity and new focal mechanisms highlight two seismogenic contractional volumes dipping at low-angle southwest-ward, at upper (<12 km) and lower crustal depths (~20–30 km). The shallow seismicity partially illuminates the Stradella thrust and its along-strike southeastward prosecution along the extent of the Stradella-Salsomaggiore Arc. Subordinately, it also illuminates some of the Emilia Arc thrust planes. The deeper seismogenic volume shows large patches of the basal thrust of the Emilia Arc fault system. We interpret the above multi-scale data as evidence of ongoing tectonic activity of the outer fronts of the Emilia Arc under a regional NNE-oriented compressional stress field, with some evidence of thrust involvement along the Pede-Apennine front. In our 3D fault-model reconstruction, all the analyzed thrust structures appear as expressions of a thick-skinned deformation that controls earthquake release at different structural levels.

Open-Source Real-Time Closed-Loop Electrical Threshold Tracking for Translational Pain Research.

Nociceptors are a class of primary afferent neurons that signal potentially harmful noxious stimuli. An increase in nociceptor excitability occurs in acute and chronic pain conditions. This produces abnormal ongoing activity or reduced activation thresholds to noxious stimuli. Identifying the cause of this increased excitability is required for the development and validation of mechanism-based treatments. Single-neuron electrical threshold tracking can quantify nociceptor excitability. Therefore, we have developed an application to allow such measurements and demonstrate its use in humans and rodents. APTrack provides real-time data visualization and action potential identification using a temporal raster plot. Algorithms detect action potentials by threshold crossing and monitor their latency after electrical stimulation. The plugin then modulates the electrical stimulation amplitude using an up-down method to estimate the electrical threshold of the nociceptors. The software was built upon the Open Ephys system (V0.54) and coded in C++ using the JUCE framework. It runs on Windows, Linux, and Mac operating systems. The open-source code is available (https://github.com/Microneurography/APTrack). The electrophysiological recordings were taken from nociceptors in both a mouse skin-nerve preparation using the teased fiber method in the saphenous nerve and in healthy human volunteers using microneurography in the superficial peroneal nerve. Nociceptors were classified by their response to thermal and mechanical stimuli, as well as by monitoring the activity-dependent slowing of the conduction velocity. The software facilitated the experiment by simplifying the action potential identification through the temporal raster plot. We demonstrate real-time closed-loop electrical threshold tracking of single-neuron action potentials duringin vivohuman microneurography, for the first time, and duringex vivomouse electrophysiological recordings of C-fibers and Aδ-fibers. We establish proof of principle by showing that the electrical threshold of a human heat-sensitive C-fiber nociceptor is reduced by heating the receptive field. This plugin enables the electrical threshold tracking of single-neuron action potentials and allows the quantification of changes in nociceptor excitability.

Treatment of status epilepticus: Physiology, pharmacology, and future directions.

The review presents retrospective, present views and future perspectives on the treatment of status epilepticus (SE). First, presynaptic, postsynaptic, and extrasynaptic mechanisms underlying sustaining ongoing seizure activity are highlighted. Next, mechanism-based choices of antiseizure medications capable of promptly arresting SE are introduced. Finally, challenges associated with translating the advances in laboratory research in clinical practice are discussed.

Epigenetic switching with asymmetric bridging interactions

Gene expression states are often stably sustained in cis despite massively disruptive events like DNA replication. This is achieved by on-going enzymatic activity that maintains parts of the DNA in either heterochromatic (packed) or euchromatic (free) states, each of which is stabilized by both positive feedback and bridging interactions between individual nucleosomes. In contrast to condensed matter, however, the dynamics is not only governed by equilibrium binding interactions but is also mediated by enzymes that recognize and act on specific amino acid tails of the nucleosomes. The mechanical result is that some nucleosomes can bind to one another and form tightly packed polymer configurations, whereas others remain unbound and form free, noncompact polymer configurations. Here, we study the consequences of such an asymmetric interaction pattern on the dynamics of epigenetic switching. We develop a 3D polymer model and show that traits associated with epigenetic switching, such as bistability and epigenetic memory, are permitted by such a model. We find, however, that the experimentally observed burst-like nature of some epigenetic switches is difficult to reproduce by this biologically motivated interaction. Instead, the behavior seen in experiments can be explained by introducing partial confinement, which particularly affects the euchromatic regions of the chromosome.

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

Cognition is entangled with metabolism: relevance for resting-state EEG-fMRI.

The brain is a living organ with distinct metabolic constraints. However, these constraints are typically considered as secondary or supportive of information processing which is primarily performed by neurons. The default operational definition of neural information processing is that (1) it is ultimately encoded as a change in individual neuronal firing rate as this correlates with the presentation of a peripheral stimulus, motor action or cognitive task. Two additional assumptions are associated with this default interpretation: (2) that the incessant background firing activity against which changes in activity are measured plays no role in assigning significance to the extrinsically evoked change in neural firing, and (3) that the metabolic energy that sustains this background activity and which correlates with differences in neuronal firing rate is merely a response to an evoked change in neuronal activity. These assumptions underlie the design, implementation, and interpretation of neuroimaging studies, particularly fMRI, which relies on changes in blood oxygen as an indirect measure of neural activity. In this article we reconsider all three of these assumptions in light of recent evidence. We suggest that by combining EEG with fMRI, new experimental work can reconcile emerging controversies in neurovascular coupling and the significance of ongoing, background activity during resting-state paradigms. A new conceptual framework for neuroimaging paradigms is developed to investigate how ongoing neural activity is "entangled" with metabolism. That is, in addition to being recruited to support locally evoked neuronal activity (the traditional hemodynamic response), changes in metabolic support may be independently "invoked" by non-local brain regions, yielding flexible neurovascular coupling dynamics that inform the cognitive context. This framework demonstrates how multimodal neuroimaging is necessary to probe the neurometabolic foundations of cognition, with implications for the study of neuropsychiatric disorders.

Effect of Previous Disease-Modifying Therapy on Treatment Effectiveness for Patients Treated With Ocrelizumab.

B cell-depleting antibodies were proven as effective strategy for the treatment of relapsing multiple sclerosis (RMS). The monoclonal antibody ocrelizumab was approved in 2017 in the United States and in 2018 in the European Union, but despite proven efficacy in randomized, controlled clinical trials, its effectiveness in the real-world setting remains to be fully elucidated. In particular, most study patients were treatment naive or switched from injectable therapies, whereas oral substances or monoclonal antibodies made up >1% of previous treatments. We evaluated ocrelizumab-treated patients with RMS enrolled in the prospective cohorts at the University Hospitals Duesseldorf and Essen, Germany. Epidemiologic data at baseline were compared, and Cox proportional hazard models were applied to evaluate outcomes. Two hundred eighty patients were included (median age: 37 years, 35% male patients). Compared with using ocrelizumab as a first-line treatment, its use as a third-line therapy increased hazard ratios (HRs) for relapse and disability progression, whereas differences between first- vs second-line and second- vs third-line remained smaller. We stratified patients according to their last previous disease-modifying treatment and here identified fingolimod (FTY) (45 patients, median age 40 years, 33% male patients) as a relevant risk factor for ongoing relapse activity despite 2nd-line (HR: 3.417 [1.007-11.600]) or 3rd-line (HR: 5.903 [2.489-13.999]) ocrelizumab treatment, disability worsening (2nd line: HR: 3.571 [1.013-12.589]; 3rd line: HR: 4.502 [1.728-11.729]), and occurrence of new/enlarging MRI lesions (2nd line: HR: 1.939 [0.604-6.228]; 3rd line: HR: 4.627 [1.982-10.802]). Effects were persistent throughout the whole follow-up. Neither peripheral B-cell repopulation nor immunoglobulin G levels were associated with rekindling disease activity. Our prospectively collected observational data suggest suboptimal effectiveness of ocrelizumab in patients switching from FTY compared with those switching from other substances or having been treatment naive. These findings support previous studies indicating abated effectiveness of immune cell-depleting therapies following FTY treatment in patients with RMS. This study provides Class IV evidence that for patients with RMS, previous treatment with FTY compared with previous treatment with other immunomodulating therapies decreases the effectiveness of ocrelizumab.

Abstract 2278: Dissecting immuno-genomic pathways of response and resistance to immunotherapy in metastatic urothelial carcinoma in a real-world cohort

Abstract Background: While Immune Checkpoint Inhibitors (ICI) are widely used for the treatment (tx) of patients (pts) with metastatic urothelial carcinoma (mUC), response rates are only around 20%. There is an unmet need to develop biomarkers of response and resistance to avoid unnecessary treatment in the majority of pts who will not respond to ICI, to spare toxicity from ICI as well as mitigate the financial burden. Here we report tumor immune-genomic characteristics associated with response and resistance to ICI in a real-world cohort of mUC pts at the Cleveland Clinic. Methods: We selected 61 mUC pts who received at least 2 cycles of ICI (atezolizumab or pembrolizumab) between 2015-2020 and had pre-tx archival fresh frozen paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as complete responders (CR; N=8), partial responders (PR; N=14), stable disease (SD; N=9), and progressive disease (PD; N=30). Tumor was macrodissected from 2-5 FFPE slides guided by an H&amp;E stained section of tumor. RNA extraction was done using Qiagen Rneasy FFPE kit. 100ng of RNA was used for transcriptomic analysis using the 770-gene Nanostring PanCancer IO 360 panel. Data normalization and analysis was carried out using nSolver 4.0. Results: Using unsupervised hierarchical clustering, when comparing molecular signatures of pts with CR vs PD respectively, we saw upregulation of exhausted CD8 (log fold change (FC) = 0.7287, p= 0.03289) and IFN downstream (logFC = 0.5929, p = 0.04986). Notably, the molecular signatures upregulated between SD vs PD respectively were IFN Gamma (logFC = 1.503, p = 0.0044), PD-L1 (logFC = 1.136, p = 0.0123), Antigen-presenting machinery (APM) (logFC = 1.103, p = 0.0006), Immunoproteasome (logFC = 0.984, p = 0.00096) and Tumor inflammatory score (logFC = 0.947, p = 0.032). Furthermore, molecular signatures were not differently upregulated between pts with PR vs PD. In our cohort, the proportion of pts who were alive at 35.9 months (median follow-up) was 62.5% for CR (5 of 8), 28.5% for PR (4 of 14), 22.2% for SD (2 of 9) and 6.2% for PD (2 of 30) even though the median overall survival was not significantly different between the groups. Conclusion: In our cohort of ICI-treated mUC pts, we found an association between existing T-cell effector function, particularly IFN-gamma responses, and response to ICI. Signatures associated with T cell exhaustion were also upregulated among pts with CR indicating ongoing anti-tumor activity. These findings need to be further validated in prospective trials. Ongoing genomic and immunologic correlative studies in our cohort will further help understand comprehensive biomarkers of response and resistance to ICI in pts with mUC are currently underway. Citation Format: Nikhil Pramod, Paul Pavicic, Scott Dawsey, Alan Shen, Roshan Lodha, Moshe Ornstein, Omar Mian, Timothy Gilligan, Christopher Wee, Amanda Nizam, Jane Nguyen, C. Marcela Diaz-Montero, Shilpa Gupta. Dissecting immuno-genomic pathways of response and resistance to immunotherapy in metastatic urothelial carcinoma in a real-world cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2278.

Intrinsic timescales in the visual cortex change with selective attention and reflect spatial connectivity

Intrinsic timescales characterize dynamics of endogenous fluctuations in neural activity. Variation of intrinsic timescales across the neocortex reflects functional specialization of cortical areas, but less is known about how intrinsic timescales change during cognitive tasks. We measured intrinsic timescales of local spiking activity within columns of area V4 in male monkeys performing spatial attention tasks. The ongoing spiking activity unfolded across at least two distinct timescales, fast and slow. The slow timescale increased when monkeys attended to the receptive fields location and correlated with reaction times. By evaluating predictions of several network models, we found that spatiotemporal correlations in V4 activity were best explained by the model in which multiple timescales arise from recurrent interactions shaped by spatially arranged connectivity, and attentional modulation of timescales results from an increase in the efficacy of recurrent interactions. Our results suggest that multiple timescales may arise from the spatial connectivity in the visual cortex and flexibly change with the cognitive state due to dynamic effective interactions between neurons.

Application of AIS‐ and flyover‐based methods to monitor illegal and legal fishing in Canada's Pacific marine conservation areas

AbstractNew approaches are required to undertake the substantial task of monitoring ongoing fishing activity in marine conservation areas to ensure conservation goals are achieved. To address this need, we applied previously developed, yet currently underused, vessel tracking methods based on Automatic Identification System (AIS) and aerial surveillance (“flyovers”) to Canada's Pacific marine conservation areas from 2012 to 2019. We used satellite and terrestrial‐based AIS receivers and flyover‐based visual observations to estimate illegal and legal fishing activity after 185 conservation area (CA) enactments (i.e., static, geographically defined areas with fishing regulations). We compared the effectiveness in detecting fishing activity between the AIS‐ and flyover‐based methods, and used the latter to determine that 93% of vessels were actively fishing in CAs without AIS. The AIS‐based method still detected 3303 h of fishing in CAs after enactment, and both methods estimated 22%–24% of fishing activity in CAs was illegal. The application of these methods also shed light on the complexity of fishing regulations across CAs (i.e., varying and CA‐specific restrictions). This highlighted the need to better align vessel tracking fishing gear classifications with CA regulation specifications, and conversely to simplify regulations (e.g., no‐take), for more accurate monitoring and evaluation moving forward.

Monitoring temporal and spatial trends of illegal and legal fishing in marine conservation areas across Canada's three oceans

AbstractExpansion of marine conservation areas (CA) necessitates resource‐efficient and achievable strategies for monitoring and evaluation of ongoing fishing activity at national levels. To demonstrate and explore such a strategy, we conducted the first extensive analysis of fishing activity within Canada's static, geographically defined marine CAs with fishing regulations (n = 264 areas). We used 8 years of Automatic Identification System data to estimate fishing effort across three oceans and conducted temporal and spatial comparisons specific to each CA's regulations and enactment date. We addressed questions on CA effectiveness, fishing displacement, fishing the line behavior, and relationships between fishing activity and spatial CA attributes. We estimated 22,000 h of fishing activity within CAs after enactments, 22% of which was identified as illegal. CA effectiveness appeared to be lowest for Atlantic CAs based on illegal fishing effort density within CAs. Fishing displacement and fishing the line was generally not apparent as buffer areas around CAs tended to already have higher fishing effort prior to enactments. CA effectiveness and responses to CAs varied considerably, as was visualized using timeseries plots and maps developed for each CA. Our evaluation of a nation's full suite of CAs provides managers with a foundation and approach for continued monitoring and reporting.

Cochlear Theta Activity Oscillates in Phase Opposition during Interaural Attention.

It is widely established that sensory perception is a rhythmic process as opposed to a continuous one. In the context of auditory perception, this effect is only established on a cortical and behavioral level. Yet, the unique architecture of the auditory sensory system allows its primary sensory cortex to modulate the processes of its sensory receptors at the cochlear level. Previously, we could demonstrate the existence of a genuine cochlear theta (∼6-Hz) rhythm that is modulated in amplitude by intermodal selective attention. As the study's paradigm was not suited to assess attentional effects on the oscillatory phase of cochlear activity, the question of whether attention can also affect the temporal organization of the cochlea's ongoing activity remained open. The present study utilizes an interaural attention paradigm to investigate ongoing otoacoustic activity during a stimulus-free cue-target interval and an omission period of the auditory target in humans. We were able to replicate the existence of the cochlear theta rhythm. Importantly, we found significant phase opposition between the two ears and attention conditions of anticipatory as well as cochlear oscillatory activity during target presentation. Yet, the amplitude was unaffected by interaural attention. These results are the first to demonstrate that intermodal and interaural attention deploy different aspects of excitation and inhibition at the first level of auditory processing. Whereas intermodal attention modulates the level of cochlear activity, interaural attention modulates the timing.