A pH-sensitive closed-loop nanomachine to control hyperexcitability at the single neuron level.

Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the difficulty of illuminating deep brain areas poses translational challenges. Thus, the search of alternative light sources is strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (E2GFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase and E2GFP which, under conditions of acidic pH, activates halorhodopsin. In primary neurons, pHIL senses the intracellular pH drop associated with hyperactivity and optogenetically aborts paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in hippocampal pyramidal neurons is effective in decreasing duration and increasing latency of pilocarpine-induced tonic-clonic seizures upon in vivo coelenterazine administration, without affecting higher brain functions. The same treatment is effective in markedly decreasing seizure manifestations in a murine model of genetic epilepsy. The results indicate that pHIL represents a potentially promising closed-loop chemo-optogenetic strategy to treat drug-refractory epilepsy.

An ordinal clinical score predicts seizure freedom after minimally invasive epilepsy surgery.

OBJECTIVE: To predict one-year seizure freedom, using a combination of relevant clinical variables, following stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy in a series of 101 patients. METHODS: Eight predictors of seizure freedom were selected based on their association with medial temporal lobe epilepsy: (1) MRI evidence of mesial temporal sclerosis (MTS); (2) unitemporal interictal epileptiform discharges; (3) absence of generalized tonic-clonic seizures; (4) history of febrile seizures; (5) onset of epilepsy ≤16 years; (6) absence of an auditory, visual, or vertiginous aura; and (7) unitemporal ictal onset; (8) unitemporal PET hypometabolism. We compared four multivariate models: "MTS," using just evidence of MTS; "FULL," using all eight binary predictors; "AIC" using backwards selection of variables; and "SCORE," using a 0-to-8-point ordinal score awarding one point for each binary predictor. RESULTS: In univariate analysis, significant predictors for seizure freedom were evidence of mesial temporal sclerosis (p = 0.011, Fisher exact) and unitemporal interictal discharges (p = 0.005). For multivariate prediction (using leave one-out cross-validation), the ordinal SCORE model had a significantly higher area under the curve (AUC 0.70) than the other three models: MTS (AUC 0.54, p = 0.002, Delong's test), FULL (AUC 0.62, p = 0.003), or AIC (AUC 0.53, p < 0.001). INTERPRETATION: An ordinal score incorporating eight independent binary clinical variables predicted seizure freedom better on novel data than a model using MTS alone, a full multivariate model, or a backwards selected model. The ordinal score model represents a simple clinical heuristic to identify which patients should be offered minimally invasive laser surgery.

De-escalation and Discontinuation of Disease-Modifying Therapies in Multiple Sclerosis.

PURPOSE OF REVIEW: Long-term use of multiple sclerosis (MS) disease-modifying therapies (DMTs) is standard practice to prevent accumulation of disability. Immunosenescence and other age-related changes lead to an altered risk-benefit ratio for older patients on DMTs. This article reviews recent research on the topic of de-escalation and discontinuation of MS DMTs. RECENT FINDINGS: Observational and interventional studies have shed light on what happens to patients who de-escalate or discontinue DMTs and the factors, such as age, treatment type, and presence of recent disease activity, that influence outcomes. Though many questions remain, recent findings have been valuable for the development of an evidence-based approach to making de-escalation and discontinuation decisions in MS.

The involvement of the piriform cortex in non-lesional temporal lobe epilepsy: an uncommon component of the epileptogenic network.

The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children's Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on patients with one or more electrode contacts in the piriform cortex. Primary objectives included determining piriform cortex involvement within the electrophysiologically defined epileptogenic network and assessing the effects of electrical stimulation. Twenty-two patients were included in the study. Notably, only one patient exhibited piriform cortex involvement at seizure onset, associated with an olfactory aura. Two patients showed early piriform cortex involvement, while others displayed late or no involvement. Electrical stimulation of the piriform cortex induced after-discharges in three patients and replicated a habitual seizure in one. These findings present a contrast to surgical outcome studies, suggesting that the piriform cortex may not typically play a significant role in the epileptogenic network among patients with non-lesional temporal lobe epilepsy.

High prevalence of albuminuria among adult males living with HIV in Botswana.

Chronic HIV disease is associated with a fivefold increase in albuminuria outside of sub-Saharan Africa. However, very little is known about albuminuria risk among people living with HIV (PLWH) in sub-Saharan Africa. Therefore, we conducted a cross-sectional observational HIV clinic-based study of albuminuria among 1533 adults aged 21 years or older between January 2020 and January 2021 in Gaborone, Botswana. Clinical albuminuria was defined using a sex-based albumin‒creatinine ratio (ACR) of 25-355 mg/g for females and 17-250 mg/g for males. The study population mean age was 48.5 (SD 10.3) years, and 764/1533 (49.7%) were female. The overall prevalence of albuminuria was 20.7% (95% CI 18.7%, 22.8%). A higher proportion of males were more likely to be categorized as having albuminuria than females, 25% (95% CI 22.0, 28.2) versus 16.4% (95% CI 13.8,19.2), P value < 0.001. In the final multivariate models, predictors of albuminuria differed by sex group. Larger longitudinal studies are required to evaluate the impact of albuminuria among PLWH with particular emphasis on the effect of sex on the risk of albuminuria.

Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity.

Objective. Therapeutic brain stimulation is conventionally delivered using constant-frequency stimulation pulses. Several recent clinical studies have explored how unconventional and irregular temporal stimulation patterns could enable better therapy. However, it is challenging to understand which irregular patterns are most effective for different therapeutic applications given the massively high-dimensional parameter space.Approach. Here we applied many irregular stimulation patterns in a single neural circuit to demonstrate how they can enable new dimensions of neural control compared to conventional stimulation, to guide future exploration of novel stimulation patterns in translational settings. We optogenetically excited the septohippocampal circuit with constant-frequency, nested pulse, sinusoidal, and randomized stimulation waveforms, systematically varying their amplitude and frequency parameters.Main results.We first found equal entrainment of hippocampal oscillations: all waveforms provided similar gamma-power increase, whereas no parameters increased theta-band power above baseline (despite the mechanistic role of the medial septum in driving hippocampal theta oscillations). We then compared each of the effects of each waveform on high-dimensional multi-band activity states using dimensionality reduction methods. Strikingly, we found that conventional stimulation drove predominantly 'artificial' (different from behavioral activity) effects, whereas all irregular waveforms induced activity patterns that more closely resembled behavioral activity.Significance. Our findings suggest that irregular stimulation patterns are not useful when the desired mechanism is to suppress or enhance a single frequency band. However, novel stimulation patterns may provide the greatest benefit for neural control applications where entraining a particular mixture of bands (e.g. if they are associated with different symptoms) or behaviorally-relevant activity is desired.

Neural pathway activation in the subthalamic region depends on stimulation polarity.

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD); however, there is limited understanding of which subthalamic pathways are recruited in response to stimulation. Here, by focusing on the polarity of the stimulus waveform (cathodic vs. anodic), our goal was to elucidate biophysical mechanisms that underlie electrical stimulation in the human brain. In clinical studies, cathodic stimulation more easily triggers behavioral responses, but anodic DBS broadens the therapeutic window. This suggests that neural pathways involved respond preferentially depending on stimulus polarity. To experimentally compare the activation of therapeutically relevant pathways during cathodic and anodic subthalamic nucleus (STN) DBS, pathway activation was quantified by measuring evoked potentials resulting from antidromic or orthodromic activation in 15 PD patients undergoing DBS implantation. Cortical evoked potentials (cEP) were recorded using subdural electrocorticography, DBS local evoked potentials (DLEP) were recorded from non-stimulating contacts and EMG activity was recorded from arm and face muscles. We measured: 1) the amplitude of short-latency cEP, previously demonstrated to reflect activation of the cortico-STN hyperdirect pathway, 2) DLEP amplitude thought to reflect activation of STN-globus pallidus (GP) pathway, and 3) amplitudes of very short-latency cEP and motor evoked potentials (mEP) for activation of cortico-spinal/bulbar tract (CSBT). We constructed recruitment and strength-duration curves for each EP/pathway to compare the excitability for different stimulation polarities. We compared experimental data with the most advanced DBS computational models. Our results provide experimental evidence that subcortical cathodic and anodic stimulation activate the same pathways in the STN region and that cathodic stimulation is in general more efficient. However, relative efficiency varies for different pathways so that anodic stimulation is the least efficient in activating CSBT, more efficient in activating the HDP and as efficient as cathodic in activating STN-GP pathway. Our experiments confirm biophysical model predictions regarding neural activations in the central nervous system and provide evidence that stimulus polarity has differential effects on passing axons, terminal synapses, and local neurons. Comparison of experimental results with clinical DBS studies provides further evidence that the hyperdirect pathway may be involved in the therapeutic mechanisms of DBS.

Targeting thalamocortical circuits for closed-loop stimulation in Lennox-Gastaut syndrome.

This paper outlines the therapeutic rationale and neurosurgical targeting technique for bilateral, closed-loop, thalamocortical stimulation in Lennox-Gastaut syndrome, a severe form of childhood-onset epilepsy. Thalamic stimulation can be an effective treatment for Lennox-Gastaut syndrome, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. We aimed to identify a cortical target by synthesizing prior neuroimaging studies, and to use this knowledge to advance a dual thalamic (centromedian) and cortical (frontal) approach for closed-loop stimulation. Multi-modal brain network maps from three group-level studies of Lennox-Gastaut syndrome were averaged to define the area of peak overlap: simultaneous EEG-functional MRI of generalized paroxysmal fast activity, [18F]fluorodeoxyglucose PET of cortical hypometabolism and diffusion MRI structural connectivity associated with clinical efficacy in a previous trial of thalamic deep brain stimulation. The resulting 'hotspot' was used as a seed in a normative functional MRI connectivity analysis to identify connected networks. Intracranial electrophysiology was reviewed in the first two trial patients undergoing bilateral implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analysed for presence and synchrony of epileptiform activity. The peak overlap was in bilateral premotor cortex/caudal middle frontal gyrus. Functional connectivity of this hotspot revealed a distributed network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-functional MRI and PET. Intracranial electrophysiology showed characteristic epileptiform activity of Lennox-Gastaut syndrome in both the cortical hotspot and thalamus; most detected events occurred first in the cortex before appearing in the thalamus. Premotor frontal cortex shows peak involvement in Lennox-Gastaut syndrome and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for a range of neuromodulation therapies, including thalamocortical stimulation and emerging non-invasive treatments like focused ultrasound or transcranial magnetic stimulation. Compared to thalamus-only approaches, the addition of this cortical target may allow more rapid detections of seizures, more diverse stimulation paradigms and broader modulation of the epileptic network. A prospective, multi-centre trial of closed-loop thalamocortical stimulation for Lennox-Gastaut syndrome is currently underway.

Optimal hippocampal targeting in responsive neurostimulation for mesial temporal lobe epilepsy.

OBJECTIVE: The aim of this study was to identify features of responsive neurostimulation (RNS) lead configuration and contact placement associated with greater seizure reduction in mesial temporal lobe epilepsy (MTLE). METHODS: A single-center series of patients with MTLE treated with RNS were retrospectively analyzed to assess the relationship between anatomical targeting and seizure reduction. Targeting was determined according to both the preoperatively conceived lead configuration and the actual placement of RNS contacts. Three lead configurations were used: 1) single bilateral, with 1 depth lead in each hippocampus; 2) single unilateral, with 1 hippocampal depth lead and another implant outside the mesial temporal lobe; and 3) dual unilateral, with 2 leads in 1 hippocampus. Contact placement on postoperative imaging was measured according to the number of hippocampal contacts per targeted hippocampus (contact density) and per patient (contact count), distribution throughout the hippocampus, and proximity to the anteromedial hippocampus. RESULTS: Dual unilateral lead placement resulted in significantly higher hippocampal contact density compared with the single hippocampal approaches, but only showed a nonsignificant trend toward a higher rate of response. However, those patients with more than 4 contacts in a single hippocampus, achievable only with dual unilateral leads, had a significantly higher rate of response. The higher likelihood of response was poorly explained by more widespread hippocampal coverage, but well correlated with proximity to the anteromedial hippocampus. CONCLUSIONS: Dual unilateral hippocampal implantation increased RNS contact density in patients with unilateral MTLE, which contributed to improved outcomes, not by stimulating more of the hippocampus, but instead by being more likely to stimulate a latent subtarget in the anterior hippocampus. It remains to be explored whether a single electrode targeted selectively to this region would also result in improved outcomes.

Comparison of minimally invasive to standard temporal lobectomy approaches to epilepsy surgery: Seizure relief and visual confrontation naming outcomes.

The purpose of this study was to systematically examine three different surgical approaches in treating left medial temporal lobe epilepsy (mTLE) (viz., subtemporal selective amygdalohippocampectomy [subSAH], stereotactic laser amygdalohippocampotomy [SLAH], and anterior temporal lobectomy [ATL]), to determine which procedures are most favorable in terms of visual confrontation naming and seizure relief outcome. This was a retrospective study of 33 adults with intractable mTLE who underwent left temporal lobe surgery at three different epilepsy surgery centers who also underwent pre-, and at least 6-month post-surgical neuropsychological testing. Measures included the Boston Naming Test (BNT) and the Engel Epilepsy Surgery Outcome Scale. Fisher's exact tests revealed a statistically significant decline in naming in ATLs compared to SLAHs, but no other significant group differences. 82% of ATL and 36% of subSAH patients showed a significant naming decline whereas no SLAH patient (0%) had a significant naming decline. Significant postoperative naming improvement was seen in 36% of SLAH patients in contrast to 9% improvement in subSAH patients and 0% improvement in ATLs. Finally, there were no statistically significant differences between surgical approaches with regard to seizure freedom outcome, although there was a trend towards better seizure relief outcome among the ATL patients. Results support a possible benefit of SLAH in preserving visual confrontation naming after left TLE surgery. While result interpretation is limited by the small sample size, findings suggest outcome is likely to differ by surgical approach, and that further research on cognitive and seizure freedom outcomes is needed to inform patients and providers of potential risks and benefits with each.

Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges.

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Selective Posterior Cerebral Artery Wada Better Predicts Good Memory and Naming Outcomes Following Selective Stereotactic Thermal Ablation for Medial Temporal Lobe Epilepsy Than Internal Carotid Artery Wada.

The conventional intracarotid amobarbital (Wada) test has been used to assess memory function in patients being considered for temporal lobe epilepsy (TLE) surgery. Minimally invasive approaches that target the medial temporal lobe (MTL) and spare neocortex are increasingly used, but a knowledge gap remains in how to assess memory and language risk from these procedures. We retrospectively compared results of two versions of the Wada test, the intracarotid artery (ICA-Wada) and posterior cerebral artery (PCA-Wada) approaches, with respect to predicting subsequent memory and language outcomes, particularly after stereotactic laser amygdalohippocampotomy (SLAH). We included all patients being considered for SLAH who underwent both ICA-Wada and PCA-Wada at a single institution. Memory and confrontation naming assessments were conducted using standardized neuropsychological tests to assess pre- to post-surgical changes in cognitive performance. Of 13 patients who initially failed the ICA-Wada, only one patient subsequently failed the PCA-Wada (p=0.003, two-sided binomial test with p 0 =0.5) demonstrating that these tests assess different brain regions or networks. PCA-Wada had a high negative predictive value for the safety of SLAH, compared to ICA-Wada, as none of the patients who underwent SLAH after passing the PCA-Wada experienced catastrophic memory decline (0 of 9 subjects, p <.004, two-sided binomial test with p 0 =0.5), and all experienced a good cognitive outcome. In contrast, the single patient who received a left anterior temporal lobectomy after failed ICA- and passed PCA-Wada experienced a persistent, near catastrophic memory decline. On confrontation naming, few patients exhibited disturbance during the PCA-Wada. Following surgery, SLAH patients showed no naming decline, while open resection patients, whose surgeries all included ipsilateral temporal lobe neocortex, experienced significant naming difficulties (Fisher's exact test, p <.05). These findings demonstrate that (1) failing the ICA-Wada falsely predicts memory decline following SLAH, (2) PCA-Wada better predicts good memory outcomes of SLAH for MTLE, and (3) the MTL brain structures affected by both PCA-Wada and SLAH are not directly involved in language processing.

Do some prefer to pay? Identifying bias against free COVID-19 tests.

Objectives: In the United States, a federal emergency program has made SARS-CoV-2 self-test kits available at no cost. It is unclear how widely free tests are preferred. We conducted a survey to estimate the proportion of respondents who do not prefer a free test. We hypothesized that free tests would not be preferred universally, and that a preference for paying would be more common among those with conservative politics than with liberal politics, regardless of income. Design: Observational study design. Methods: A national sample of US adults completed an online survey. To reduce potential enrollment bias, the survey's focus was not specified beforehand. To prioritize a high-risk group, participation was limited to those who were unvaccinated or were incompletely vaccinated in the primary series against COVID-19. Participants reported their testing preferences and socio-demographic characteristics, including political affiliation. The main outcome assessed if a participant preferred to pay for a self-test or receive a free one (subsidized by the US government). Results: Among 1215 participants, (73%, n = 886) preferred free self-testing, while 27% (n = 329) preferred to pay for the same testing. After adjusting for income, the odds of preferring to pay for self-testing were 66% higher in "strong" Republicans compared to "strong" Democrats (odds ratio = 1.66, 95% confidence interval = 1.07-2.62). Conclusions: More than a quarter of individuals preferred paying for these tests. This preference was more likely among those with right-wing politics. Policy implications are discussed, along with future research directions.

Adolescent Preferences for a Pediatric Primary Care-based Sexually Transmitted Infection and HIV Prevention Intervention.

PURPOSE: We sought to elicit perspectives on HIV and sexually transmitted infection (STI) prevention among adolescents with recent STIs in primary care to optimize acceptability and effectiveness in designing a novel HIV/STI prevention intervention. METHODS: We enrolled 13-19 year-olds with recent gonorrhea, chlamydia, trichomonas, and/or syphilis in a multimethods cross-sectional study at two primary care clinics. Participants completed surveys and interviews. We used an integrated analytic approach deductively coding data using the Integrated Behavioral Model, then inductively coding to identify themes not represented in the Integrated Behavioral Model. RESULTS: Participants (n = 35) were 85% cisgender female, 14% cisgender male, 1% transgender female; 25% identified as lesbian, bisexual, or queer. Most (97%) identified as non-Latinx Black. None used condoms consistently, 26% were aware of pre-exposure prophylaxis (PrEP), and 31% were never HIV tested. Five key themes emerged. 1) Mental health was central to HIV prevention behavior uptake and coping with STI diagnosis. 2) Youth desired prevention counseling that allowed decisional autonomy and individualized goal setting. 3) Negative social norms around condoms and absent norms around HIV testing and PrEP limited method uptake. 4) Both confidence and concrete skills were needed to initiate prevention methods. 5) Youth desired education at the time of STI diagnosis to improve subsequent prevention decision making. DISCUSSION: Key intervention design considerations included 1) integrating mental health assessment and referral to services, 2) promoting individualized goal setting, 4) building communication skills, 4) providing navigation and material support for PrEP uptake and HIV testing, and 5) augmenting comprehensive STI and HIV prevention education.

Salient beliefs related to secondary distribution of COVID-19 self-test kits within social networks.

Background: Widespread access to testing is critical to public health efforts to control the COVID-19 pandemic. Secondary distribution of COVID-19 self-test kits, where an individual distributes test kits to others in their social networks, is a potential strategy to improve access to testing. In this qualitative study, we identified salient beliefs about distributing and accepting COVID-19 self-test kits within one's social network, as well as ordering COVID-19 self-test kits from the government. Methods: We recruited 61 participants from a randomized controlled trial (NCT04797858) in Philadelphia, Pennsylvania to elicit beliefs about (1) distributing COVID-19 self-test kits within one's social network, (2) receiving test kits from social contacts, and (3) ordering self-test kits from the government. Using validated, open-ended question stems, we identified the most common set of beliefs underlying attitudes, perceived norms (or social referents), and perceived behavioral control (or self-efficacy) toward each of these behaviors. Results: Twenty-seven out of 30 (90%) of participants who received self-test kits reported distributing the kits to social contacts. These participants described altruistic beliefs about giving others access to testing, and felt approval from family members, friends, and others in their social networks. When receiving test kits from social network contacts, participants described advantages of test kit convenience, but some voiced concern about test kit tampering and confusing instructions. Participants also described perceived logistic barriers to distributing and receiving self-test kits, such as delivering or transporting test kits, or finding time to meet. Participants who ordered test kits from the government also described increased convenience of test access, but described different logistic barriers such as delays in test kit delivery, or not receiving test kits at all. Conclusion: In comparison with government-ordered test kits, the secondary distribution of COVID-19 self-test kits raised unique concerns about test kit quality and instructions, as well as distinctive logistic barriers related to distributing self-test kits to network contacts, which were not raised for test kits ordered from the government. This study demonstrates that beliefs may vary depending on the type of testing behavior, and behavioral interventions may benefit from developing messages tailored to specific testing strategies.

Food Insecurity and Undernutrition Are Associated With Distinct Immunologic Profiles in People With Tuberculosis and Advanced HIV Starting Antiretroviral Therapy.

BACKGROUND: Food insecurity and undernutrition are related but distinct concepts contributing to poor HIV and tuberculosis outcomes. Pathways linking them with immunologic profile, which may relate to clinical outcomes, remain understudied. METHODS: We analyzed data from a cohort study of 165 antiretroviral therapy (ART)-naïve adults with advanced HIV and newly diagnosed tuberculosis in Botswana from 2009 to 2013. Twenty-nine plasma biomarkers were measured pre-ART and 4 weeks post-ART initiation. We used principal components analysis (PCA) and multivariable linear regression models to assess relationships between immunological profiles and food insecurity (based on the Household Food Insecurity Access Scale), undernutrition (body mass index <18.5 kg/m 2 ), and clinical outcomes. RESULTS: PCA identified 5 principal components with eigenvalues >1. After adjustment, food insecurity was associated with PC3 pre-ART (0.19 per increased category of severity, 95% CI: 0.02 to 0.36) and post-ART (0.24, 95% CI: 0.07 to 0.41). PC3 was driven by higher levels of IFN-α, IFN-γ, interleukin (IL)-12p40, vascular endothelial growth factor, IL-1α, and IL-8 and decreased concentrations of IL-3. Undernutrition was associated with PC5 post-ART (0.49, 95% CI: 0.16 to 0.82). PC5 was driven by higher levels of IL-8, MIP-1α, IL-6, and IL-10 and decreased concentrations in IP-10 and IFN-α. Post-ART PC3 (4.3 percentage point increased risk per increased score of 1, 95% CI: 0.3 to 8.9) and post-ART PC5 (4.8, 95% CI: 0.6 to 8.9) were associated with death in adjusted models. DISCUSSION: We identified 2 distinct immunologic profiles associated with food insecurity, undernutrition, and clinical outcomes in patients with advanced HIV and tuberculosis. Different pathophysiologic processes may link food insecurity and undernutrition with poor outcomes in this vulnerable patient population. Future studies should assess the impact of improving food access and intake on immune function and clinical outcomes.

Seizure event detection using intravital two-photon calcium imaging data.

Significance: Intravital cellular calcium imaging has emerged as a powerful tool to investigate how different types of neurons interact at the microcircuit level to produce seizure activity, with newfound potential to understand epilepsy. Although many methods exist to measure seizure-related activity in traditional electrophysiology, few yet exist for calcium imaging. Aim: To demonstrate an automated algorithmic framework to detect seizure-related events using calcium imaging-including the detection of pre-ictal spike events, propagation of the seizure wavefront, and terminal spreading waves for both population-level activity and that of individual cells. Approach: We developed an algorithm for precise recruitment detection of population and individual cells during seizure-associated events, which broadly leverages averaged population activity and high-magnitude slope features to detect single-cell pre-ictal spike and seizure recruitment. We applied this method to data recorded using awake in vivo two-photon calcium imaging during pentylenetetrazol-induced seizures in mice. Results: We demonstrate that our detected recruitment times are concordant with visually identified labels provided by an expert reviewer and are sufficiently accurate to model the spatiotemporal progression of seizure-associated traveling waves. Conclusions: Our algorithm enables accurate cell recruitment detection and will serve as a useful tool for researchers investigating seizure dynamics using calcium imaging.

Impact of white matter networks on risk for memory decline following resection versus ablation in temporal lobe epilepsy.

BACKGROUND: With expanding neurosurgical options in epilepsy, it is important to characterise each options' risk for postoperative cognitive decline. Here, we characterise how patients' preoperative white matter (WM) networks relates to postoperative memory changes following different epilepsy surgeries. METHODS: Eighty-nine patients with temporal lobe epilepsy with T1-weighted and diffusion-weighted imaging as well as preoperative and postoperative verbal memory scores (prose recall) underwent either anterior temporal lobectomy (ATL: n=38) or stereotactic laser amygdalohippocampotomy (SLAH; n=51). We computed laterality indices (ie, asymmetry) for volume of the hippocampus and fractional anisotropy (FA) of two deep WM tracts (uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF)). RESULTS: Preoperatively, left-lateralised FA of the ILF was associated with higher prose recall (p<0.01). This pattern was not observed for the UF or hippocampus (ps>0.05). Postoperatively, right-lateralised FA of the UF was associated with less decline following left ATL (p<0.05) but not left SLAH (p>0.05), while right-lateralised hippocampal asymmetry was associated with less decline following both left ATL and SLAH (ps<0.05). After accounting for preoperative memory score, age of onset and hippocampal asymmetry, the association between UF and memory decline in left ATL remained significant (p<0.01). CONCLUSIONS: Asymmetry of the hippocampus is an important predictor of risk for memory decline following both surgeries. However, asymmetry of UF integrity, which is only severed during ATL, is an important predictor of memory decline after ATL only. As surgical procedures and pre-surgical mapping evolve, understanding the role of frontal-temporal WM in memory networks could help to guide more targeted surgical approaches to mitigate cognitive decline.