Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis.

Friedreich's ataxia (FRDA) is a devastating, multisystemic disorder caused by recessive mutations in the mitochondrial protein frataxin (FXN). FXN participates in the biosynthesis of Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O2, FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in vitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis. In a mouse model of FRDA, breathing 11% O2 attenuates the progression of ataxia, whereas breathing 55% O2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.

Attenuating midline thalamus bursting to mitigate absence epilepsy.

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

Computational models of compound nerve action potentials: Efficient filter-based methods to quantify effects of tissue conductivities, conduction distance, and nerve fiber parameters.

BACKGROUND: Peripheral nerve recordings can enhance the efficacy of neurostimulation therapies by providing a feedback signal to adjust stimulation settings for greater efficacy or reduced side effects. Computational models can accelerate the development of interfaces with high signal-to-noise ratio and selective recording. However, validation and tuning of model outputs against in vivo recordings remains computationally prohibitive due to the large number of fibers in a nerve. METHODS: We designed and implemented highly efficient modeling methods for simulating electrically evoked compound nerve action potential (CNAP) signals. The method simulated a subset of fiber diameters present in the nerve using NEURON, interpolated action potential templates across fiber diameters, and filtered the templates with a weighting function derived from fiber-specific conduction velocity and electromagnetic reciprocity outputs of a volume conductor model. We applied the methods to simulate CNAPs from rat cervical vagus nerve. RESULTS: Brute force simulation of a rat vagal CNAP with all 1,759 myelinated and 13,283 unmyelinated fibers in NEURON required 286 and 15,860 CPU hours, respectively, while filtering interpolated templates required 30 and 38 seconds on a desktop computer while maintaining accuracy. Modeled CNAP amplitude could vary by over two orders of magnitude depending on tissue conductivities and cuff opening within experimentally relevant ranges. Conduction distance and fiber diameter distribution also strongly influenced the modeled CNAP amplitude, shape, and latency. Modeled and in vivo signals had comparable shape, amplitude, and latency for myelinated fibers but not for unmyelinated fibers. CONCLUSIONS: Highly efficient methods of modeling neural recordings quantified the large impact that tissue properties, conduction distance, and nerve fiber parameters have on CNAPs. These methods expand the computational accessibility of neural recording models, enable efficient model tuning for validation, and facilitate the design of novel recording interfaces for neurostimulation feedback and understanding physiological systems.

At home adaptive dual target deep brain stimulation in Parkinson's disease with proportional control.

Continuous deep brain stimulation (cDBS) of the subthalamic nucleus (STN) or globus pallidus is an effective treatment for the motor symptoms of Parkinson's disease. The relative benefit of one region over the other is of great interest but cannot usually be compared in the same patient. Simultaneous DBS of both regions may synergistically increase the therapeutic benefit. Continuous DBS is limited by a lack of responsiveness to dynamic, fluctuating symptoms intrinsic to the disease. Adaptive DBS (aDBS) adjusts stimulation in response to biomarkers to improve efficacy, side effects, and efficiency. We combined bilateral DBS of both STN and globus pallidus (dual target DBS) in a prospective within-participant, clinical trial in six patients with Parkinson's disease (n = 6, 55-65 years, n = 2 females). Dual target cDBS was tested for Parkinson's disease symptom control annually over 2 years, measured by motor rating scales, on time without dyskinesia, and medication reduction. Random amplitude experiments probed system dynamics to estimate parameters for aDBS. We then implemented proportional-plus-integral aDBS using a novel distributed (off-implant) architecture. In the home setting, we collected tremor and dyskinesia scores as well as individualized ß and DBS amplitudes. Dual target cDBS reduced motor symptoms as measured by Unified Parkinson's Disease Rating Scale (UPDRS) to a greater degree than either region alone (P < 0.05, linear mixed model) in the cohort. The amplitude of ß-oscillations in the STN correlated to the speed of hand grasp movements for five of six participants (P < 0.05, Pearson correlation). Random amplitude experiments provided insight into temporal windowing to avoid stimulation artefacts and demonstrated a correlation between STN ß amplitude and DBS amplitude. Proportional plus integral control of aDBS reduced average power, while preserving UPDRS III scores in the clinic (P = 0.28, Wilcoxon signed rank), and tremor and dyskinesia scores during blinded testing at home (n = 3, P > 0.05, Wilcoxon ranked sum). In the home setting, DBS power reductions were slight but significant. Dual target cDBS may offer an improvement in treatment of motor symptoms of Parkinson's disease over DBS of either the STN or globus pallidus alone. When combined with proportional plus integral aDBS, stimulation power may be reduced, while preserving the increased benefit of dual target DBS.

The Therapeutic Frequency Profile of Subthalamic Nucleus Deep Brain Stimulation in Rats Is Shaped by Antidromic Spike Failure.

The therapeutic mechanisms of subthalamic nucleus (STN) deep brain stimulation (DBS) may depend on antidromic activation of cortex via the hyperdirect pathway. However, hyperdirect pathway neurons cannot reliably follow high-stimulation frequencies, and the spike failure rate appears to correlate with symptom relief as a function of stimulation frequency. We hypothesized that antidromic spike failure contributes to the cortical desynchronization caused by DBS. We measured in vivo evoked cortical activity in female Sprague Dawley rats and developed a computational model of cortical activation from STN DBS. We modeled stochastic antidromic spike failure to determine how spike failure affected the desynchronization of pathophysiological oscillatory activity in cortex. We found that high-frequency STN DBS desynchronized pathologic oscillations via the masking of intrinsic spiking through a combination of spike collision, refractoriness, and synaptic depletion. Antidromic spike failure shaped the parabolic relationship between DBS frequency and cortical desynchronization, with maximum desynchronization at ∼130 Hz. These findings reveal that antidromic spike failure plays a critical role in mediating the dependency of symptom relief on stimulation frequency.SIGNIFICANCE STATEMENT Deep brain stimulation (DBS) is a highly effective neuromodulation therapy, yet it remains uncertain why conventionally used stimulation frequencies (e.g., ∼130 Hz) are optimal. In this study, we demonstrate a potential explanation for the stimulation frequency dependency of DBS through a combination of in vivo experimental measurements and computational modeling. We show that high-frequency stimulation can desynchronize pathologic firing patterns in populations of neurons by inducing an informational lesion. However, sporadic spike failure at these high frequencies limits the efficacy of the informational lesion, yielding a parabolic profile with optimal effects at ∼130 Hz. This work provides a potential explanation for the therapeutic mechanism of DBS, and highlights the importance of considering spike failure in mechanistic models of DBS.

Multi-parametric analysis of 57 SYNGAP1 variants reveal impacts on GTPase signaling, localization, and protein stability.

SYNGAP1 is a neuronal Ras and Rap GTPase-activating protein with important roles in regulating excitatory synaptic plasticity. While many SYNGAP1 missense and nonsense mutations have been associated with intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder (ASD), whether and how they contribute to individual disease phenotypes is often unknown. Here, we characterize 57 variants in seven assays that examine multiple aspects of SYNGAP1 function. Specifically, we used multiplex phospho-flow cytometry to measure variant impact on protein stability, pERK, pGSK3ß, pp38, pCREB, and high-content imaging to examine subcellular localization. We find variants ranging from complete loss-of-function (LoF) to wild-type (WT)-like in their regulation of pERK and pGSK3ß, while all variants retain at least partial ability to dephosphorylate pCREB. Interestingly, our assays reveal that a larger proportion of variants located within the disordered domain of unknown function (DUF) comprising the C-terminal half of SYNGAP1 exhibited higher LoF, compared to variants within the better studied catalytic domain. Moreover, we find protein instability to be a major contributor to dysfunction for only two missense variants, both located within the catalytic domain. Using high-content imaging, we find variants located within the C2 domain known to mediate membrane lipid interactions exhibit significantly larger cytoplasmic speckles than WT SYNGAP1. Moreover, this subcellular phenotype shows both correlation with altered catalytic activity and unique deviation from signaling assay results, highlighting multiple independent molecular mechanisms underlying variant dysfunction. Our multidimensional dataset allows clustering of variants based on functional phenotypes and provides high-confidence, multi-functional measures for making pathogenicity predictions.

Diagnostic miRNA Signatures in Paired Tumor, Plasma, and Urine Specimens From Renal Cell Carcinoma Patients.

BACKGROUND: The incidence of patients diagnosed with renal cell carcinoma (RCC) is increasing. There are no approved biofluid biomarkers for routine diagnosis of RCC patients. This retrospective study aims to identify cell-free microRNA (cfmiR) signatures in urine samples that can be utilized as biomarkers for early diagnosis of sporadic RCC patients. METHODS: Tissue, plasma, and urine samples (n = 221) from 56 sporadic RCC patients and respective normal healthy donors were profiled for 2083 microRNAs (miRs) using the next-generation sequencing-based HTG EdgeSeq miR Whole Transcriptome Assay. DESeq2 (FC |1.2|, false discovery rate <0.05) was performed to identify differentially expressed miRs. Data from RCC tissue samples of The Cancer Genome Atlas database were used for miR validation. RESULTS: We found a 10-miR signature that distinguished RCC tissues from remote normal kidney tissue or benign kidney lesion samples. Additionally, we identified subtype-specific miRs (miR-122-5p, miR-210-3p, and miR-21-3p) and miRs specific for all RCC subtypes (miR-106b-3p, miR-629-5p, and miR-885-5p). We observed that miR-155-5p was associated with tumor size. Using The Cancer Genome Atlas data sets, we validated the miRs found in RCC tissue samples. In plasma or urine analysis, we found cfmiRs that were consistently and significantly upregulated in RCC tissue samples. A 15-cfmiR signature was proposed in urine samples of RCC patients, of which miR-1275 was consistently upregulated in tissue, plasma, and urine samples. CONCLUSIONS: This integrative study found diagnostic miRs/cfmiRs for RCC patients, which were validated using The Cancer Genome Atlas data sets. Distinctive cfmiR signatures found in urine may have clinical utility for the diagnosis of RCC.

The provision of general surgery in rural Australia: a narrative review.

Rural surgery is most commonly provided by general surgeons to the 29% of people (7 million) living in rural Australia. The provision of rural general surgery to enable equitable and safe surgical care for rural Australians is a multifaceted issue concerning recruitment, training, retention, surgical procedures and surgical outcomes. Sustaining the rural general surgical workforce will be dependent upon growing an increased number of resident rural general surgeons, as well as changed models of care, with a need for ongoing review to track the outcomes of these changes. To increase recruitment, rural general surgical training must improve to be less stressful for trainees and to be incorporated alongside a rural-facing generalist curriculum. Rural general surgical outcomes (excluding some oncology conditions) achieve comparable results to metropolitan centres. Access to, and outcomes of, surgical oncology services continues to be inequitable for rural Australians and should be a major focus for improved service delivery.

Effect of twice daily inhaled albuterol on cardiopulmonary exercise outcomes, dynamic hyperinflation, and symptoms in secondhand tobacco-exposed persons with preserved spirometry and air trapping: a randomized controlled trial.

BACKGROUND: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping. METHODS: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed. RESULTS: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity. CONCLUSIONS: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.

Response to "Letter to the Editor-Exploring the Unknown: Evaluating ChatGPT's Performance in Uncovering Novel Aspects of Plastic Surgery and Identifying Areas for Future Innovation".

We appreciate Dr. Qi and Dr. Niu for their insightful comments on our study, "Exploring the Unknown: Evaluating ChatGPT's Performance in Uncovering Novel Aspects of Plastic Surgery and Identifying Areas for Future Innovation." Their observations underscore significant considerations in the application of artificial intelligence (AI) in plastic surgery. We agree with their concern about potential biases in ChatGPT's responses. The AI's frequent attribution of the title "parent of plastic surgery" to Sir Harold Delf Gillies, despite gender-neutral terminology, highlights underlying biases from training data. These biases often reflect historical texts and contemporary writings. Addressing them requires refining training datasets for balanced representation and developing algorithms that adjust dynamically to diverse inputs. The authors also question the criteria ChatGPT uses to identify key contributions to plastic surgery. The AI's focus on microsurgery, minimally invasive techniques, and tissue engineering, while significant, may prioritize keyword prevalence over a holistic evaluation. Enhancing ChatGPT's capabilities through targeted training and input from subject matter experts could improve the AI's ability to generate more balanced outputs. The identified bias favoring reconstructive over cosmetic procedures is another critical point. While reconstructive advancements are transformative, cosmetic surgery also has significant innovations. Ensuring ChatGPT presents a balanced view of both reconstructive and cosmetic advancements is essential. This can be achieved by diversifying training data and calibrating the AI to give equitable weight to different subspecialties within plastic surgery. AI models like ChatGPT are proficient in processing and generating information but lack the human elements of creativity, intuition, and emotional depth critical for groundbreaking innovations. AI should complement, not replace, the expert judgment and innovative thinking of skilled plastic surgeons. Ensuring the accuracy of AI-generated responses is crucial. Clinicians must verify AIgenerated information against established medical literature and clinical guidelines to maintain accuracy in medical practice. Continuous feedback and improvement mechanisms are vital to enhance AI's clinical utility. The improvement of AI in plastic surgery will be driven by active involvement from surgeons, providing comprehensive and balanced data for training to ensure AI systems evolve to support and enhance clinical practice effectively.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors  www.springer.com/00266 .

Exploring the Unknown: Evaluating ChatGPT's Performance in Uncovering Novel Aspects of Plastic Surgery and Identifying Areas for Future Innovation.

BACKGROUND: Artificial intelligence (AI) has emerged as a powerful tool in various medical fields, including plastic surgery. This study aims to evaluate the performance of ChatGPT, an AI language model, in elucidating historical aspects of plastic surgery and identifying potential avenues for innovation. METHODS: A comprehensive analysis of ChatGPT's responses to a diverse range of plastic surgery-related inquiries was performed. The quality of the AI-generated responses was assessed based on their relevance, accuracy, and novelty. Additionally, the study examined the AI's ability to recognize gaps in existing knowledge and propose innovative solutions. ChatGPT's responses were analysed by specialist plastic surgeons with extensive research experience, and quantitatively analysed with a Likert scale. RESULTS: ChatGPT demonstrated a high degree of proficiency in addressing a wide array of plastic surgery-related topics. The AI-generated responses were found to be relevant and accurate in most cases. However, it demonstrated convergent thinking and failed to generate genuinely novel ideas to revolutionize plastic surgery. Instead, it suggested currently popular trends that demonstrate great potential for further advancements. Some of the references presented were also erroneous as they cannot be validated against the existing literature. CONCLUSION: Although ChatGPT requires major improvements, this study highlights its potential as an effective tool for uncovering novel aspects of plastic surgery and identifying areas for future innovation. By leveraging the capabilities of AI language models, plastic surgeons may drive advancements in the field. Further studies are needed to cautiously explore the integration of AI-driven insights into clinical practice and to evaluate their impact on patient outcomes. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Thermal Challenges in Dynamic Infrared Thermography Used for Perforator Mapping.

BACKGROUND: The aim of this study is to investigate the different approaches to thermal challenges, both cold and warm, used in dynamic infrared thermography for reconstructive surgery, and explore whether it affects the success of preoperative perforator mapping. METHODS: Literature was collected from Ovid Medline, Embase, PubMed, and Cochrane. The references of the full-text articles located from the original search were also appraised. Thirteen articles were extracted for the final qualitative analysis. A systematic review was then conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Thirteen articles looked at a cold challenge, which included airflow cooling, direct contact cooling, and evaporation-based cooling. Two articles investigated warm challenges. One paper used no challenge, suggesting it unnecessary with a highly sensitive camera. All cold challenges were positively supported by a high level of flap perfusion success and/or a high level of correlation with other forms of investigation. CONCLUSION: Cold challenges were overall superior to no challenge and warm challenges; however, this conclusion is limited by the small participant size, the possibility of detection bias, and poor methodology detailing. Airflow cooling-specifically, using a desktop fan to blow air for 2 minutes-was noted to likely cause the least discomfort due to a low cooling capacity yet simultaneously maintain effectiveness and allow for a uniform cooling application. Warm challenges showed less conclusive results and were restricted by lack of studies. This topic would benefit from larger scale studies that compare multiple approaches while using standardized equipment to eliminate confounding factors.

Anomalous anatomic variation of an absent deep inferior epigastric artery: implications for autologous breast reconstruction.

Autologous breast reconstruction using abdominally based perforator flaps has become increasingly popular following mastectomy for breast cancer. Of these, the deep inferior epigastric artery perforator (DIEP) flap represents one of the most popular techniques. However, surgeons must remain cognizant of anatomic variations in the abdominal wall vasculature that could complicate or preclude planned DIEP flaps. In this case, a 64-year-old female with a history of prior tubal ligations and caesarean sections underwent preoperative computed tomographic angiography (CTA) for planned autologous breast reconstruction with a DIEP flap. CTA revealed complete absence of the left deep inferior epigastric artery, with a sizeable left abdominal wall perforator visualized receiving retrograde flow from a crossing midline branch originating from the contralateral right deep inferior epigastric system. This vessel traversed the midline in a superficial plane in the subcutaneous tissue. Despite this aberrant anatomy, the surgical team successfully raised a unilateral DIEP flap based on the right pedicle. This case represents a unique anatomical variation of the abdominal wall and emphasises the importance of preoperative imaging when planning abdominally based free flaps.

Relative contributions of different neural sources to the EEG.

Dogma dictates that the EEG signal is generated by postsynaptic currents (PSCs) because there are an enormous number of synapses in the brain, and PSCs have relatively long durations. However, PSCs are not the only potential source of electric fields in the brain. Action potentials, afterpolarizations, and presynaptic activity can also generate electric fields. Experimentally it is exceedingly difficult to delineate the contributions of different sources because they are casually linked. However, using computational modeling, we can interrogate the relative contributions of different neural elements to the EEG. We used a library of neuron models with morphologically realistic axonal arbors to quantify the relative contributions of PSCs, action potentials, and presynaptic activity to the EEG signal. Consistent with prior assertions, PSCs were the largest contributor to the EEG, but action potentials and afterpolarizations can also make appreciable contributions. For a population of neurons generating simultaneous PSCs and action potentials, we found that the action potentials accounted for up to 20% of the source strength while PSCs accounted for the other 80% and presynaptic activity negligibly contributed. Additionally, L5 PCs generated the largest PSC and action potential signals indicating that they the dominant EEG signal generator. Further, action potentials and afterpolarizations were sufficient to generate physiological oscillations, indicating that they are valid source contributors to the EEG. The EEG emerges from a combination of multiple different source, and, while PSCs are the largest contributor, other sources are non-negligible and should be included in modeling, analysis and interpretation of the EEG.

Rapid estimation of cortical neuron activation thresholds by transcranial magnetic stimulation using convolutional neural networks.

BACKGROUND: Transcranial magnetic stimulation (TMS) can modulate neural activity by evoking action potentials in cortical neurons. TMS neural activation can be predicted by coupling subject-specific head models of the TMS-induced electric field (E-field) to populations of biophysically realistic neuron models; however, the significant computational cost associated with these models limits their utility and eventual translation to clinically relevant applications. OBJECTIVE: To develop computationally efficient estimators of the activation thresholds of multi-compartmental cortical neuron models in response to TMS-induced E-field distributions. METHODS: Multi-scale models combining anatomically accurate finite element method (FEM) simulations of the TMS E-field with layer-specific representations of cortical neurons were used to generate a large dataset of activation thresholds. 3D convolutional neural networks (CNNs) were trained on these data to predict thresholds of model neurons given their local E-field distribution. The CNN estimator was compared to an approach using the uniform E-field approximation to estimate thresholds in the non-uniform TMS-induced E-field. RESULTS: The 3D CNNs estimated thresholds with mean absolute percent error (MAPE) on the test dataset below 2.5% and strong correlation between the CNN predicted and actual thresholds for all cell types (R2 > 0.96). The CNNs estimated thresholds with a 2-4 orders of magnitude reduction in the computational cost of the multi-compartmental neuron models. The CNNs were also trained to predict the median threshold of populations of neurons, speeding up computation further. CONCLUSION: 3D CNNs can estimate rapidly and accurately the TMS activation thresholds of biophysically realistic neuron models using sparse samples of the local E-field, enabling simulating responses of large neuron populations or parameter space exploration on a personal computer.

Pathways and parameters of sacral neuromodulation in rats.

The stimulation paradigm for sacral neuromodulation has remained largely unchanged since its inception. We sought to determine, in rats, whether stimulation-induced increases in bladder capacity correlated with the proportion of sensory pudendal (PudS) neurons at each stimulated location (L6, S1). If supported, this finding could guide the choice of stimulation side (left/right) and level (S2, S3, S4) in humans. Unexpectedly, we observed that acute stimulation at clinically relevant (low) amplitudes [1-1.5 × motor threshold (Tm)], did not increase bladder capacity, regardless of stimulus location (L6 or S1). More importantly for the ability to test our hypothesis, there was little anatomic variation, and S1 infrequently contributed nerve fibers to the PudS nerve. During mapping studies we noticed that large increases in PudS nerve activation occurred at amplitudes exceeding 2Tm. Thus, additional cystometric studies were conducted, this time with stimulation of the L6-S1 trunk, to examine further the relationship between stimulation amplitude and cystometric parameters. Stimulation at 1Tm to 6Tm evoked increases in bladder capacity and decreases in voiding efficiency that mirrored those produced by PudS nerve stimulation. Many animal studies involving electrical stimulation of nerves of the lower urinary tract use stimulation amplitudes that exceed those used clinically (∼1Tm). Our results confirm that high amplitudes generate immediate changes in cystometric parameters; however, the relationship to low-amplitude chronic stimulation in humans remains unclear. Additional studies are needed to understand changes that occur with chronic stimulation, how these changes relate to therapeutic outcomes, and the contribution of specific nerve fibers to these changes.NEW & NOTEWORTHY Acute low-amplitude electrical stimulation of sacral nerve (sacral neuromodulation) did not increase bladder capacity in anesthetized CD, obese-prone, or obese-resistant rats. Increasing stimulation amplitude correlated with increases in bladder capacity and pudendal sensory nerve recruitment. It is unclear how the high-amplitude acute stimulation that is commonly used in animal experiments to generate immediate effects compares mechanistically to the chronic low-amplitude stimulation used clinically.

Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from nonnociceptive Aß-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that links nonnociceptive Aß-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons. The excitatory pathway and the NS projection neuron were in turn gated by inhibitory interneurons with connections based on prior patch-clamp recordings. Changing synaptic weights in the computational model to replicate neuropathic pain states unmasked a low-threshold excitatory pathway to NS neurons similar to experimental recordings. Spinal cord stimulation (SCS) is an effective therapy for neuropathic pain, and accumulating experimental evidence indicates that NS neurons in the SDH also respond to SCS. Accounting for these responses may inform therapeutic improvements, and we quantified responses to SCS in the SDH network model and examined the role of different modes of inhibitory control in modulating NS neuron responses to SCS. We combined the SDH network model with a previously published model of the deep dorsal horn (DDH) and identified optimal stimulation frequencies across different neuropathic pain conditions. Finally, we found that SCS-generated inhibition did not completely suppress model NS activity during simulated pinch inputs, providing an explanation of why SCS does not eliminate acute pain.NEW & NOTEWORTHY Chronic pain is a severe public health problem that reduces the quality of life for those affected and exacts an enormous socio-economic burden worldwide. Spinal cord stimulation (SCS) is an effective treatment for chronic pain, but SCS efficacy has not significantly improved over time, in part because the mechanisms of action remain unclear. Most preclinical studies investigating pain and SCS mechanisms have focused on the responses of deep dorsal horn (DDH) neurons, but neural networks in the superficial dorsal horn (SDH) are also important for processing nociceptive information. This work synthesizes heterogeneous experimental recordings from the SDH into a computational model that replicates experimental responses and that can be used to quantify neuronal responses to SCS under neuropathic pain conditions.

The effect of weight loss on recurrence of atrial fibrillation after catheter ablation: A systematic review and meta-analysis.

BACKGROUND: Obesity is associated with an increased risk of developing recurrent atrial fibrillation (AF) after catheter ablation (CA). However, the current data on weight loss interventions show inconsistent results in preventing the recurrence of AF after CA. METHODS: We conducted a systematic search in MEDLINE and EMBASE to identify studies that reported the outcome of recurrence of AF after CA in obese patients undergoing weight interventions. The subgroup analysis included: (1) Weight loss versus no weight loss, (2) >10% weight loss versus <10% weight loss, (3) <10% weight loss versus no weight loss, (4) Follow-up <12 months, and (5) Follow-up >12 months after CA. Mantel-Haenszel risk ratios with a 95% confidence interval (CI) were calculated using a random effects model and for heterogeneity, I2 statistics were reported. RESULTS: A total of 10 studies (one randomized controlled trial and nine observational studies) comprising 1851 patients were included. The recurrence of AF was numerically reduced in the weight loss group (34.5%) versus no weight loss group (58.2%), but no statistically significant difference was observed (risk ratio [RR] = 0.76; 95% CI: 0.49-1.18, p = .22). However, there was a statistically significant reduction in recurrence of AF with weight loss versus no weight loss at follow-up >12 months after CA (RR = 0.47; 95% CI: 0.32-0.68, p < .0001). At follow-up >12 months after CA, both >10% weight loss versus <10% weight loss (RR = 0.49; 95% CI: 0.31-0.80, p = .004) and <10% weight loss versus no weight loss (RR = 0.39; 95% CI: 0.31-0.49, p < .00001) were associated with a statistically significant reduction in recurrent AF. CONCLUSION: In patients with AF undergoing CA, weight loss is associated with reducing recurrent AF at > 12 months after ablation and these benefits are consistently seen with both >10% and <10% weight loss. The benefits of weight loss in preventing recurrent AF after CA should be examined in larger studies with extended follow-up duration.

Development of nitric oxide generators to produce high-dose nitric oxide for inhalation therapy.

BACKGROUND: Several nitric oxide (NO) generating devices have been developed to deliver NO between 1 part per million (ppm) and 80 ppm. Although inhalation of high-dose NO may exert antimicrobial effects, the feasibility and safety of producing high-dose (more than 100 ppm) NO remains to be established. In the current study, we designed, developed, and tested three high-dose NO generating devices. METHODS: We constructed three NO generating devices: a double spark plug NO generator, a high-pressure single spark plug NO generator, and a gliding arc NO generator. The NO and NO2 concentrations were measured at different gas flows and under various atmospheric pressures. The double spark plug NO generator was designed to deliver gas through an oxygenator and mixing with pure oxygen. The high-pressure and gliding arc NO generators were used to deliver gas through a ventilator into artificial lungs to mimic delivering high-dose NO in the clinical settings. The energy consumption was measured and compared among the three NO generators. RESULTS: The double spark plug NO generator produced 200 ± 2 ppm (mean ± SD) of NO at gas flow of 8 L/min (or 320 ± 3 ppm at gas flow of 5 L/min) with electrode gap of 3 mm. The nitrogen dioxide (NO2) levels were below 3.0 ± 0.1 ppm when mixing with various volumes of pure oxygen. The addition of a second generator increased the delivered NO from 80 (with one spark plug) to 200 ppm. With the high-pressure chamber, the NO concentration reached 407 ± 3 ppm with continuous air flow at 5 L/min when employing the 3 mm electrode gap under 2.0 atmospheric pressure (ATA). When compared to 1 ATA, NO production was increased 22% at 1.5 ATA and 34% at 2 ATA. The NO level was 180 ± 1 ppm when connecting the device to a ventilator with a constant inspiratory airflow of 15 L/min, and NO2 levels were below 1 (0.93 ± 0.02) ppm. The gliding arc NO generator produced up to 180 ± 4 ppm of NO when connecting the device to a ventilator, and the NO2 level was below 1 (0.91 ± 0.02) ppm in all testing conditions. The gliding arc device required more power (in watts) to generate the same concentrations of NO when compared to double spark plug or high-pressure NO generators. CONCLUSIONS: Our results demonstrated that it is feasible to enhance NO production (more than 100 ppm) while maintaining NO2 level relatively low (less than 3 ppm) with the three recently developed NO generating devices. Future studies might include these novel designs to deliver high doses of inhaled NO as an antimicrobial used to treat upper and lower respiratory tract infections.