Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer.

Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the mechanisms underlying the formation of these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are a rich source of enhancers displaying cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic MAPK/AP1 signaling drives the activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements regulate tumor-specific expression of multiple genes associated with tumorigenesis, such as ATG12 and XRCC4. Within the human population, individual LTR10 elements exhibit germline and somatic structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers contribute to transcriptional dysregulation in response to oncogenic signaling and shape the evolution of cancer-specific regulatory networks.

Best Practice Guidelines for the Management of Patients with Post-Stroke Spasticity: A Modified Scoping Review.

This article aims to provide a concise overview of the best available evidence for managing post-stroke spasticity. A modified scoping review, conducted following the PRISMA guidelines and the PRISMA Extension for Scoping Reviews (PRISMA-ScR), involved an intensive search on Medline and PubMed from 1 January 2000 to 31 August 2023. The focus was placed on high-quality (GRADE A) medical, rehabilitation, and surgical interventions. In total, 32 treatments for post-stroke spasticity were identified. Two independent reviewers rigorously assessed studies, extracting data, and evaluating bias using GRADE criteria. Only interventions with GRADE A evidence were considered. The data included the study type, number of trials, participant characteristics, interventions, parameters, controls, outcomes, and limitations. The results revealed eleven treatments supported by GRADE A evidence, comprising 14 studies. Thirteen were systematic reviews and meta-analyses, and one was randomized control trial. The GRADE A treatments included stretching exercises, static stretching with positional orthosis, transcutaneous electrical nerve stimulation, extracorporeal shock wave therapy, peripheral magnetic stimulation, non-invasive brain stimulation, botulinum toxin A injection, dry needling, intrathecal baclofen, whole body vibration, and localized muscle vibration. In conclusion, this modified scoping review highlights the multimodal treatments supported by GRADE A evidence as being effective for improving functional recovery and quality of life in post-stroke spasticity. Further research and exploration of new therapeutic options are encouraged.

Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients.

BACKGROUND AND AIMS: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. METHODS: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. RESULTS: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. INTERPRETATION: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

Regulation of human interferon signaling by transposon exonization.

Innate immune signaling is essential for clearing pathogens and damaged cells, and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues, and functions as a decoy receptor that potently inhibits interferon signaling including in cells infected with SARS-CoV-2. Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.

Continuous speech with pauses inserted between words increases cortical tracking of speech envelope.

The decoding multivariate Temporal Response Function (decoder) or speech envelope reconstruction approach is a well-known tool for assessing the cortical tracking of speech envelope. It is used to analyse the correlation between the speech stimulus and the neural response. It is known that auditory late responses are enhanced with longer gaps between stimuli, but it is not clear if this applies to the decoder, and whether the addition of gaps/pauses in continuous speech could be used to increase the envelope reconstruction accuracy. We investigated this in normal hearing participants who listened to continuous speech with no added pauses (natural speech), and then with short (250 ms) or long (500 ms) silent pauses inserted between each word. The total duration for continuous speech stimulus with no, short, and long pauses were approximately, 10 minutes, 16 minutes, and 21 minutes, respectively. EEG and speech envelope were simultaneously acquired and then filtered into delta (1-4 Hz) and theta (4-8 Hz) frequency bands. In addition to analysing responses to the whole speech envelope, speech envelope was also segmented to focus response analysis on onset and non-onset regions of speech separately. Our results show that continuous speech with additional pauses inserted between words significantly increases the speech envelope reconstruction correlations compared to using natural speech, in both the delta and theta frequency bands. It also appears that these increase in speech envelope reconstruction are dominated by the onset regions in the speech envelope. Introducing pauses in speech stimuli has potential clinical benefit for increasing auditory evoked response detectability, though with the disadvantage of speech sounding less natural. The strong effect of pauses and onsets on the decoder should be considered when comparing results from different speech corpora. Whether the increased cortical response, when longer pauses are introduced, reflect improved intelligibility requires further investigation.

Mouse B2 SINE elements function as IFN-inducible enhancers.

Regulatory networks underlying innate immunity continually face selective pressures to adapt to new and evolving pathogens. Transposable elements (TEs) can affect immune gene expression as a source of inducible regulatory elements, but the significance of these elements in facilitating evolutionary diversification of innate immunity remains largely unexplored. Here, we investigated the mouse epigenomic response to type II interferon (IFN) signaling and discovered that elements from a subfamily of B2 SINE (B2_Mm2) contain STAT1 binding sites and function as IFN-inducible enhancers. CRISPR deletion experiments in mouse cells demonstrated that a B2_Mm2 element has been co-opted as an enhancer driving IFN-inducible expression of Dicer1. The rodent-specific B2 SINE family is highly abundant in the mouse genome and elements have been previously characterized to exhibit promoter, insulator, and non-coding RNA activity. Our work establishes a new role for B2 elements as inducible enhancer elements that influence mouse immunity, and exemplifies how lineage-specific TEs can facilitate evolutionary turnover and divergence of innate immune regulatory networks.

Genetic Knockout of TE Insertions by CRISPR-Cas9.

Transposable elements (TEs) are abundant in the genome, and specific insertions may be co-opted to act as coding or noncoding functional elements. CRISPR-based genome editing technologies enable functional studies of TE insertions in cell lines. Here, we describe the use of CRISPR-Cas9 to create and validate genetic knockouts of TEs in mammalian cell lines.

Point-Counterpoint: Transfer function analysis of dynamic cerebral autoregulation: To band or not to band?

Transfer function analysis (TFA) is the most frequently adopted method for assessing dynamic cerebral autoregulation (CA) with continuously recorded arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Conventionally, values of autoregulatory metrics (e.g., gain and phase) derived from TFA are averaged within three frequency bands separated by cut-off frequencies at 0.07 Hz and 0.20 Hz, respectively, to represent the efficiency of dynamic CA. However, this is of increasing concerns, as there remains no solid evidence for choosing these specific cut-off frequencies, and the rigid adoption of these bands can stifle further developments in TFA of dynamic CA. In this 'Point-Counterpoint' mini-review, we provide evidence against the fixed banding, indicate possible alternatives, and call for awareness of the risk of the 'one-size-fits-all' banding becoming dogmatic. We conclude that we need to remain open to the multiple possibilities offered by TFA to realize its full potential in studies of human dynamic CA.

Transfer function analysis of dynamic cerebral autoregulation: A CARNet white paper 2022 update.

Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.

Detecting cortical responses to continuous running speech using EEG data from only one channel.

OBJECTIVE: To explore the detection of cortical responses to continuous speech using a single EEG channel. Particularly, to compare detection rates and times using a cross-correlation approach and parameters extracted from the temporal response function (TRF). DESIGN: EEG from 32-channels were recorded whilst presenting 25-min continuous English speech. Detection parameters were cross-correlation between speech and EEG (XCOR), peak value and power of the TRF filter (TRF-peak and TRF-power), and correlation between predicted TRF and true EEG (TRF-COR). A bootstrap analysis was used to determine response statistical significance. Different electrode configurations were compared: Using single channels Cz or Fz, or selecting channels with the highest correlation value. STUDY SAMPLE: Seventeen native English-speaking subjects with mild-to-moderate hearing loss. RESULTS: Significant cortical responses were detected from all subjects at Fz channel with XCOR and TRF-COR. Lower detection time was seen for XCOR (mean = 4.8 min) over TRF parameters (best TRF-COR, mean = 6.4 min), with significant time differences from XCOR to TRF-peak and TRF-power. Analysing multiple EEG channels and testing channels with the highest correlation between envelope and EEG reduced detection sensitivity compared to Fz alone. CONCLUSIONS: Cortical responses to continuous speech can be detected from a single channel with recording times that may be suitable for clinical application.

Comparison of Ultrasound and Electrical Stimulation Guidance for Onabotulinum Toxin-A Injections: A Randomized Crossover Study.

Background: Botulinum neurotoxin (BoNT) injection is an established therapy for limb spasticity and focal limb dystonia. Comparative benefits of injection guidance procedures have not been rigorously studied. Objectives: We compared 2 targeting techniques for onabotulinumtoxin-A (onabotA) injection for the treatment of focal hand dystonia and upper limb spasticity: electrophysiologic guidance using electrical stimulation (E-stim) and ultrasound (US). Methods: This was a 2-center, randomized, crossover, assessor-blinded trial. Participants with focal hand dystonia or upper limb spasticity, on stable onabotA therapy for at least 2 previous injection cycles, were randomly assigned to either E-stim or US with crossover at 3 months. The primary outcome was improvement in dystonia or spasticity severity on a visual analog scale (VAS; 0-100) measured 1 month after each injection. The secondary outcome was participant discomfort assessed on a VAS. Repeated-measures analysis of covariance was used with linear mixed-model covariate selection. Results: A total of 19 participants (13 men) completed the study, 10 with upper limb spasticity and 9 with dystonia. Benefit was equivalent between the 2 techniques (VAS least-square mean [LSmean] 51.5 mm with US and 53.1 with E-stim). E-stim was perceived as more uncomfortable by participants (VAS LSmean 34.5 vs. 19.9 for E-stim and US, respectively). Procedure duration was similar with the 2 procedures. There were no serious adverse events related to either approach. Conclusions: US and E-Stim localization guidance techniques provide equivalent efficacy in onabotA injections for spasticity and dystonia. US guidance injections are more comfortable for participants. Both techniques are effective guidance methods, with US potentially preferable based on participant comfort.

Point/counterpoint: We should not take the direction of blood pressure change into consideration for dynamic cerebral autoregulation quantification.

Over the past years, a wide range of studies have provided evidence of asymmetry in the response of static and dynamic cerebral autoregulation (CA) during increasing and decreasing pressure challenges. The main message is that CA is stronger during transient increases of arterial blood pressure rather than decreases. Here we do not argue against the presence of CA asymmetry but we seek to raise questions regarding the measurement of the effect and whether this effect needs to be taken into account, especially in clinical settings.

The role of the capsaicin 8% patch in the treatment of painful diabetic peripheral neuropathy.

Treatment of painful diabetic peripheral neuropathy (PDPN) is challenging and often limited by drug tolerability and adverse effects. This review article focuses on the high-dose (8%) capsaicin patch that allows for improved efficacy and reduced application frequency in comparison to low-dose capsaicin formulations. Systemic absorption is minimal resulting in fewer systemic side effects than first-line oral medications. There is evidence that capsaicin patch treatment is well-tolerated, safe and provides effective pain relief maintained for several weeks; well-powered studies are needed to confirm these findings. The capsaicin 8% patch may benefit patients at high risk for adverse effects from oral medication, polypharmacy or inadequate pain relief from first-line therapies.

Treatment of nerve pain in the feet and other regions due to nerve damage from diabetes is challenging, often due to the unwanted side effects of medications. This review article focuses on the high-dose (8%) capsaicin patch, which can be applied directly to the feet. It is more potent than the low-dose formulations, allowing patients to apply it less often while also working more effectively compared with low-dose capsaicin creams. Because it acts directly on the skin, there are fewer systemic side effects such as drowsiness or urinary retention. There is evidence that capsaicin patch treatment is safe and provides pain relief for several weeks. More large studies are needed to confirm these findings. The capsaicin 8% patch may benefit patients at high risk for side effects from oral medications or inadequate pain relief from first-line medications.

Autoimmune conditions in the World Trade Center general responder cohort: A nested case-control and standardized incidence ratio analysis.

BACKGROUND: The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions. OBJECTIVES: Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC. METHODS: Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases. RESULTS: Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's. CONCLUSIONS: The study found no statistically significant increased risk of autoimmune conditions with WTC exposures.

Auditory Brainstem Response Detection Using Machine Learning: A Comparison With Statistical Detection Methods.

OBJECTIVES: The primary objective of this study was to train and test machine learning algorithms to be able to detect accurately whether EEG data contains an auditory brainstem response (ABR) or not and recommend suitable machine learning methods. In addition, the performance of the best machine learning algorithm was compared with that of prominent statistical detection methods. DESIGN: Four machine learning algorithms were trained and evaluated using nested k-fold cross-validation: a random forest, a convolutional long short-term memory network, a stacked ensemble, and a multilayer perceptron. The best method was evaluated on a separate test set and compared with conventional detection methods: Fsp, Fmp, q-sample uniform scores test, and Hotelling's T2 test. The models were trained and tested on simulated data that were generated based on recorded ABRs collected from 12 normal-hearing participants and no-stimulus EEG data from 15 participants. Simulation allowed the ground truth of the data ("response present" or "response absent") to be known. RESULTS: The sensitivity of the best machine learning algorithm, a stacked ensemble, was significantly greater than that of the conventional detection methods evaluated. The stacked ensemble, evaluated using a bootstrap approach, consistently achieved a high and stable level of specificity across ensemble sizes. CONCLUSIONS: The stacked ensemble model presented was more effective than conventional statistical ABR detection methods and the alternative machine learning approaches tested. The stacked ensemble detection method may have potential both in automated ABR screening devices as well as in evoked potential software, assisting clinicians in making decisions regarding a patient's ABR threshold. Further assessment of the model's generalizability using a large cohort of subject recorded data, including participants of different ages and hearing status, is a recommended next step.

Small fiber neuropathy associated with SARS-CoV-2 infection.

INTRODUCTION/AIMS: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as "long-haul" syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection. METHODS: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS-CoV-2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy. RESULTS: We identified 13 patients, Eight women and five men with age ranging from 38-67 y. Follow-up duration ranged from 8 to 12 mo. All patients developed new-onset paresthesias within 2 mo following SARS-CoV-2 infection, with an acute onset in seven and co-existing autonomic symptoms in seven. Three patients had pre-existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID-19); the remainder experienced mild COVID-19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%). DISCUSSION: Our findings suggest that symptoms of SFN may develop during or shortly after COVID-19. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms.

The INfoMATAS project: Methods for assessing cerebral autoregulation in stroke.

Cerebral autoregulation refers to the physiological mechanism that aims to maintain blood flow to the brain approximately constant when blood pressure changes. Impairment of this protective mechanism has been linked to a number of serious clinical conditions, including carotid stenosis, head trauma, subarachnoid haemorrhage and stroke. While the concept and experimental evidence is well established, methods for the assessment of autoregulation in individual patients remains an open challenge, with no gold-standard having emerged. In the current review paper, we will outline some of the basic concepts of autoregulation, as a foundation for experimental protocols and signal analysis methods used to extract indexes of cerebral autoregulation. Measurement methods for blood flow and pressure are discussed, followed by an outline of signal pre-processing steps. An outline of the data analysis methods is then provided, linking the different approaches through their underlying principles and rationale. The methods cover correlation based approaches (e.g. Mx) through Transfer Function Analysis to non-linear, multivariate and time-variant approaches. Challenges in choosing which method may be 'best' and some directions for ongoing and future research conclude this work.

Adapting stepped care: Changes to service delivery format in the context of high demand.

Given the ongoing dilemma for college counseling centers to meet steady increases in demand for services, this study outlines the implementation of an adapted stepped care model in a university counseling center. Our adapted model focused, as do other stepped care models, on treatment planning and lower-intensity interventions, with the addition of the intensive therapy option being provided on a weekly basis. We adopted our stepped care model across a large center and hypothesized that after implementation we would be able to serve a similar number of clients as our previous model and that treatment outcomes for these clients would improve. Descriptive data and regression analyses demonstrated support for our hypotheses, including an increased likelihood of clinically significant improvement for clients postimplementation. Implications for adapting service delivery models using practice-based evidence are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

What are they doing? A national survey of help-seeking and relationship-repair behavior of individuals who are thinking about divorce.

Guided by the Stages of Change (SOC) model, we explored relationship-repair behaviors among those thinking about divorce, employing a recent national longitudinal survey of married individuals (N = 745). Person-centered analyses explored whether there were distinct typologies of relationship-repair behaviors. We found four distinct classes: Intense Seekers (6%), who engaged at high levels of all kinds of repair behaviors, including professional services; Moderate-fading Seekers (14%), who engaged in moderate levels of various repair behaviors, including professional services, but did not sustain that behavior over a year; and Minimal-private Seekers (42%) and Private-sustained Seekers (38%), who eschewed professional services and engaged in low-to-moderate personal and private repair behaviors. We discuss possible applications of the SOC model to the divorce decision-making process and conclude with implications for practice, including the need to allocate greater attention to personal and self-help interventions that match the way most people try to repair their relationships.