Chronic low back pain (CLBP) is a major health issue, yet its underlying mechanisms remain unknown. Studies have demonstrated the importance of emotion and cognition in chronic pain; however, the ...relevant brain physiology in magnetic resonance imaging (MRI) studies are unclear in CLBP populations. Therefore, this review aimed to identify MRI brain changes and examine their potential relationship with emotional and cognitive processes in CLBP.
A systematic search was conducted in 5 databases. Studies that recruited adult, CLBP populations, and used brain MRI protocols were included.
In total, 55 studies met the inclusion criteria. Of the structural MRI studies, 10 of 15 studies found decreased gray matter and 7 of 8 studies found white matter changes in CLBP groups compared with controls. Fourteen resting-state functional MRI studies all reported differences between CLBP and control groups in the default mode network. Interestingly, only 3 of 10 functional MRI studies observed significant differences during noxious stimulation between CLBP and control groups, whereas 13 of 16 studies observed significant brain activation differences in CLBP groups during various external tasks. Finally, there were 3 studies that observed a degree of recovery in functional connectivity following intervention.
The brain changes in CLBP groups were mainly observed in areas and networks important in emotion and cognition, rather than those typically associated with nociception. This supports the understanding that emotional and cognitive processes may be the core contributor to the CLBP experience; however, future studies need to explore these processes further.
In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this ...study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.
Abstract In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram ...(EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17 ). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.
Sepsis is the most frequent cause of death in hospitalized patients, and severe sepsis is a leading contributory factor to acute respiratory distress syndrome (ARDS). At present, there is no ...effective treatment for these conditions, and care is primarily supportive. Murine sialic acid-binding immunoglobulin-like lectin-E (Siglec-E) and its human orthologs Siglec-7 and Siglec-9 are immunomodulatory receptors found predominantly on hematopoietic cells. These receptors are important negative regulators of acute inflammatory responses and are potential targets for the treatment of sepsis and ARDS. We describe a Siglec-targeting platform consisting of poly(lactic-co-glycolic acid) nanoparticles decorated with a natural Siglec ligand, di(α2→8) N-acetylneuraminic acid (α2,8 NANA-NP). This nanoparticle induced enhanced oligomerization of the murine Siglec-E receptor on the surface of macrophages, unlike the free α2,8 NANA ligand. Furthermore, treatment of murine macrophages with these nanoparticles blocked the production of lipopolysaccharide-induced inflammatory cytokines in a Siglec-E-dependent manner. The nanoparticles were also therapeutically beneficial in vivo in both systemic and pulmonary murine models replicating inflammatory features of sepsis and ARDS. Moreover, we confirmed the anti-inflammatory effect of these nanoparticles on human monocytes and macrophages in vitro and in a human ex vivo lung perfusion (EVLP) model of lung injury. We also established that interleukin-10 (IL-10) induced Siglec-E expression and α2,8 NANA-NP further augmented the expression of IL-10. Indeed, the effectiveness of the nanoparticle depended on IL-10. Collectively, these results demonstrated a therapeutic effect of targeting Siglec receptors with a nanoparticle-based platform under inflammatory conditions.
IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Although IL-17A is the archetypal cytokine of T-helper 17 ...cells, it is produced by a number of lymphocytes, the source during ARDS being unknown.
To identify the cellular source and the role of IL-17A in the early phase of lung injury.
Lung injury was induced in wild-type (C57BL/6) and IL-17 knockout (KO) mice with aerosolized LPS (100 μg) or Pseudomonas aeruginosa infection. Detailed phenotyping of the cells expressing RORγt, the transcriptional regulator of IL-17 production, in the mouse lung at 24 hours was performed by flow cytometry.
A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared with wild-type mice. The majority of RORγt(+) cells in the mouse lung were the recently identified group 3 innate lymphoid cells (ILC3s). Detailed characterization revealed these pulmonary ILC3s (pILC3s) to be discrete from those described in the gut. The critical role of these cells was verified by inducing injury in recombinase-activating gene 2 KO mice, which lack T cells but retain innate lymphoid cells. No amelioration of pathology was observed in the recombinase-activating gene 2 KO mice.
IL-17 is rapidly produced during lung injury and significantly contributes to early immunopathogenesis. This is orchestrated largely by a distinct population of pILC3s. Modulation of the activity of pILC3s may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets.
Recent GWAS have identified SNPs at a human chromosom1 locus associated with coronary artery disease risk and LDL cholesterol levels. The SNPs are also associated with altered expression of hepatic ...sortilin-1 (SORT1), which encodes a protein thought to be involved in apoB trafficking and degradation. Here, we investigated the regulation of Sort1 expression in mouse models of obesity. Sort1 expression was markedly repressed in both genetic (ob/ob) and high-fat diet models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and apoB secretion. Mouse models of obesity also exhibit increased hepatic activity of mammalian target of rapamycin complex 1 (mTORC1) and ER stress, and we found that administration of the mTOR inhibitor rapamycin to ob/ob mice reduced ER stress and increased hepatic sortilin-1 levels. Conversely, genetically increased hepatic mTORC1 activity was associated with repressed Sort1 and increased apoB secretion. Treating WT mice with the ER stressor tunicamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemical chaperone PBA to ob/ob mice led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride secretion. Moreover, the ER stress target Atf3 acted at the SORT1 promoter region as a transcriptional repressor, whereas knockdown of Atf3 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride secretion. Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease.
We sought in-depth understanding on the evolution of factors influencing COVID-19 booster dose and bivalent vaccine hesitancy in a longitudinal semi-structured interview-based qualitative study. ...Serial interviews were conducted between July 25th and September 1
, 2022 (Phase I: univalent booster dose availability), and between November 21
, 2022 and January 11
, 2023 (Phase II: bivalent vaccine availability). Adults (≥18 years) in Canada who had received an initial primary series and had not received a COVID-19 booster dose were eligible for Phase I, and subsequently invited to participate in Phase II. Twenty-two of twenty-three (96%) participants completed interviews for both phases (45 interviews). Nearly half of participants identified as a woman (
= 11), the median age was 37 years (interquartile range: 32-48), and most participants were employed full-time (
= 12); no participant reported needing to vaccinate (with a primary series) for their workplace. No participant reported having received a COVID-19 booster dose at the time of their interview in Phase II. Three themes relating to the development of hesitancy toward continued vaccination against COVID-19 were identified: 1) effectiveness (frequency concerns; infection despite vaccination); 2) necessity (less threatening, low urgency, alternate protective measures); and 3) information (need for data, contradiction and confusion, lack of trust, decreased motivation). The data from interviews with individuals who had not received a COVID-19 booster dose or bivalent vaccine despite having received a primary series of COVID-19 vaccines highlights actionable targets to address vaccine hesitancy and improve public health literacy.
•Timelines of NPS mentions on Reddit were compared to comprehensive toxicology data.•Seven of eight evaluated NPS were mentioned online prior to emergence in exposure cases.•Peak mentions generally ...preceded peak exposure, indicating usefulness as a predictor.•Exposure events generally tracked similar yet delayed trajectories vs. mentions.
Novel psychoactive substances (NPS) present continuous and growing challenges for the scientific, medical, and interventional communities as emerging substances on recreational drug markets change national and international drug landscapes. NPS account for an increasing proportion of adverse events, hospitalizations, and deaths due to increasing potency and unanticipated biological effects compared to predecessors. This study evaluated the utility of drug use forums as an early indicator or predictor of impending intoxications with potentially harmful or lethal outcomes prior to their occurrences.
Eight NPS were selected for evaluation to assess the relationship between online mentions of drugs and their involvement in toxic exposures or overdoses. Mentions on Reddit drug forum discussions were tallied and toxicology testing results from forensic investigations in the US were assessed. The selected NPS covered several subclasses and a predetermined time range (2013–2020). They included carfentanil, U-47700, eutylone, flualprazolam, N-ethylpentylone, 5F-MDMB-PICA, isotonitazene, and brorphine.
Seven NPS (excluding 5F-MDMB-PICA) appeared in discussions on Reddit prior to their implication in poisonings or intoxications. Distinct increases and decreases in number of mentions and number of exposures were observed. For most substances (n = 5, 63%), a rise in Reddit mentions was soon followed by a corresponding rise in toxicology positivity. Peak positivity for carfentanil and flualprazolam, however, preceded peak Reddit mentions.
This study demonstrated the utility of social media sites, such as Reddit, as a predictor for future trends in NPS-related exposures. These results provide confirmation that activity on drug use forums in the virtual world can help predict changes in exposures associated with new or re-emerging NPS in the real world. The results warrant further evaluation as a strategy for inclusion in early warning systems.
Ultra-marathon running is an extremely demanding sport. Psychological factors that affect responses to stressors and may contribute to ultra-runners' ability to engage in their sport include ...resilience, personality characteristics, and affective processing. This exploratory study investigated ultra-runners' resilience, personality traits, emotion regulation abilities, and self-report and physiological responses to emotionally negative stimuli.
Twenty ultra-runners and 20 non-running controls completed the Connor-Davidson Resilience Scale (CD-RISC), Emotion Regulation Questionnaire, Cognitive Emotion Regulation Questionnaire (CERQ), and Multidimensional Personality Questionnaire-Brief Form (MPQ-BF). Participants also completed a computerised emotion regulation task in which they were instructed to down-regulate their responses to emotionally negative images. They provided self-report ratings of their responses to the images and their heart rate and skin conductance responses were also recorded.
The ultra-runners scored higher than controls on the CD-RISC (p = .014; d = 0.81) and Positive Reappraisal subscale of the CERQ (p = .034; d = 0.70). They also scored lower on the Social Closeness scale of the MPQ-BF (p = .037; d = −0.68). In the emotion regulation task, they did not differ in their self-report responses to negative images but displayed smaller cardiac and skin conductance responses to these images (both p = .04;
η
p
2
≥ .11).
Compared with non-runners, ultra-runners appear to be more resilient, more likely to engage in positive reappraisal, lower in affiliative extraversion, and less physiologically responsive to emotionally negative stimuli. They otherwise appear to be broadly similar to non-runners with respect to their personality traits and emotion regulation processes.
Athletes seem to have higher pain tolerance than the normally active population. It is unknown whether psychological factors contribute to their supranormal pain tolerance. The aim of this pilot ...study was to examine pain-related psychological processes in ultramarathon runners ('ultrarunners') and to explore whether psychological factors mediate the elevated pain tolerance displayed by ultrarunners. Forty participants took part in the study: 20 ultrarunners and 20 age- and gender-matched controls. Participants underwent the cold pressor test using water cooled to 0.1 to 0.5°C and completed the Pain Catastrophizing Scale, Pain Anxiety Symptoms Scale-20, Pain Vigilance and Awareness Questionnaire, and Pain Resilience Scale. Immersion time on the cold pressor test was significantly longer for the ultrarunners (P = .007) and they also had lower scores on all Pain Anxiety Symptoms Scale-20 subscales (P ≤ .030). The 2 groups did not differ significantly on the other questionnaires. Mediation analysis revealed that reduced pain-related escape and avoidance behaviors accounted for 40% of the difference in immersion time between the groups (P = .020). Our results suggest that ultrarunners have lower levels of pain-related anxiety than the general population and that their supranormal pain tolerance is partially mediated by reduced pain-related escape and avoidance behaviors. PERSPECTIVE: This study investigated whether psychological factors contribute to the supranormal pain tolerance displayed by ultrarunners. It found that ultrarunners have lower levels of pain-related anxiety than nonrunning controls and that reduced pain-related escape and avoidance behaviors partially mediate their elevated pain tolerance.
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