Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Rectified Latent Variable Model-Based EMG Factorization of Inhibitory Muscle Synergy Components Related to Aging, Expertise and Force-Tempo Variations.

Muscle synergy has been widely acknowledged as a possible strategy of neuromotor control, but current research has ignored the potential inhibitory components in muscle synergies. Our study aims to identify and characterize the inhibitory components within motor modules derived from electromyography (EMG), investigate the impact of aging and motor expertise on these components, and better understand the nervous system's adaptions to varying task demands. We utilized a rectified latent variable model (RLVM) to factorize motor modules with inhibitory components from EMG signals recorded from ten expert pianists when they played scales and pieces at different tempo-force combinations. We found that older participants showed a higher proportion of inhibitory components compared with the younger group. Senior experts had a higher proportion of inhibitory components on the left hand, and most inhibitory components became less negative with increased tempo or decreased force. Our results demonstrated that the inhibitory components in muscle synergies could be shaped by aging and expertise, and also took part in motor control for adapting to different conditions in complex tasks.

Can Occupation-Based Interventions for People Living with Dementia and Their Spousal Caregivers Support Positive Aspects of Caregiving? A Scoping Review.

This scoping review aimed to explore the characteristics and outcomes of occupation-based interventions for people living with dementia and their spousal caregivers relating to positive aspects of caregiving. A conceptualization of positive aspects of caregiving was developed based on the existing literature encompassing three domains - quality of the caregiver/care receiver relationship, meaning of the caregiver's role in daily life, and caregiver's feeling of accomplishment. Arksey and O'Malley's guidelines were used and four databases were searched to identify studies discussing occupation-based interventions involving spousal caregivers and persons living with dementia in the community that addressed at least one of three domains of positive aspects of caregiving identified in our conceptualization. After screening 1,560 articles, 18 articles were included for analysis. Three types of interventions were identified (i.e. music therapy, reminiscence therapy and a tailored activity program) involving three components contributing to positive aspects of caregiving: socializing outside the dyad, producing tangible end products, and education for the caregiver or dyad. Findings indicate that occupation-based interventions can support positive experiences for the dyad by improving the quality of the dyadic relationship and caregivers' feelings of accomplishment.

Motor patterns of patients with spinal muscular atrophy suggestive of sensory and corticospinal contributions to the development of locomotor muscle synergies.

Complex locomotor patterns are generated by combination of muscle synergies. How genetic processes, early sensorimotor experiences, and the developmental dynamics of neuronal circuits contribute to the expression of muscle synergies remains elusive. We shed light on the factors that influence development of muscle synergies by studying subjects with spinal muscular atrophy (SMA, types II/IIIa), a disorder associated with degeneration and deafferentation of motoneurons and possibly motor cortical and cerebellar abnormalities, from which the afflicted would have atypical sensorimotor histories around typical walking onset. Muscle synergies of children with SMA were identified from electromyographic signals recorded during active-assisted leg motions or walking, and compared with those of age-matched controls. We found that the earlier the SMA onset age, the more different the SMA synergies were from the normative. These alterations could not just be explained by the different degrees of uneven motoneuronal losses across muscles. The SMA-specific synergies had activations in muscles from multiple limb compartments, a finding reminiscent of the neonatal synergies of typically developing infants. Overall, while the synergies shared between SMA and control subjects may reflect components of a core modular infrastructure determined early in life, the SMA-specific synergies may be developmentally immature synergies that arise from inadequate activity-dependent interneuronal sculpting due to abnormal sensorimotor experience and other factors. Other mechanisms including SMA-induced intraspinal changes and altered cortical-spinal interactions may also contribute to synergy changes. Our interpretation highlights the roles of the sensory and descending systems to the typical and abnormal development of locomotor modules.NEW & NOTEWORTHY This is likely the first report of locomotor muscle synergies of children with spinal muscular atrophy (SMA), a subject group with atypical developmental sensorimotor experience. We found that the earlier the SMA onset age, the more the subjects' synergies deviated from those of age-matched controls. This result suggests contributions of the sensory/corticospinal activities to the typical expression of locomotor modules, and how their disruptions during a critical period of development may lead to abnormal motor modules.

Cognitive and sensory expectations independently shape musical expectancy and pleasure.

Expectation is crucial for our enjoyment of music, yet the underlying generative mechanisms remain unclear. While sensory models derive predictions based on local acoustic information in the auditory signal, cognitive models assume abstract knowledge of music structure acquired over the long term. To evaluate these two contrasting mechanisms, we compared simulations from four computational models of musical expectancy against subjective expectancy and pleasantness ratings of over 1000 chords sampled from 739 US Billboard pop songs. Bayesian model comparison revealed that listeners' expectancy and pleasantness ratings were predicted by the independent, non-overlapping, contributions of cognitive and sensory expectations. Furthermore, cognitive expectations explained over twice the variance in listeners' perceived surprise compared to sensory expectations, suggesting a larger relative importance of long-term representations of music structure over short-term sensory-acoustic information in musical expectancy. Our results thus emphasize the distinct, albeit complementary, roles of cognitive and sensory expectations in shaping musical pleasure, and suggest that this expectancy-driven mechanism depends on musical information represented at different levels of abstraction along the neural hierarchy. This article is part of the theme issue 'Art, aesthetics and predictive processing: theoretical and empirical perspectives'.

Gradient descent decomposition of force-field motor primitives optogenetically elicited for motor mapping of the murine lumbosacral spinal cord.

Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system (CNS) of all animals. During movement execution, the CNS performs complex calculations to control a large number of neuromusculoskeletal elements. The theory of modular motor control proposes that spinal interneurons are organized in discrete modules that can be linearly combined to generate a variety of behavioral patterns. These modules have been previously represented as stimulus-evoked force fields (FFs) comprising isometric limb-endpoint forces across workspace locations. Here, we ask whether FFs elicited by different stimulations indeed represent the most elementary units of motor control or are themselves the combination of a limited number of even more fundamental motor modules. To probe for potentially more elementary modules, we optogenetically stimulated the lumbosacral spinal cord of intact and spinalized Thy1-ChR2 transgenic mice ( n=21), eliciting FFs from as many single stimulation loci as possible (20-70 loci per mouse) at minimally necessary power. We found that the resulting varieties of FFs defied simple categorization with just a few clusters. We used gradient descent to further decompose the FFs into their underlying basic force fields (BFFs), whose linear combination explained FF variability. Across mice, we identified 4-5 BFFs with partially localizable but overlapping representations along the spinal cord. The BFFs were structured and topographically distributed in such a way that a rostral-to-caudal traveling wave of activity across the lumbosacral spinal cord may generate a swing-to-stance gait cycle. These BFFs may represent more rudimentary submodules that can be flexibly merged to produce a library of motor modules for building different motor behaviors.

Medical students' perception of the application of a virtual reality training model to acquire vaginal examination skills.

OBJECTIVE: To review the perception of and feedback from medical students on the application of a virtual reality (VR) model to acquire vaginal examination (VE) skills. METHODS: A specially designed VR training model on VE was developed with the aim of enhancing medical students' VE skills. Medical students attending the gynecology clinic were invited to try this VR training model. Their participation was voluntary and at the completion of their VR training, they were asked to complete an anonymous questionnaire to give their feedback and perception regarding this learning experience. RESULTS: Sixty-five sixth-year medical students completed the VR training and the feedback questionnaire: 55 (84.7%) of them reported that the training instructions were clear and 60 (92.4%) considered the training to the helpful in recalling the details of the tasks. It was also reported that VR technology could facilitate learning and interaction, and motivate learning in 80.1% and 66.2% of medical students, respectively. CONCLUSION: VR technology is a potential teaching modality for medical students to acquire VE skills. However, further evaluation is needed to determine whether this learning tool is effective in enhancing clinical competence.

Clinical presentation, investigation, underlying causes, and subsequent pregnancy outcomes among different phenotypes of second trimester miscarriage.

AIM: To evaluate the causes of miscarriage and subsequent pregnancy outcomes among different phenotypes of second trimester miscarriage. METHODS: Retrospective analysis of 170 consecutive second trimester miscarriages between 14 + 0 and 23 + 6 weeks recorded in the Clinical Data Analysis and Reporting System from 2012 to 2021. Cases were excluded if miscarriages occurred before 14 + 0 weeks of gestation, data were incomplete, or passage of the fetus happened before the clinical assessment. Cases were classified with a stepwise approach into three phenotypic groups including silent miscarriages (ST-SM), rupture of membranes (ST-ROM), and inevitable miscarriages (ST-IM) depending on the fetal heart pulsation and leakage of liquor at presentation. Clinical investigation of the underlying causes and the outcome of the subsequent pregnancy was then reviewed. RESULTS: There were 97 cases of ST-SM, 21 cases of ST-ROM, and 52 cases of ST-IM. Placental histology and karyotype examination were more likely to yield significant results in the cases of ST-ROM and ST-SM (p < 0.05). The phenotypic examination identified different underlying causes including fetal anomaly, suspected cervical insufficiency, diabetes mellitus, and unknown causes (p < 0.001). Sixty-four cases achieved a subsequent pregnancy. Although women with history of ST-ROM and ST-IM received more cervical length monitoring and cervical cerclage than those with ST-SM (66.7% vs. 44.4% vs. 7.5%, p = 0.0002; and 16.7% vs. 22.2% vs. 2.5%, p = 0.031, respectively), the risk of recurrent second trimester miscarriage was higher in ST-ROM and ST-IM than in ST-SM (16.7% vs. 0%, p = 0.018). CONCLUSION: The classification can differentiate different second trimester miscarriage phenotypes, which offers essential information to guide investigation panels of the underlying cause of miscarriages, and the prognosis and management of subsequent pregnancy. Future researches focused on second trimester miscarriage should report their findings according to different phenotypes.

The role of the angular gyrus in semantic cognition: a synthesis of five functional neuroimaging studies.

Semantic knowledge is central to human cognition. The angular gyrus (AG) is widely considered a key brain region for semantic cognition. However, the role of the AG in semantic processing is controversial. Key controversies concern response polarity (activation vs. deactivation) and its relation to task difficulty, lateralization (left vs. right AG), and functional-anatomical subdivision (PGa vs. PGp subregions). Here, we combined the fMRI data of five studies on semantic processing (n = 172) and analyzed the response profiles from the same anatomical regions-of-interest for left and right PGa and PGp. We found that the AG was consistently deactivated during non-semantic conditions, whereas response polarity during semantic conditions was inconsistent. However, the AG consistently showed relative response differences between semantic and non-semantic conditions, and between different semantic conditions. A combined analysis across all studies revealed that AG responses could be best explained by separable effects of task difficulty and semantic processing demand. Task difficulty effects were stronger in PGa than PGp, regardless of hemisphere. Semantic effects were stronger in left than right AG, regardless of subregion. These results suggest that the AG is engaged in both domain-general task-difficulty-related processes and domain-specific semantic processes. In semantic processing, we propose that left AG acts as a "multimodal convergence zone" that binds different semantic features associated with the same concept, enabling efficient access to task-relevant features.

Ultrasonography in the diagnosis of vulvar abscess.

This case image demonstrates the usefulness of vulvar ultrasound in the diagnosis of vulvar abscess.

Age-Related Modifications of Muscle Synergies and Their Temporal Activations for Overground Walking.

Healthy ageing modifies neuromuscular control of human overground walking. Previous studies found that ageing changes gait biomechanics, but whether there is concurrent ageing-related modulation of neuromuscular control remains unclear. We analyzed gait kinematics and electromyographic signals (EMGs; 14 lower-limb and trunk muscles) collected at three speeds during overground walking in 11 healthy young adults (mean age of 23.4 years) and 11 healthy elderlies (67.2 years). Neuromuscular control was characterized by extracting muscle synergies from EMGs and the synergies of both groups were k -means-clustered. The synergies of the two groups were grossly similar, but we observed numerous cluster- and muscle-specific differences between the age groups. At the population level, some hip-motion-related synergy clusters were more frequently identified in elderlies while others, more frequent in young adults. Such differences in synergy prevalence between the age groups are consistent with the finding that elderlies had a larger hip flexion range. For the synergies shared between both groups, the elderlies had higher inter-subject variability of the temporal activations than young adults. To further explore what synergy characteristics may be related to this inter-subject variability, we found that the inter-subject variance of temporal activations correlated negatively with the sparseness of the synergies in elderlies but not young adults during slow walking. Overall, our results suggest that as humans age, not only are the muscle synergies for walking fine-tuned in structure, but their temporal activation patterns are also more heterogeneous across individuals, possibly reflecting individual differences in prior sensorimotor experience or ageing-related changes in limb neuro-musculoskeletal properties.

Successful Control of Heavy Menstrual Bleeding Using High-Intensity Focused Ultrasound Ablation of Fibroid Uterus in a Woman With Eisenmenger Syndrome.

Uterine fibroid causes heavy menstrual bleeding and can be difficult to manage particularly in patients with complicated medical history. We present a woman with Eisenmenger syndrome, who presented with heavy menses due to fibroid uterus. She was advised against having hormonal therapy or major surgery under general anesthesia. We successfully controlled her heavy menses and avoided surgery using high-intensity focused ultrasound ablation of her fibroid.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

Applying muscle synergy analysis to forearm high-density electromyography of healthy people.

Introduction: Muscle synergy is regarded as a motor control strategy deployed by the central nervous system (CNS). Clarifying the modulation of muscle synergies under different strength training modes is important for the rehabilitation of motor-impaired patients. Methods: To represent the subtle variation of neuromuscular activities from the smaller forearm muscles during wrist motion, we proposed to apply muscle synergy analysis to preprocessed high-density electromyographic data (HDEMG). Here, modulation of muscle synergies within and across the isometric and isotonic training modes for strengthening muscles across the wrist were investigated. Surface HDEMGs were recorded from healthy subjects (N = 10). Three different HDEMG electrode configurations were used for comparison and validation of the extracted muscle synergies. The cosine of principal angles (CPA) and the Euclidian distance (ED) between synergy vectors were used to evaluate the intra- and inter-mode similarity of muscle synergies. Then, how the activation coefficients modulate the excitation of specific synergy under each mode was examined by pattern recognition. Next, for a closer look at the mode-specific synergies and the synergies shared by the two training modes, k-means clustering was applied. Results: We observed high similarity of muscle synergies across different tasks within each training mode, but decreased similarity of muscle synergies across different training modes. Both intra- and intermode similarity of muscle synergies were consistently robust to electrode configurations regardless of the similarity metric used. Discussion: Overall, our findings suggest that applying muscle synergy analysis to HDEMG is feasible, and that the traditional muscle synergies defined by whole-muscle components may be broadened to include sub-muscle components represented by the HDEMG channels. This work may lead to an appropriate neuromuscular analysis method for motor function evaluation in clinical settings and provide valuable insights for the prescription of rehabilitation training therapies.

Muscle Synergies and Clinical Outcome Measures Describe Different Factors of Upper Limb Motor Function in Stroke Survivors Undergoing Rehabilitation in a Virtual Reality Environment.

Recent studies have investigated muscle synergies as biomarkers for stroke, but it remains controversial if muscle synergies and clinical observation convey the same information on motor impairment. We aim to identify whether muscle synergies and clinical scales convey the same information or not. Post-stroke patients were administered an upper limb treatment. Before (T0) and after (T1) treatment, we assessed motor performance with clinical scales and motor output with EMG-derived muscle synergies. We implemented an exploratory factor analysis (EFA) and a confirmatory factor analysis (CFA) to identify the underlying relationships among all variables, at T0 and T1, and a general linear regression model to infer any relationships between the similarity between the affected and unaffected synergies (Median-sp) and clinical outcomes at T0. Clinical variables improved with rehabilitation whereas muscle-synergy parameters did not show any significant change. EFA and CFA showed that clinical variables and muscle-synergy parameters (except Median-sp) were grouped into different factors. Regression model showed that Median-sp could be well predicted by clinical scales. The information underlying clinical scales and muscle synergies are therefore different. However, clinical scales well predicted the similarity between the affected and unaffected synergies. Our results may have implications on personalizing rehabilitation protocols.

Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis.

BACKGROUND & AIMS: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. METHODS: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. RESULTS: We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. CONCLUSIONS: Interferon gamma-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.

Neocortical substrates of feelings evoked with music in the ACC, insula, and somatosensory cortex.

Neurobiological models of emotion focus traditionally on limbic/paralimbic regions as neural substrates of emotion generation, and insular cortex (in conjunction with isocortical anterior cingulate cortex, ACC) as the neural substrate of feelings. An emerging view, however, highlights the importance of isocortical regions beyond insula and ACC for the subjective feeling of emotions. We used music to evoke feelings of joy and fear, and multivariate pattern analysis (MVPA) to decode representations of feeling states in functional magnetic resonance (fMRI) data of n = 24 participants. Most of the brain regions providing information about feeling representations were neocortical regions. These included, in addition to granular insula and cingulate cortex, primary and secondary somatosensory cortex, premotor cortex, frontal operculum, and auditory cortex. The multivoxel activity patterns corresponding to feeling representations emerged within a few seconds, gained in strength with increasing stimulus duration, and replicated results of a hypothesis-generating decoding analysis from an independent experiment. Our results indicate that several neocortical regions (including insula, cingulate, somatosensory and premotor cortices) are important for the generation and modulation of feeling states. We propose that secondary somatosensory cortex, which covers the parietal operculum and encroaches on the posterior insula, is of particular importance for the encoding of emotion percepts, i.e., preverbal representations of subjective feeling.

Approaches to revealing the neural basis of muscle synergies: a review and a critique.

The central nervous system (CNS) may produce coordinated motor outputs via the combination of motor modules representable as muscle synergies. Identification of muscle synergies has hitherto relied on applying factorization algorithms to multimuscle electromyographic data (EMGs) recorded during motor behaviors. Recent studies have attempted to validate the neural basis of the muscle synergies identified by independently retrieving the muscle synergies through CNS manipulations and analytic techniques such as spike-triggered averaging of EMGs. Experimental data have demonstrated the pivotal role of the spinal premotor interneurons in the synergies' organization and the presence of motor cortical loci whose stimulations offer access to the synergies, but whether the motor cortex is also involved in organizing the synergies has remained unsettled. We argue that one difficulty inherent in current approaches to probing the synergies' neural basis is that the EMG generative model based on linear combination of synergies and the decomposition algorithms used for synergy identification are not grounded on enough prior knowledge from neurophysiology. Progress may be facilitated by constraining or updating the model and algorithms with knowledge derived directly from CNS manipulations or recordings. An investigative framework based on evaluating the relevance of neurophysiologically constrained models of muscle synergies to natural motor behaviors will allow a more sophisticated understanding of motor modularity, which will help the community move forward from the current debate on the neural versus nonneural origin of muscle synergies.