Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene.

PURPOSE: Exfoliation syndrome (XFS) is a systemic disease of elastin-rich tissues involving a deposition of fibrillar exfoliative material (XFM) in the anterior chamber of the eye, which can promote glaucoma. The purpose of this study was to create mice with CRISPR/Cas9-induced variations in candidate genes identified from human genome-wide association studies (GWAS) and screen them for indices of XFS. METHODS: Variants predicted to be deleterious were sought in the Agpat1, Cacna1a, Loxl1, Pomp, Rbms3, Sema6a, and Tlcd5 genes of C57BL/6J mice using CRISPR/Cas9-based gene editing. Strains were phenotyped by slit-lamp, SD-OCT imaging, and fundus exams at 1-5 mos of age. Smaller cohorts of 12-mos-old mice were also studied. RESULTS: Deleterious variants were identified in six targets; Pomp was recalcitrant to targeting. Multiple alleles of some targets were isolated, yielding 12 strains. Across all genotypes and ages, 277 mice were assessed by 902 slit-lamp exams, 928 SD-OCT exams, and 358 fundus exams. Homozygosity for Agpat1 or Cacna1a mutations led to early lethality; homozygosity for Loxl1 mutations led to pelvic organ prolapse, preventing aging. Loxl1 homozygotes exhibited a conjunctival phenotype of potential relevance to XFS. Multiple other genotype-specific phenotypes were variously identified. XFM was not observed in any mice. CONCLUSIONS: This study did not detect XFM in any of the strains. This may have been due to species-specific differences, background dependence, or insufficient aging. Alternatively, it is possible that the current candidates, selected based on proximity to GWAS signals, are not effectors acting via monogenic loss-of-function mechanisms.

Distinct SAP102 and PSD-95 Nano-organization Defines Multiple Types of Synaptic Scaffold Protein Domains at Single Synapses.

MAGUK scaffold proteins play a central role in maintaining and modulating synaptic signaling, providing a framework to retain and position receptors, signaling molecules, and other synaptic components. In particular, the MAGUKs SAP102 and PSD-95 are essential for synaptic function at distinct developmental timepoints and perform both overlapping and unique roles. While their similar structures allow for common binding partners, SAP102 is expressed earlier in synapse development and is required for synaptogenesis, whereas PSD-95 expression peaks later and is associated with synapse maturation. PSD-95 and other key synaptic proteins organize into subsynaptic nanodomains that have a significant impact on synaptic transmission, but the nanoscale organization of SAP102 is unknown. How SAP102 is organized within the synapse, and how it relates spatially to PSD-95 on a nanometer scale, could underlie its unique functions and impact how SAP102 scaffolds synaptic proteins. Here we used DNA-PAINT super-resolution microscopy to measure SAP102 nano-organization and its spatial relationship to PSD-95 at individual synapses in mixed-sex rat cultured neurons. We found that like PSD-95, SAP102 accumulates in high-density subsynaptic nanoclusters (NCs). However, SAP102 NCs were smaller and denser than PSD-95 NCs across development. Additionally, only a subset of SAP102 NCs co-organized with PSD-95, revealing MAGUK nanodomains within individual synapses containing either one or both proteins. These MAGUK nanodomain types had distinct NC properties and were differentially enriched with the presynaptic release protein Munc13-1. This organization into both shared and distinct subsynaptic nanodomains may underlie the ability of SAP102 and PSD-95 to perform both common and unique synaptic functions.

Observing the suppression of individual aversive memories from conscious awareness.

When reminded of an unpleasant experience, people often try to exclude the unwanted memory from awareness, a process known as retrieval suppression. Here we used multivariate decoding (MVPA) and representational similarity analyses on EEG data to track how suppression unfolds in time and to reveal its impact on item-specific cortical patterns. We presented reminders to aversive scenes and asked people to either suppress or to retrieve the scene. During suppression, mid-frontal theta power within the first 500 ms distinguished suppression from passive viewing of the reminder, indicating that suppression rapidly recruited control. During retrieval, we could discern EEG cortical patterns relating to individual memories-initially, based on theta-driven visual perception of the reminders (0 to 500 ms) and later, based on alpha-driven reinstatement of the aversive scene (500 to 3000 ms). Critically, suppressing retrieval weakened (during 360 to 600 ms) and eventually abolished item-specific cortical patterns, a robust effect that persisted until the reminder disappeared (780 to 3000 ms). Representational similarity analyses provided converging evidence that retrieval suppression weakened the representation of target scenes during the 500 to 3000 ms reinstatement window. Together, rapid top-down control during retrieval suppression abolished cortical patterns of individual memories, and precipitated later forgetting. These findings reveal a precise chronometry on the voluntary suppression of individual memories.

Dystrophin missense mutations alter focal adhesion tension and mechanotransduction.

Dystrophin is an essential muscle protein that contributes to cell membrane stability by mechanically linking the actin cytoskeleton to the extracellular matrix via an adhesion complex called the dystrophin-glycoprotein complex. The absence or impaired function of dystrophin causes muscular dystrophy. Focal adhesions (FAs) are also mechanosensitive adhesion complexes that connect the cytoskeleton to the extracellular matrix. However, the interplay between dystrophin and FA force transmission has not been investigated. Using a vinculin-based bioluminescent tension sensor, we measured FA tension in transgenic C2C12 myoblasts expressing wild-type (WT) dystrophin, a nonpathogenic single nucleotide polymorphism (SNP) (I232M), or two missense mutations associated with Duchenne (L54R), or Becker muscular dystrophy (L172H). Our data revealed cross talk between dystrophin and FAs, as the expression of WT or I232M dystrophin increased FA tension compared to dystrophin-less nontransgenic myoblasts. In contrast, the expression of L54R or L172H did not increase FA tension, indicating that these disease-causing mutations compromise the mechanical function of dystrophin as an FA allosteric regulator. Decreased FA tension caused by these mutations manifests as defective migration, as well as decreased Yes-associated protein 1 (YAP) activation, possibly by the disruption of the ability of FAs to transmit forces between the extracellular matrix and cytoskeleton. Our results indicate that dystrophin influences FA tension and suggest that dystrophin disease-causing missense mutations may disrupt a cellular tension-sensing pathway in dystrophic skeletal muscle.

Outcomes After Respiratory Extracorporeal Life Support in Teens and Young Adults: An Extracorporeal Life Support Organization Registry Analysis.

OBJECTIVES: A recent study from Germany found that survival after respiratory extracorporeal life support (ECLS) was lower among patients 10-20 years old than 20-30 years old. The objective of this study was to compare survival between teenage and young adult patients who receive respiratory ECLS. DESIGN: Retrospective cohort study. SETTING: Extracorporeal Life Support Organization registry, an international prospective quality improvement database. PATIENTS: All patients ages 16-30 years cannulated for respiratory indications from 1990 to 2020 were included. Patients were divided into two groups, teens (16-19 yr old) and young adults (20-30 yr old). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was survival to discharge. Variables were considered for the multivariate logistic regression model if there was both a statistically significant difference (p ≤ 0.05) and a clinically meaningful absolute difference between the groups. A total of 5,751 patients were included, of whom 1,653 (29%) were teens and 4,098 (71%) were young adults. Survival to discharge was higher in young adults than teens, 69% versus 63% (p < 0.001). Severity of illness was higher among teens; however, survival within each stratum defined by Pao2/Fio2 ratio was higher in young adults than in teens. Use of venoarterial ECLS was higher in teens than in young adults, 15% versus 7%, respectively. Teens were more likely to receive high-frequency oscillatory ventilation and this therapy was associated with a longer time from admission to ECLS initiation. After adjusting for variables that differ significantly between the groups, the odds ratio for survival in young adults compared with teens was 1.14 (95% CI, 1.004-1.3). CONCLUSIONS: In this large multicenter retrospective study, mortality was higher in teens than in young adults who received respiratory ECLS. This difference persisted after adjusting for multiple variables and the mechanism underlying these findings remains unclear.

Enhancing global insight into AMR spread and generation: prospects and limitations of the WHO and quadripartite research agendas.

In Summer 2023, the World Health Organisation (WHO) and the Food and Agriculture Organization of the United Nations (FAO)-United Nations Environment Programme (UNEP) WHO-World Organisation for Animal Health (OIE) Quadripartite published two separate research agendas on antimicrobial resistance (AMR). While the publication of these research agendas on AMR creates a significant opportunity to align research priorities internationally, we emphasize a number of limitations. Firstly, the production of two separate AMR research agendas, in human health and One Health, rather than one integrated research agenda, risks the continued deprioritization of the One Health agenda. Furthermore, neither research agenda addressed the need to study the relationship between climate change and AMR despite growing evidence to suggest this may be significant. Finally, there are also missed opportunities in directing the study of appropriate treatment regimens and in clarifying the overall most resource-efficient path to combatting AMR. Moving forward, the international research agenda for AMR needs to be continually redefined in an inclusive, transparent and independent manner. This could be the task of the proposed, but so far not realized, Independent Panel on Evidence for Action against AMR.

Effects of Home-Based Primary Care on Hospital Use for High-Need Medicare Patients: an Observational Study.

BACKGROUND: High-need, high-cost Medicare patients can have difficulties accessing office-based primary care. Home-based primary care (HBPC) can reduce access barriers and allow a clinician to obtain valuable information not obtained during office visit, possibly leading to reductions in hospital use. OBJECTIVE: To determine whether HBPC for high-need, high-cost patients reduces hospitalizations and Medicare inpatient expenditures. DESIGN: We conducted a matched retrospective cohort study using a difference-in-differences analysis to examine patients 2 years before and 2 years after their first home visit (HBPC group). PARTICIPANTS: The study included high-need, high-cost fee-for-service Medicare patients without prior HBPC use, of which 55,303 were new HBPC recipients and 156,142 were matched comparison patients. INTERVENTION: Receipt of at least two HBPC visits and, within 6 months of the index HBPC visit, a majority of a patient's primary care visits in the home. MAIN MEASURES: Total and potentially avoidable hospitalizations and Medicare inpatient expenditures. KEY RESULTS: HBPC reduced total hospitalization rates, but the marginal effects were not statistically significant: a reduction of 11 total hospitalizations per 1000 patients in the first year (- 0.6%, p = 0.19) and 14 in the second year (- 0.7%, p = 0.16). However, HBPC reduced potentially avoidable hospitalization rates in the second year. The estimated marginal effect was a reduction of 6 potentially avoidable hospitalizations per 1000 patients in the first year (- 1.6%, p = 0.16) and 11 in the second (- 3.1%, p = 0.01). The estimated effect of HBPC was a small decrease in inpatient expenditures of $24 per patient per month (- 1.1%, p = 0.10) in the first year and $0 (0.0%, p = 0.99) in the second. CONCLUSIONS: After high-need, high-cost patients started receiving HBPC, they did not experience fewer total hospitalizations or lower inpatient spending but may have had lower rates of potentially avoidable hospitalizations after 2 years.

Reduced hippocampal-cortical connectivity during memory suppression predicts the ability to forget unwanted memories.

The ability to suppress unwelcome memories is important for productivity and well-being. Successful memory suppression is associated with hippocampal deactivations and a concomitant disruption of this region's functionality. Much of the previous neuroimaging literature exploring such suppression-related hippocampal modulations has focused on the region's negative coupling with the prefrontal cortex. Task-based changes in functional connectivity between the hippocampus and other brain regions still need further exploration. In the present study, we utilize psychophysiological interactions and seed connectome-based predictive modeling to investigate the relationship between the hippocampus and the rest of the brain as 134 participants attempted to suppress unwanted memories during the Think/No-Think task. The results show that during retrieval suppression, the right hippocampus exhibited decreased functional connectivity with visual cortical areas (lingual and cuneus gyrus), left nucleus accumbens and the brain-stem that predicted superior forgetting of unwanted memories on later memory tests. Validation tests verified that prediction performance was not an artifact of head motion or prediction method and that the negative features remained consistent across different brain parcellations. These findings suggest that systemic memory suppression involves more than the modulation of hippocampal activity-it alters functional connectivity patterns between the hippocampus and visual cortex, leading to successful forgetting.

Understanding factors impacting patient-reported outcome measures integration in routine clinical practice: an umbrella review.

PURPOSE: Patient-report outcome measures (PROMs) have gained widespread support as a mechanism to improve healthcare quality. We aimed to map out key enablers and barriers influencing PROMs implementation strategies in routine clinical practice. METHODS: An umbrella review was conducted to identify reviews exploring enablers and barriers related to the integration of PROMs in routine clinical practice from January 2000 to June 2023. Information on key enablers and barriers was extracted and summarised thematically according to the Theoretical Domains Framework. RESULTS: 34 reviews met our criteria for inclusion. Identified reviews highlighted barriers such as limited PROMs awareness among clinicians and patients, perceived low value by clinicians and patients, PROMs that were too complex or difficult for patients to complete, poor usability of PROMs systems, delayed feedback of PROMs data, clinician concerns related to use of PROMs as a performance management tool, patient concerns regarding privacy and security, and resource constraints. Enablers encompassed phased implementation, professional training, stakeholder engagement prior to implementation, clear strategies and goals, 'change champions' to support PROMs implementation, systems to respond to issues raised by PROMs, and integration into patient pathways. No consensus favoured paper or electronic PROMs, yet offering both options to mitigate digital literacy bias and integrating PROMs into electronic health records emerged as important facilitators. CONCLUSIONS: The sustainable implementation of PROMs is a complex process that requires multicomponent organisational strategies covering training and guidance, necessary time and resources, roles and responsibilities, and consultation with patients and clinicians.

Germline pathogenic SMARCA4 variants in neuroblastoma.

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4 Median age at diagnosis was 5 years (range 2 months-26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum of SMARCA4-associated tumours.

Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.

BACKGROUND: Germline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications. METHODS: CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories. RESULTS: Updated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing. CONCLUSIONS: The development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.

The Year in Thoracic Anesthesia: Selected Highlights from 2022.

This article reviews research highlights in the field of thoracic anesthesia. The highlights of this year included new developments in the preoperative assessment and prehabilitation of patients requiring thoracic surgery, updates on the use of devices for one-lung ventilation (OLV) in adults and children, updates on the anesthetic and postoperative management of these patients, including protective OLV ventilation, the use of opioid-sparing techniques and regional anesthesia, and outcomes using enhanced recovery after surgery, as well as the use of expanding indications for extracorporeal membrane oxygenation, specialized anesthetic techniques for airway surgery, and nonintubated video-assisted thoracic surgery.

Naming racism as a root cause of inequities in palliative care research: a scoping review.

BACKGROUND: Racial and ethnic inequities in palliative care are well-established. The way researchers design and interpret studies investigating race- and ethnicity-based disparities has future implications on the interventions aimed to reduce these inequities. If racism is not discussed when contextualizing findings, it is less likely to be addressed and inequities will persist. OBJECTIVE: To summarize the characteristics of 12 years of academic literature that investigates race- or ethnicity-based disparities in palliative care access, outcomes and experiences, and determine the extent to which racism is discussed when interpreting findings. METHODS: Following Arksey & O'Malley's methodology for scoping reviews, we searched bibliographic databases for primary, peer reviewed studies globally, in all languages, that collected race or ethnicity variables in a palliative care context (January 1, 2011 to October 17, 2023). We recorded study characteristics and categorized citations based on their research focus-whether race or ethnicity were examined as a major focus (analyzed as a primary independent variable or population of interest) or minor focus (analyzed as a secondary variable) of the research purpose, and the interpretation of findings-whether authors directly or indirectly discussed racism when contextualizing the study results. RESULTS: We identified 3000 citations and included 181 in our review. Of these, most were from the United States (88.95%) and examined race or ethnicity as a major focus (71.27%). When interpreting findings, authors directly named racism in 7.18% of publications. They were more likely to use words closely associated with racism (20.44%) or describe systemic or individual factors (41.44%). Racism was directly named in 33.33% of articles published since 2021 versus 3.92% in the 10 years prior, suggesting it is becoming more common. CONCLUSION: While the focus on race and ethnicity in palliative care research is increasing, there is room for improvement when acknowledging systemic factors - including racism - during data analysis. Researchers must be purposeful when investigating race and ethnicity, and identify how racism shapes palliative care access, outcomes and experiences of racially and ethnically minoritized patients.

Training simulated participants for role portrayal and feedback practices in communication skills training: A BEME scoping review: BEME Guide No. 86.

BACKGROUND: Providing feedback is a key aspect of simulated participants' (SPs) educational work. In teaching contexts, the ability to provide feedback to learners is central to their role. Suboptimal feedback practices may deny learners the valuable feedback they need to learn and improve. This scoping review systematically maps the evidence related to SPs' role as educators and identifies how SPs prepare for their role and feedback practices. METHODS: The authors conducted a scoping review and included a group of international stakeholders with experience and expertise in SP methodology. Five online databases were systematically searched and ERIC, MedEdPortal and MedEdPublish were hand searched to identify relevant studies. Inclusion/exclusion criteria were developed. Data screening and subsequently data charting were performed in pairs. The results of data charting were thematically analysed including categories relating to the Association of SP Educators (ASPE) Standards of Best Practice (SOBP). RESULTS: From 8179 articles identified for the title and abstract screening, 98 studies were included. Studies reported the benefit of SPs' authentic role portrayal and feedback interactions for learners and on the reported learning outcomes. Data was heterogeneous with a notable lack of consistency in the detail regarding the scenario formats for communication skills training interventions, SP characteristics, and approaches to training for feedback and role portrayal. CONCLUSIONS: The published literature has considerable heterogeneity in reporting how SPs are prepared for role portrayal and feedback interactions. Additionally, our work has identified gaps in the implementation of the ASPE SOBP, which promotes effective SP-learner feedback interactions. Further research is required to identify effective applications of SP methodology to prepare SPs for their role as educators.

Memory control immediately improves unpleasant emotions associated with autobiographical memories of past immoral actions.

The ability to stop unwanted memories from coming to mind is theorised to be essential for maintaining good mental health. People can employ intentional strategies to prevent conscious intrusions of negative memories, and repeated attempts to stop retrieval both reduces the frequency of intrusions and improves subsequent emotions elicited by those memories. However, it is still unknown whether memory control can improve negative emotions immediately, at the time control is attempted. It is also not clear which strategy is most beneficial for emotion regulation; clearing the mind of any thoughts of negative memories via direct suppression, or substituting memory recall with alternative thoughts. Here, we provide novel evidence that memory control immediately regulates negative emotions associated with autobiographical memories of morally wrong actions. Repeated control significantly improved negative emotions over time, regardless of the strategy used to implement control. Thought substitution involving either positive diversionary thinking or counterfactual thinking both induced positive feelings, whereas direct suppression neutralised emotions, regardless of whether memories were positive or negative. These empirical findings have implications for clinical practice as they indicate that memory control strategies could be effective emotion regulation methods for real-world intrusive memories.

Association Between Digitally Provided Education and 90-Day Return to Sexual Activity Following Total Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: Contemporary total knee arthroplasty patients have increased expectations of returning to predisease function, including sexual activity (SA). The purpose of this study was to determine whether patients using a digital care management platform (DCMP) were more likely to have a higher rate and frequency of return to SA. METHODS: We conducted an exploratory analysis of a prospective, multicenter, randomized controlled trial that enrolled patients undergoing total knee arthroplasty. A total of 304 patients were randomized to a DCMP (n = 119) providing preoperative and postoperative education regarding return to SA or standard postoperative care (control group; n = 185). Return to SA, assessed via questionnaire, patient-reported outcome measures, Timed Up and Go test, single leg stance, active range of motion and need for manipulation under anesthesia were assessed at 90 days postoperatively. RESULTS: More patients in the DCMP group returned to SA compared to control at 90 days (58.4 versus 39.6%, P = .018); however, the control group resumed SA sooner (33.1 versus 42.0 days, P = .023). Patients who returned to SA were younger (61.6 versus 65.9 year), more often men (56 versus 35%) (P < .001), higher performing on the Timed Up and Go and single leg stance tests (P < .001), and had greater active range of motion (P = .007). There were no differences in patient-reported outcome measures or need for manipulation under anesthesia between patients that returned to SA and those who did not. CONCLUSIONS: More patients using a DCMP resumed SA at 90 days; however, patients in the control group returned to SA sooner. Those who returned to SA were younger, possessed greater physical function, and were more often men.

Everything you ever wanted to know about the Think/No-Think task, but forgot to ask.

The Think/No-Think (TNT) task has just celebrated 20 years since its inception, and its use has been growing as a tool to investigate the mechanisms underlying memory control and its neural underpinnings. Here, we present a theoretical and practical guide for designing, implementing, and running TNT studies. For this purpose, we provide a step-by-step description of the structure of the TNT task, methodological choices that can be made, parameters that can be chosen, instruments available, aspects to be aware of, systematic information about how to run a study and analyze the data. Importantly, we provide a TNT training package (as Supplementary Material), that is, a series of multimedia materials (e.g., tutorial videos, informative HTML pages, MATLAB code to run experiments, questionnaires, scoring sheets, etc.) to complement this method paper and facilitate a deeper understanding of the TNT task, its rationale, and how to set it up in practice. Given the recent discussion about the replication crisis in the behavioral sciences, we hope that this contribution will increase standardization, reliability, and replicability across laboratories.

Anterior Cingulate Cortex Signals the Need to Control Intrusive Thoughts during Motivated Forgetting.

How do people limit awareness of unwanted memories? When such memories intrude, a control process engages the right DLPFC (rDLPFC) to inhibit hippocampal activity and stop retrieval. It remains unknown how the need for control is detected, and whether control operates proactively to prevent unwelcome memories from being retrieved, or responds reactively, to counteract intrusions. We hypothesized that dorsal ACC (dACC) detects the emergence of an unwanted trace in awareness and transmits the need for inhibitory control to rDLPFC. During a memory suppression task, we measured in humans (both sexes) trial-by-trial variations in the theta power and N2 amplitude of dACC, two EEG markers that are thought to reflect the need for control. With simultaneous EEG-fMRI recordings, we tracked interactions among dACC, rDLPFC, and hippocampus during suppression. We found a clear role of dACC in detecting the need for memory control and upregulating prefrontal inhibition. Importantly, we identified distinct early (300-450 ms) and late (500-700 ms) dACC contributions, suggesting both proactive control before recollection and reactive control in response to intrusions. Stronger early activity was associated with reduced hippocampal activity and diminished BOLD signal in dACC and rDLPFC, suggesting that preempting retrieval reduced overall control demands. In the later window, dACC activity was larger, and effective connectivity analyses revealed robust communication from dACC to rDLPFC and from rDLPFC to hippocampus, which are tied to successful forgetting. Together, our findings support a model in which dACC detects the emergence of unwanted content, triggering top-down inhibitory control, and in which rDLPFC countermands intruding thoughts that penetrate awareness.SIGNIFICANCE STATEMENT Preventing unwanted memories from coming to mind is an adaptive ability of humans. This ability relies on inhibitory control processes in the prefrontal cortex to modulate hippocampal retrieval processes. How and when reminders to unwelcome memories come to trigger prefrontal control mechanisms remains unknown. Here we acquired neuroimaging data with both high spatial and temporal resolution as participants suppressed specific memories. We found that the anterior cingulate cortex detects the need for memory control, responding both proactively to early warning signals about unwelcome content and reactively to intrusive thoughts themselves. When unwanted traces emerge in awareness, anterior cingulate communicates with prefrontal cortex and triggers top-down inhibitory control over the hippocampus through specific neural oscillatory networks.