Tumour budding as a prognostic biomarker in biopsies and resections of neoadjuvant-treated rectal adenocarcinoma.

BACKGROUND: Tumour budding (TB) is a marker of tumour aggressiveness which, when measured in rectal cancer resection specimens, predicts worse outcomes and response to neoadjuvant therapy. We investigated the utility of TB assessment in the setting of neoadjuvant treatment. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted. TB was assessed using the hot-spot International Tumour Budding Consortium (ITBCC) method and classified by the revised ITBCC criteria. Haematoxylin and eosin (H&E) and AE1/AE3 cytokeratin (CK) stains for ITB (intratumoural budding) in biopsies with PTB (peritumoural budding) and ITB (intratumoural budding) in resection specimens were compared. Logistic regression assessed budding as predictors of lymph node metastasis (LNM). Cox regression and Kaplan-Meier analyses investigated their utility as a predictor of disease-free (DFS) and overall (OS) survival. A total of 146 patients were included; 91 were male (62.3%). Thirty-seven cases (25.3%) had ITB on H&E and 79 (54.1%) had ITB on CK assessment of biopsy tissue. In univariable analysis, H&E ITB [odds (OR) = 2.709, 95% confidence interval (CI) = 1.261-5.822, P = 0.011] and CK ITB (OR = 2.165, 95% CI = 1.076-4.357, P = 0.030) predicted LNM. Biopsy-assessed H&E ITB (OR = 2.749, 95% CI = 1.258-6.528, P = 0.022) was an independent predictor of LNM. In Kaplan-Meier analysis, ITB identified on biopsy was associated with worse OS (H&E, P = 0.003, CK: P = 0.009) and DFS (H&E, P = 0.012; CK, P = 0.045). In resection specimens, CK PTB was associated with worse OS (P = 0.047), and both CK PTB and ITB with worse DFS (PTB, P = 0.014; ITB: P = 0.019). In multivariable analysis H&E ITB predicted OS (HR = 2.930, 95% CI = 1.261-6.809) and DFS (HR = 2.072, 95% CI = 1.031-4.164). CK PTB grading on resection also independently predicted OS (HR = 3.417, 95% CI = 1.45-8.053, P = 0.005). CONCLUSION: Assessment of TB using H&E and CK may be feasible in rectal cancer biopsy and post-neoadjuvant therapy-treated resection specimens and is associated with LNM and worse survival outcomes. Future management strategies for rectal cancer might be tailored to incorporate these findings.

Face and context integration in emotion inference is limited and variable across categories and individuals.

The ability to make nuanced inferences about other people's emotional states is central to social functioning. While emotion inferences can be sensitive to both facial movements and the situational context that they occur in, relatively little is understood about when these two sources of information are integrated across emotion categories and individuals. In a series of studies, we use one archival and five empirical datasets to demonstrate that people could be integrating, but that emotion inferences are just as well (and sometimes better) captured by knowledge of the situation alone, while isolated facial cues are insufficient. Further, people integrate facial cues more for categories for which they most frequently encounter facial expressions in everyday life (e.g., happiness). People are also moderately stable over time in their reliance on situational cues and integration of cues and those who reliably utilize situation cues more also have better situated emotion knowledge. These findings underscore the importance of studying variability in reliance on and integration of cues.

Aberrant cognitive empathy in individuals with elevated social anxiety and regulation with emotional working memory training.

Social anxiety may disrupt the empathic process, and well-regulated empathy is critical for navigating the social world. Two studies aimed to further understand empathy in the context of social anxiety. Study 1 compared individuals with elevated or normative social anxiety on a measure assessing cognitive and affective empathy for positive and negative emotions conveyed by other people ("targets"), completed under social threat. Relative to individuals with normative social anxiety, individuals with elevated social anxiety had greater cognitive empathy and no differences in affective empathy, regardless of emotion type. As greater cognitive empathy can be maladaptive, Study 2 tested whether this could be down-regulated. Individuals with elevated social anxiety underwent emotional working memory training (eWMT) for negative emotional information, or control training (CT). Effects on an empathy measure completed under social threat were assessed. Cognitive empathy for negative emotions decreased following eWMT but not CT, and this was only evident for those with higher pre-training working memory capacity. Cognitive empathy for positive emotions and affective empathy were not affected. Overall, social anxiety is associated with aberrant elevated cognitive empathy for negative and positive emotions, and the deviation in cognitive empathy for negative emotions can be regulated with eWMT for certain individuals.Trial registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12618001196235..

Combining experiment and energy landscapes to explore anaerobic heme breakdown in multifunctional hemoproteins.

To survive, many pathogens extract heme from their host organism and break down the porphyrin scaffold to sequester the Fe2+ ion via a heme oxygenase. Recent studies have revealed that certain pathogens can anaerobically degrade heme. Our own research has shown that one such pathway proceeds via NADH-dependent heme degradation, which has been identified in a family of hemoproteins from a range of bacteria. HemS, from Yersinia enterocolitica, is the main focus of this work, along with HmuS (Yersinia pestis), ChuS (Escherichia coli) and ShuS (Shigella dysenteriae). We combine experiments, Energy Landscape Theory, and a bioinformatic investigation to place these homologues within a wider phylogenetic context. A subset of these hemoproteins are known to bind certain DNA promoter regions, suggesting not only that they can catalytically degrade heme, but that they are also involved in transcriptional modulation responding to heme flux. Many of the bacterial species responsible for these hemoproteins (including those that produce HemS, ChuS and ShuS) are known to specifically target oxygen-depleted regions of the gastrointestinal tract. A deeper understanding of anaerobic heme breakdown processes exploited by these pathogens could therefore prove useful in the development of future strategies for disease prevention.

The Attachment Mapping Protocol (AMP): An Assessment and Treatment Tool for General Psychotherapy, Systemic Family Therapy and Multifaith Spiritual Care.

This paper introduces the Attachment Mapping Protocol (AMP), which is an assessment and treatment tool for use in individual psychotherapy, systemic family therapy and multifaith spiritual care, using a bio-psycho-social-spiritual model of care. Attachment theory has a long and significant history in psychology, with an evolving relationship within the above clinical domains. A central aim of this paper will be to recognize and affirm the extension of attachment theory beyond the traditional parameters of nascent parental, guardianship bonds and individual, developmental psychology, to reveal a much broader spectrum of valid attachment considerations for mental health and spiritual well-being. A case study will be applied to the interviewing instrument to demonstrate its utility for broadening assessment beyond attachment figures to include surrogate attachments of other persons, places and things. A model of spiritual discernment derived from the Spiritual Exercises of Ignatius of Loyola will undergird this larger worldview of attachment considerations.

Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

Socio-demographic and neighbourhood factors influencing urban green space use and development at home: A population-based survey in Accra, Ghana.

In Sub-Saharan Africa and other developing regions, there has been very little systematic attempt to document the uses and perceived health benefits of urban green spaces in cities and the factors influencing usage. We therefore sought to establish the availability, accessibility and use of urban green spaces, and the perceived health benefits in an African population. We also ascertained the factors influencing use and development of green spaces at home. A population-based survey was conducted in Accra, the capital city of Ghana, spanning 11 Municipal and 3 Sub-Metropolitan areas. Multivariable binary logistic regression adjusting for potential confounders was used to establish the association between green space use and development at home, and socio-demographic, neighbourhood and health factors. Odds ratios and their corresponding 95% confidence intervals were estimated from the models. Several socio-demographic (gender, age, marital status, occupation, ethnicity, religion) and district-level (population density, income level, neighbourhood greenness) factors were associated with use of green spaces and development of green spaces at home in Accra. Residents who were worried about depletion of green spaces in their community were more likely to develop green spaces at home. In neighbourhoods with moderate and high level of greenness, residents were less likely to develop green spaces at home. Five-percent and 47% of green space users in Accra reported witnessing an improvement in their physical and mental health, respectively, from use of green spaces. The study findings can inform policy action for promoting use and development of green spaces in African cities and for mitigating depletion and degradation of the limited urban greenery.

Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin.

BACKGROUND: Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. OBJECTIVES: To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. METHODS: We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. RESULTS: Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1ß and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1ß and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation. CONCLUSIONS: These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.

Comparison of Incremental Costs and Medicare Reimbursement for Simple vs Complex Cataract Surgery Using Time-Driven Activity-Based Costing.

Importance: Cataract surgery is one of the most commonly performed surgeries across medicine and an integral part of ophthalmologic care. Complex cataract surgery requires more time and resources than simple cataract surgery, yet it remains unclear whether the incremental reimbursement for complex cataract surgery, compared with simple cataract surgery, offsets the increased costs. Objective: To measure the difference in day-of-surgery costs and net earnings between simple and complex cataract surgery. Design, Setting, and Participants: This study is an economic analysis at a single academic institution using time-driven activity-based costing methodology to determine the operative-day costs of simple and complex cataract surgery. Process flow mapping was used to define the operative episode limited to the day of surgery. Simple and complex cataract surgery cases (Current Procedural Terminology codes 66984 and 66982, respectively) at the University of Michigan Kellogg Eye Center from 2017 to 2021 were included in the analysis. Time estimates were obtained using an internal anesthesia record system. Financial estimates were obtained using a mix of internal sources and prior literature. Supply costs were obtained from the electronic health record. Main Outcomes and Measures: Difference in day-of-surgery costs and net earnings. Results: A total of 16 092 cataract surgeries were included, 13 904 simple and 2188 complex. Time-based day-of-surgery costs for simple and complex cataract surgery were $1486.24 and $2205.83, respectively, with a mean difference of $719.59 (95% CI, $684.09-$755.09; P < .001). Complex cataract surgery required $158.26 more for costs of supplies and materials (95% CI, $117.00-$199.60; P < .001). The total difference in day-of-surgery costs between complex and simple cataract surgery was $877.85. Incremental reimbursement for complex cataract surgery was $231.01; therefore, complex cataract surgery had a negative earnings difference of $646.84 compared with simple cataract surgery. Conclusions and Relevance: This economic analysis suggests that the incremental reimbursement for complex cataract surgery undervalues the resource costs required for the procedure, failing to cover increased costs and accounting for less than 2 minutes of increased operating time. These findings may affect ophthalmologist practice patterns and access to care for certain patients, which may ultimately justify increasing cataract surgery reimbursement.

Rates and outcomes of testing for lynch syndrome in a national colorectal cancer screening programme.

BACKGROUND: Lynch Syndrome (LS), the most common cause of hereditary colorectal cancer (CRC), is characterised by pathogenic variants in mismatch repair (MMR) genes. Universal testing of all CRCs for LS can increase detection. Rates and outcomes of testing in Ireland's national CRC screening programme have not been examined previously. METHODS: CRCs diagnosed at two screening sites between 2015 and 2020 were identified. Patient records were used to determine if CRCs had been tested for MMR deficiency and if detected, what downstream testing to rule out LS or genetic testing to confirm LS was undertaken. RESULTS: Over five years, 206 CRCs were diagnosed. Testing for LS was carried out for 100% of CRCs at site A and 69% of CRCs at site B. Of CRCs tested for LS, 14 (8%) were MMR deficient. After downstream testing for BRAF mutation or hypermethylation of MLH1, three CRCs were identified as potentially LS-related. Of these two individuals declined genetic testing and one was lost to follow-up. CONCLUSIONS: By 2020 both sites had implemented universal testing of all CRCs for LS. A small number of individuals were identified as being eligible for genetic testing for LS, however those offered declined testing and one individual was lost to follow up. This highlights the importance of universal testing and the need for referral pathways to ensure all appropriate individuals are referred onwards to genetic services.

Investigating Formate, Sulfate, and Halide Anions in Reversible Zinc Electrodeposition Dynamic Windows.

Reversible metal electrodeposition (RME) is an emerging and promising method for designing dynamic windows with electrically controllable transmission, excellent color neutrality, and wide dynamic range. Zn is a viable option for metal-based dynamic windows due to its fast switching kinetics and reversibility despite its very negative deposition voltage. In this manuscript, we study the effect of the supporting electrolyte anions for Zn electrodeposition on transparent tin-doped indium oxide. Through systematic additions or removal of components of the electrolytes, we are able to establish a link between the anions and the effectiveness of Zn RME. This insight allows us to design practical two-electrode 25 cm2 Zn dynamic windows that switch to <1% within 20 s. Lastly, we demonstrate that the accumulation of Zn(OH)2 species on the working electrode degrades the optical contrast of Zn windows during long-term cycling. However, the elimination of these species through acid immersion allows the windows to cycle at least 500 times. Reversible Zn electrodeposition in the presence of a polyethylene glycol additive further improves the cycle life to greater than 1000 cycles. Taken together, these studies highlight important design principles for the construction of robust dynamic windows based on Zn RME.

Real-world effectiveness of a social-psychological intervention translated from controlled trials to classrooms.

Social-psychological interventions have raised the learning and performance of students in rigorous efficacy trials. Yet, after they are distributed "in the wild" for students to self-administer, there has been little research following up on their translational effectiveness. We used cutting-edge educational technology to tailor, scale up, and track a previously-validated Strategic Resource Use intervention among 12,065 college students in 14 STEM and Economics classes. Students who self-administered this "Exam Playbook" benefitted by an average of 2.17 percentage points (i.e., a standardized effect size of 0.18), compared to non-users. This effect size was 1.65 percentage points when controlling for college entrance exam scores and 1.75 [-1.88] for adding [dropping] the Exam Playbook in stratified matching analyses. Average benefits differed in magnitude by the conduciveness of the class climate (including peer norms and incentives), gender, first-generation status, as well as how often and how early they used the intervention. These findings on how, when, and who naturally adopts these resources address a need to improve prediction, translation, and scalability of social-psychological intervention benefits.

A systematic study of microplastic occurrence in urban water networks of a metropolis.

The release of microplastics from sewage treatment works (STWs) into the oceans around coastal cities is well documented. However, there are fewer studies on the microplastic abundance in stormwater drains and their emissions into the coastal marine environment via sewage and stormwater drainage networks. Here, we comprehensively investigated microplastic abundance in 66 sewage and 18 sludge samples collected from different process stages at three typical STWs and 36 water samples taken from six major stormwater drains during the dry and wet seasons in Hong Kong, which is a metropolitan city in south China. The results showed that microplastics were detected in all the sewage and stormwater samples, with the abundance ranging from 0.07 to 91.9 and from 0.4 to 36.48 particles/L, respectively, and in all the sludge samples with the abundance ranging from 167 to 936 particles/g (d. w.). There were no significant seasonal variations in the microplastic abundance across all samples of sewage, sludge, and stormwater. For both waterborne sample types, a smaller size (0.02-0.3 mm) and fiber shape were the dominant characteristics of the microplastics. Polyethylene terephthalate (PET) and polypropylene (PP) were the most abundant polymer types in the sewage samples, while polyethylene (PE), PET, PP, and PE-PP copolymer were the most abundant polymer types in the stormwater samples. The estimated range of total daily microplastic loads in the effluent from STWs in Hong Kong is estimated to be 4.48 × 109 - 2.68 × 1010 particles/day, demonstrating that STWs are major pathways of microplastics in coastal environments despite the high removal percentage of microplastics in sewage treatment processes examined. This is the first comprehensive study on microplastics in the urban waters of a coastal metropolis. However, further studies on other coastal cities will enable an accurate estimation of the microplastic contribution of stormwater drains to the world's oceans.

Implications of the presence of private equity in ophthalmology: an academic perspective.

PURPOSE OF REVIEW: Private equity acquisitions of ophthalmology private practices have been steadily increasing over the past decade with far-reaching implications. Ophthalmology departments at academic medical centers are not insulated from the impact of this trend. RECENT FINDINGS: The limited data on this subject in the ophthalmology literature identify the growing number of practice acquisitions. However, the lack of transparency obfuscates a clear understanding of the effect on patients and practice patterns. SUMMARY: Leaders at academic medical centers need to be aware of surrounding practice consolidation because of private equity as this could affect revenue streams and patient referral patterns, accelerating expansion. Trainees are entering an uncertain job marketplace that may create a compelling argument to practice in an academic medical center ophthalmology department.

A brief intervention to motivate empathy among middle school students.

Empathy tracks socioemotional adjustment during early adolescence, yet adolescents this age tend to show reductions in empathy compared with younger children. Here we took a novel approach to building empathy among early adolescents in four middle schools (n = 857). Rather than addressing the ability to empathize, we targeted the motivation to empathize. To do so, we leveraged strategies demonstrated to change motivation among early adolescents: social norms and mindsets. Compared with those in other conditions, students who received a norms-based intervention reported greater motivation to empathize with others, which was in turn associated with increased peer-reported prosocial behaviors, as well as lower levels of loneliness and aggression. The effects of this norms condition were strongest at schools with relatively high engagement with the intervention. Findings suggest a novel avenue for increasing empathy among early adolescents-focusing on peer-driven motivation-and underscore the importance of context in shaping intervention outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Amplification in the evaluation of multiple emotional expressions over time.

Social interactions are dynamic and unfold over time. To make sense of social interactions, people must aggregate sequential information into summary, global evaluations. But how do people do this? Here, to address this question, we conducted nine studies (N = 1,583) using a diverse set of stimuli. Our focus was a central aspect of social interaction-namely, the evaluation of others' emotional responses. The results suggest that when aggregating sequences of images and videos expressing varying degrees of emotion, perceivers overestimate the sequence's average emotional intensity. This tendency for overestimation is driven by stronger memory of more emotional expressions. A computational model supports this account and shows that amplification cannot be explained only by nonlinear perception of individual exemplars. Our results demonstrate an amplification effect in the perception of sequential emotional information, which may have implications for the many types of social interactions that involve repeated emotion estimation.

Mu rhythm suppression over sensorimotor regions is associated with greater empathic accuracy.

When people encounter others' emotions, they engage multiple brain systems, including parts of the sensorimotor cortex associated with motor simulation. Simulation-related brain activity is commonly described as a 'low-level' component of empathy and social cognition. It remains unclear whether and how sensorimotor simulation contributes to complex empathic judgments. Here, we combine a naturalistic social paradigm with a reliable index of sensorimotor cortex-based simulation: electroencephalography suppression of oscillatory activity in the mu frequency band. We recruited participants to watch naturalistic video clips of people ('targets') describing emotional life events. In two experiments, participants viewed these clips (i) with video and sound, (ii) with only video or (iii) with only sound and provided continuous ratings of how they believed the target felt. We operationalized 'empathic accuracy' as the correlation between participants' inferences and targets' self-report. In Experiment 1 (US sample), across all conditions, right-lateralized mu suppression tracked empathic accuracy. In Experiment 2 (Israeli sample), this replicated only when using individualized frequency-bands and only for the visual stimuli. Our results provide novel evidence that sensorimotor representations-as measured through mu suppression-play a role not only in low-level motor simulation, but also in higher-level inferences about others' emotions, especially when visual cues are crucial for accuracy.