Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4ß7 in conventional T cells while preserving α4ß7 in regulatory T cells, with findings suggesting increased ß1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4ß7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.

Multidisciplinary Management of Cutaneous Gluteus Vaginal Fistula After Sacrospinous Ligament Fixation.

Introduction: Cutaneous gluteal vaginal fistula is a rare but significant postoperative complication which may present years after sacrospinous ligament fixation (SSLF) surgery There is limited data on the management of cutaneous vaginal fistula following SSLF. Case description: This case report describes a 77-year-old who presents twenty years after SSLF with cutaneous gluteal vaginal abscess and fistula. She underwent successful management with CT-guided percutaneous drainage of gluteal abscess and placement of guiding cutaneous vaginal catheter, laparoscopic pelvic wall dissection and evaluation, and transvaginal localization and removal of the infected permanent suture. Discussion: Multi-disciplinary approach should be considered in the treatment of chronic fistula status post SSLF, including interventional radiology, urogynecology, and minimally invasive gynecologic surgery.

Evaluation of a Multifaceted Protocol in Reducing Unnecessary Telemetry Monitoring across a Large Healthcare System.

OBJECTIVES: Telemetry is frequently overused in hospitals. The goal of this study was to evaluate a telemetry protocol aimed at decreasing inappropriate telemetry utilization across four different hospitals within a large healthcare system by modifying the electronic telemetry order to incorporate the 2017 American Heart Association practice guidelines on the appropriate use of telemetry and using an electronic nursing screening task form to safely discontinue telemetry. METHODS: We performed a retrospective analysis of telemetry utilization before and after we implemented a protocol across four hospitals within a large healthcare system. We compared the average number of days of telemetry monitoring and hospital length of stay during the preintervention period with the 6-month postintervention period. RESULTS: There were a total of 23,774 encounters evaluated. There was a statistically and clinically significant 24% decrease in telemetry duration between pre- and postintervention time periods (P < 0.0001). The mean (standard error) telemetry duration was 4.11 (0.17) and 2.36 (0.13) days in pre- and postintervention periods, respectively. CONCLUSIONS: The results of our study demonstrate a statistically significant decrease in overall duration of telemetry monitoring by nearly 1.75 days across each of the four hospitals with the implementation of a multifaceted telemetry protocol that included hardwiring the American Heart Association practice guidelines into the electronic order and using a nursing-driven discontinuation protocol.

Tuning pro-survival effects of human induced pluripotent stem cell-derived exosomes using elastin-like polypeptides.

Exosome-based regenerative therapies are potentially easier to manufacture and safer to apply compared to cell-based therapies. However, many questions remain about how to bio-manufacture reproducible and potent exosomes using animal-free reagents. Here we evaluate the hypothesis that designer biomaterial substrates can be used to alter the potency of exosomes secreted by human induced pluripotent stem cells (iPSCs). Two animal-free designer matrices were fabricated based on recombinant elastin-like polypeptides (ELPs): one including a cell-adhesive RGD ligand and a second with a non-adhesive RDG peptide. While iPSCs cultured on these two substrates and Matrigel-coated controls had similar levels of proliferation, the RDG-ELP substrate significantly increased protein expression of stemness markers OCT4 and SOX2 and suppressed spontaneous differentiation compared to those on RGD-ELP. The pro-survival potency of iPSC-derived exosomes was evaluated using three distinct stress tests: serum starvation in murine fibroblasts, hypoxia in human endothelial cells, and hyperosmolarity in canine kidney cells. In all three cases, exosomes produced by iPSCs grown on RDG-ELP substrates had similar pro-survival effects to those produced using iPSCs grown on Matrigel, while use of RGD-ELP substrates led to significantly reduced exosome potency. These data demonstrate that recombinant substrates can be designed for the robust bio-manufacturing of iPSC-derived, pro-survival exosomes.

Developing an Automated Assessment of In-session Patient Activation for Psychological Therapy: Codevelopment Approach.

BACKGROUND: Patient activation is defined as a patient's confidence and perceived ability to manage their own health. Patient activation has been a consistent predictor of long-term health and care costs, particularly for people with multiple long-term health conditions. However, there is currently no means of measuring patient activation from what is said in health care consultations. This may be particularly important for psychological therapy because most current methods for evaluating therapy content cannot be used routinely due to time and cost restraints. Natural language processing (NLP) has been used increasingly to classify and evaluate the contents of psychological therapy. This aims to make the routine, systematic evaluation of psychological therapy contents more accessible in terms of time and cost restraints. However, comparatively little attention has been paid to algorithmic trust and interpretability, with few studies in the field involving end users or stakeholders in algorithm development. OBJECTIVE: This study applied a responsible design to use NLP in the development of an artificial intelligence model to automate the ratings assigned by a psychological therapy process measure: the consultation interactions coding scheme (CICS). The CICS assesses the level of patient activation observable from turn-by-turn psychological therapy interactions. METHODS: With consent, 128 sessions of remotely delivered cognitive behavioral therapy from 53 participants experiencing multiple physical and mental health problems were anonymously transcribed and rated by trained human CICS coders. Using participatory methodology, a multidisciplinary team proposed candidate language features that they thought would discriminate between high and low patient activation. The team included service-user researchers, psychological therapists, applied linguists, digital research experts, artificial intelligence ethics researchers, and NLP researchers. Identified language features were extracted from the transcripts alongside demographic features, and machine learning was applied using k-nearest neighbors and bagged trees algorithms to assess whether in-session patient activation and interaction types could be accurately classified. RESULTS: The k-nearest neighbors classifier obtained 73% accuracy (82% precision and 80% recall) in a test data set. The bagged trees classifier obtained 81% accuracy for test data (87% precision and 75% recall) in differentiating between interactions rated high in patient activation and those rated low or neutral. CONCLUSIONS: Coproduced language features identified through a multidisciplinary collaboration can be used to discriminate among psychological therapy session contents based on patient activation among patients experiencing multiple long-term physical and mental health conditions.

A WHO key informant language survey of people with lived experiences of diabetes: Media misconceptions, values-based messaging, stigma, framings and communications considerations.

AIMS: This study aimed to learn from people with lived experiences of diabetes to raise the quality of diabetes communications. METHODS: An online key informant survey for people (18+) with a direct and/or adjacent (caregiver, friend, family-member etc.,) lived experience of diabetes. Through thematic analysis, we gathered insights on perceptions of media reporting on diabetes and communicating with accuracy, impact and without stigma. Descriptive analysis also investigated effective values for WHO to communicate diabetes with key audiences of policy-makers, funding partners and the general public. RESULTS: 918 respondents in 58 WHO Member States were analysed. Participants identified five key themes requiring more appropriate consideration in the media: accurately defining diabetes types, over-emphasis on sugar and lifestyle, negative impacts of diabetes stigma, burden of costs (financial, personal and interpersonal) and mental health. Irrespective of audience, key values-based messages identified as important for WHO to convey included: 'urgency', 'preventing suffering', 'improving wellbeing' and 'meaningful engagement' of people with lived experience. CONCLUSION: Learning from people with lived experience of diabetes identifies key diabetes communication considerations. Continued meaningful engagement of this group, including in WHO's work and the multistakeholder diffusion of this methodology to local contexts, could improve public discourse on diabetes and related policies.

The nutrition transition, food retail transformations, and policy responses to overnutrition in the East Asia region: A descriptive review.

BACKGROUND: The East Asia region is facing an increasing burden of overweight, obesity and related noncommunicable diseases, resulting from an ongoing nutrition transition. This study aimed to document the growing burden of overweight and obesity, and the accompanying dietary shifts, in the East Asia region and describe the policy responses to this. METHODS: We present noncommunicable disease risk factor collaboration data on trends in the burden of malnutrition, and Euromonitor International data on trends in dietary purchases, in the East Asia region. We searched the NOURISHING and GINA databases to identify food and nutrition policies implemented in these countries. RESULTS: There is an ongoing nutrition transition in the East Asia region, notably in upper-middle and lower-middle income countries. The prevalence of overweight, obesity, and accompanying health conditions, purchases of ultra-processed foods and beverages, and purchasing from supermarkets, fast-food and takeaway outlets, and other convenience retailers, are increasing. The policy response to this nutrition transition is limited, with the majority of policies implemented in higher-income countries. CONCLUSIONS: East Asian countries are facing a growing burden of malnutrition, due in part to the dietary shifts occurring here. An ecological approach to policy intervention is needed to drive transformative food systems change.

An Epidemic Supplanted by a Pandemic: Vaping-Related Illness and COVID-19.

Before the coronavirus disease 2019 (COVID-19) pandemic, vaping-related illness was the prevailing public health concern. The incidence of vaping-related illnesses-mainly e-cigarette, or vaping, product use-associated lung injury (EVALI)-went from a peak in September 2019 to a low in February 2020, and the Centers for Disease Control and Prevention decided to discontinue the collection of EVALI case reports. Despite the decrease in EVALI with the arrival of COVID-19, EVALI should still be considered a differential diagnosis for people with COVID-19 for reasons outlined in this review. This narrative review describes vaping devices, summarizes the adverse health effects of vaping on the lungs and other systems, considers the potential interplay between vaping and COVID-19, and highlights gaps in knowledge about vaping that warrant further research.

Social Semiotics of Gangstalking Evidence Videos on YouTube: Multimodal Discourse Analysis of a Novel Persecutory Belief System.

BACKGROUND: Gangstalking refers to a novel persecutory belief system wherein sufferers believe that they are being followed, watched, and harassed by a vast network of people in their community who have been recruited as complicit perpetrators. They are frequently diagnosed as mentally ill, although they reject this formulation. Those affected by this belief system self-identify as targeted individuals (TIs). They seek to prove the veracity of their persecution and dispute the notion that they are mentally ill by posting videos online that purport to provide evidence of their claims. OBJECTIVE: The objective of the study was to characterize the multimodal social semiotic practices used in gangstalking evidence videos. METHODS: We assembled a group of 50 evidence videos posted on YouTube by self-identified TIs and performed a multimodal social semiotic discourse analysis using a grounded theory approach to data analysis. RESULTS: TIs accomplished several social and interpersonal tasks in the videos. They constructed their own identity as subjects of persecution and refuted the notion that they suffered from mental illness. They also cultivated positive ambient affiliation with viewers of the videos but manifested hostility toward people who appeared in the videos. They made extensive use of multimodal deixis to generate salience and construe the gangstalking belief system. The act of filming itself was a source of conflict and served as a self-fulfilling prophecy; filming was undertaken to neutrally record hostility directed toward video bloggers (vloggers). However, the act of filming precipitated the very behaviors that they set out to document. Finally, the act of filming was also regarded as an act of resistance and empowerment by vloggers. CONCLUSIONS: These data provide insight into a novel persecutory belief system. Interpersonal concerns are important for people affected, and they construe others as either sympathetic or hostile. They create positive ambient affiliation with viewers. We found that vloggers use multimodal deixis to illustrate the salience of the belief system. The videos highlighted the Derridean concept of différance, wherein the meaning of polysemous signifiers is deferred without definitive resolution. This may be important in communicating with people and patients with persecutory belief systems. Clinicians may consider stepping away from the traditional true/false dichotomy endorsed by psychiatric classification systems and focus on the ambiguity in semiotic systems generally and in persecutory belief systems specifically.

Corporate political activity in the context of unhealthy food advertising restrictions across Transport for London: A qualitative case study.

BACKGROUND: Diets with high proportions of foods high in fat, sugar, and/or salt (HFSS) contribute to malnutrition and rising rates of childhood obesity, with effects throughout the life course. Given compelling evidence on the detrimental impact HFSS advertising has on children's diets, the World Health Organization unequivocally supports the adoption of restrictions on HFSS marketing and advertising. In February 2019, the Greater London Authority introduced novel restrictions on HFSS advertising across Transport for London (TfL), one of the most valuable out-of-home advertising estates. In this study, we examined whether and how commercial actors attempted to influence the development of these advertising restrictions. METHODS AND FINDINGS: Using requests under the Freedom of Information Act, we obtained industry responses to the London Food Strategy consultation, correspondence between officials and key industry actors, and information on meetings. We used an existing model of corporate political activity, the Policy Dystopia Model, to systematically analyse arguments and activities used to counter the policy. The majority of food and advertising industry consultation respondents opposed the proposed advertising restrictions, many promoting voluntary approaches instead. Industry actors who supported the policy were predominantly smaller businesses. To oppose the policy, industry respondents deployed a range of strategies. They exaggerated potential costs and underplayed potential benefits of the policy, for instance, warning of negative economic consequences and questioning the evidence underlying the proposal. Despite challenging the evidence for the policy, they offered little evidence in support of their own claims. Commercial actors had significant access to the policy process and officials through the consultation and numerous meetings, yet attempted to increase access, for example, in applying to join the London Child Obesity Taskforce and inviting its members to events. They also employed coalition management, engaging directly and through business associations to amplify their arguments. Some advertising industry actors also raised the potential of legal challenges. The key limitation of this study is that our data focused on industry-policymaker interactions; thus, our findings are unable to present a comprehensive picture of political activity. CONCLUSIONS: In this study, we identified substantial opposition from food and advertising industry actors to the TfL advertising restrictions. We mapped arguments and activities used to oppose the policy, which might help other public authorities anticipate industry efforts to prevent similar restrictions in HFSS advertising. Given the potential consequences of commercial influence in these kinds of policy spaces, public bodies should consider how they engage with industry actors.

Engineered Matrices Enable the Culture of Human Patient-Derived Intestinal Organoids.

Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer matrix, termed hyaluronan elastin-like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue-derived, epithelial-only intestinal organoids. HELP enables the encapsulation of dissociated patient-derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal-derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin-ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid-matrix interactions and potential patient-specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G' ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10-3-1 × 10-3 m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal-derived products or synthetic polyethylene glycol for potential clinical translation.

Linguistic Analysis of Online Communication About a Novel Persecutory Belief System (Gangstalking): Mixed Methods Study.

BACKGROUND: Gangstalking is a novel persecutory belief system whereby those affected believe they are being followed, stalked, and harassed by a large number of people, often numbering in the thousands. The harassment is experienced as an accretion of innumerable individually benign acts such as people clearing their throat, muttering under their breath, or giving dirty looks as they pass on the street. Individuals affected by this belief system congregate in online fora to seek support, share experiences, and interact with other like-minded individuals. Such people identify themselves as targeted individuals. OBJECTIVE: The objective of the study was to characterize the linguistic and rhetorical practices used by contributors to the gangstalking forum to construct, develop, and contest the gangstalking belief system. METHODS: This mixed methods study employed corpus linguistics, which involves using computational techniques to examine recurring linguistic patterns in large, digitized bodies of authentic language data. Discourse analysis is an approach to text analysis which focuses on the ways in which linguistic choices made by text creators contribute to particular functions and representations. We assembled a 225,000-word corpus of postings on a gangstalking support forum. We analyzed these data using keyword analysis, collocation analysis, and manual examination of concordances to identify discursive and rhetorical practices among self-identified targeted individuals. RESULTS: The gangstalking forum served as a site of discursive contest between 2 opposing worldviews. One is that gangstalking is a widespread, insidious, and centrally coordinated system of persecution employing community members, figures of authority, and state actors. This was the dominant discourse in the study corpus. The opposing view is a medicalized discourse supporting gangstalking as a form of mental disorder. Contributors used linguistic practices such as presupposition, nominalization, and the use of specialized jargon to construct gangstalking as real and external to the individual affected. Although contributors generally rejected the notion that they were affected by mental disorder, in some instances, they did label others in the forum as impacted/affected by mental illness if their accounts if their accounts were deemed to be too extreme or bizarre. Those affected demonstrated a concern with accumulating evidence to prove their position to incredulous others. CONCLUSIONS: The study found that contributors to the study corpus accomplished a number of tasks. They used linguistic practices to co-construct an internally coherent and systematized persecutory belief system. They advanced a position that gangstalking is real and contested the medicalizing discourse that gangstalking is a form of mental disorder. They supported one another by sharing similar experiences and providing encouragement and advice. Finally, they commiserated over the challenges of proving the existence of gangstalking.

Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8+ T cells drive gastrointestinal acute graft-versus-host disease.

Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8+ T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8+ T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (TRM) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules (ITGB2), specific chemokines (CCL3 and CCL4L1) and chemokine receptors (CD74), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8+ T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8+ TRM cells during aGVHD in primate transplant recipients.

Management of Refractory Breathlessness: a Review for General Internists.

Internists frequently care for patients who suffer from breathlessness in both the inpatient and the outpatient settings. Patients may experience chronic refractory breathlessness despite thorough evaluation and management of their underlying medical illnesses. Left unmanaged, chronic breathlessness is associated with worsened quality of life, more frequent visits to the emergency room, and decreased activity levels, as well as increased levels of depression and anxiety. This narrative review summarizes recent research on interventions for the relief of breathlessness, including both non-pharmacologic and pharmacologic options.

How food companies use social media to influence policy debates: a framework of Australian ultra-processed food industry Twitter data.

OBJECTIVE: To understand if, and how, Australian ultra-processed food industry actors use Twitter to influence food and health policy debates and produce a conceptual framework to describe such influence. DESIGN: Twitter data of prominent industry actors were defined through purposive sampling and inductively coded to investigate possible influence on food and health policy debates. These are described using descriptive statistics and coded extracts. SETTING: Australia. PARTICIPANTS: Twitter accounts of nine prominent ultra-processed food industry actors, including major trade associations. RESULTS: Ultra-processed food industry actors actively used Twitter to influence food and health policy debates. Seven overarching strategies were identified: co-opting public health narratives; opposing regulation; supporting voluntary, co- or self-regulation; engaging policy processes and decision-makers; linking regulatory environments to the need for ongoing profitability; affecting public perceptions and value judgements; and using ignorance claims to distort policy narratives. Each lobbying strategy is underpinned with tactics described throughout and captured in a framework. CONCLUSIONS: The current study creates a framework to monitor how food industry actors can use social media to influence food and health policy debates. As such, social media appears to be not only an important commercial determinant of health for brand marketing, but also an extension of lobbying practices to reshape public perceptions of corporate conduct and policy-making.

IL-2 enhances ex vivo-expanded regulatory T-cell persistence after adoptive transfer.

As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin inhibition can increase the stability of thymic Tregs. In this study, we investigated the transcriptomic signatures of ex vivo-expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a nonhuman primate (NHP) model as a prelude to future transplant studies. Here, we found that adding interleukin-2 (IL-2) to rapamycin in vivo supported a logarithmic increase in the half-life of adoptively transferred carboxyfluorescein diacetate succinimidyl ester-labeled, autologous NHP Tregs, effectively doubling the number of cells in the peripheral blood Treg compartment compared with Treg infusion when rapamycin was given alone. Using single-cell transcriptomics, we found that transferred ex vivo-expanded Tregs initially exhibit a gene expression signature consistent with an activated state. Moreover, those cells with the highest levels of activation also expressed genes associated with p53-mediated apoptosis. In contrast, transferred Tregs interrogated at day +20 posttransfer demonstrated a gene signature more similar to published profiles of resting Tregs. Together, these preclinical data further support combining IL-2 and rapamycin in vivo as adjunctive therapy for ex vivo-expanded adoptively transferred Tregs and suggest that the activation status of ex vivo-expanded Tregs is critical to their persistence.