The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors.

Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.

Correlates of Mild Behavioral Impairment in Older Adults: Protocol for a Scoping Review.

BACKGROUND: Understanding mild behavioral impairment, a relatively recent notion in neuropsychological studies, provides significant insights into early behavioral indicators of cognitive decline and predicts the onset of dementia in older adults. Although the importance of understanding mild behavioral impairment is acknowledged, comprehensive reviews of its correlates with older adults are limited. OBJECTIVE: This scoping review aims to identify the impact of mild behavioral impairment on health outcomes in older adults and the factors associated with mild behavioral impairment. METHODS: The review will adhere to the Joanna Briggs Institute's methodological principles for scoping reviews. We will include studies focusing mainly on mild behavioral impairment in older adults, with the literature on this topic being limited to the period from 2003 to the present. Other clinical diagnoses, such as cognitive impairment, Parkinson disease, and multiple sclerosis, will not be included. We will use databases including PubMed (MEDLINE), CINAHL, Web of Science, Embase, PsycINFO, Cochrane, and Scopus for relevant articles published in English. Both gray literature and peer-reviewed articles will be considered during screening. Three independent reviewers will extract data using a predefined data extraction tool. Extracted data will be presented using tables, figures, and a narrative summary aligned with review questions, accompanied by an analysis of study characteristics and categorization of mild behavioral impairment correlates. RESULTS: The results will be presented as a descriptive summary, structured according to the associated factors related to mild behavioral impairment, and the health outcomes. Additionally, the data on study characteristics will be presented in tabular format. An exploratory search was conducted in July 2023 to establish a comprehensive search strategy, and iterative refinements to the scoping review protocol and formalization of methods were completed. A follow-up search is planned for May 2024, with the aim of submitting the findings for publication in peer-reviewed journals. CONCLUSIONS: To our knowledge, this would be the first study to map the literature on the health-related factors and outcomes of mild behavioral impairment. The findings will support the development of interventions to prevent the occurrence of mild behavioral impairment and mitigate the negative outcomes of mild behavioral impairment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/60009.

Development of a High-Throughput Pipeline to Characterize Microglia Morphological States at a Single-Cell Resolution.

As rapid responders to their environments, microglia engage in functions that are mirrored by their cellular morphology. Microglia are classically thought to exhibit a ramified morphology under homeostatic conditions which switches to an ameboid form during inflammatory conditions. However, microglia display a wide spectrum of morphologies outside of this dichotomy, including rod-like, ramified, ameboid, and hypertrophic states, which have been observed across brain regions, neurodevelopmental timepoints, and various pathological contexts. We applied dimensionality reduction and clustering to consider contributions of multiple morphology measures together to define a spectrum of microglial morphological states in a mouse dataset that we used to demonstrate the utility of our toolset. Using ImageJ, we first developed a semiautomated approach to characterize 27 morphology features from hundreds to thousands of individual microglial cells in a brain region-specific manner. Within this pool of features, we defined distinct sets of highly correlated features that describe different aspects of morphology, including branch length, branching complexity, territory span, and circularity. When considered together, these sets of features drove different morphological clusters. Our tools captured morphological states similarly and robustly when applied to independent datasets and using different immunofluorescent markers for microglia. We have compiled our morphology analysis pipeline into an accessible, easy-to-use, and fully open-source ImageJ macro and R package that the neuroscience community can expand upon and directly apply to their own analyses. Outcomes from this work will supply the field with new tools to systematically evaluate the heterogeneity of microglia morphological states across various experimental models and research questions.

Mapping Strategies for Reaching Socioeconomically Disadvantaged Populations in Clinical Trials.

Importance: Socioeconomically disadvantaged patients, such as persons with low income and those with low educational attainment, are less likely to participate in clinical trials than those with higher earnings and higher educational attainment, despite the former being more likely to have chronic medical conditions. Ways to improve the representation of socioeconomically disadvantaged patients in clinical trials deserve attention. Objective: To examine whether current recruitment and enrollment strategies used by US clinical research sites appropriately include patients from socioeconomically disadvantaged backgrounds. Design, Setting, and Participants: This survey study was conducted between April and July 2023. An online survey was distributed among US clinical research sites to explore their use of these strategies and the types of patient sociodemographic and socioeconomic data they collect. The survey was distributed by 13 pharmaceutical companies and 1 clinical research organization. Eight targeted strategies known to increase the recruitment and retention of socioeconomically disadvantaged participants as well as 6 general strategies to recruit and retain clinical trial participants were identified. Data analysis was performed between August and September 2023. Main Outcomes and Measures: Proportions of for-profit vs nonprofit or governmental sites that use recruitment and retention strategies, proportions that have partnerships with community organizations that target socioeconomically disadvantaged groups, and the distribution of sociodemographic and socioeconomic data collected by sites about their patients. A χ2 test of independence was performed to assess the association between research site ownership type and levels of adoption of strategies. Results: A total of 492 responses were collected from 381 clinical research sites in the US (219 for-profit sites [57.5%] and 162 nonprofit or governmental sites [42.5%]). Overall, compared with nonprofit or governmental sites, for-profit sites reported higher use of strategies shown to increase the recruitment and retention of socioeconomically disadvantaged populations, including always or often providing after-hours visits (84 of 173 for-profit sites [48.6%]; 22 of 123 nonprofit or governmental sites [17.9%]) and offering financial compensation (135 of 162 for-profit sites [83.3%]; 60 of 123 nonprofit or governmental sites [48.8%]). Additionally, there was an association between research site ownership type and levels of adoption of these strategies; for example, for-profit sites were more likely to provide after-hours visits (χ2 = 30.33; P < .001) and offer financial compensation (χ2 = 49.35; P < .001). Only 7.2% of for-profit sites (12 of 167) and 13.0% of nonprofit or governmental sites (16 of 123) collected information on the patient's annual income. Conclusions and Relevance: In this survey study, we found an association between a clinical research site's ownership type (for-profit vs nonprofit or governmental) and how often it used strategies to engage socioeconomically diverse populations in clinical research. Regardless of ownership type, most clinical research sites did not collect socioeconomic information from patients. Adoption of strategies to engage socioeconomically diverse populations, particularly by nonprofit or governmental sites, may help minimize barriers to participation for socioeconomically disadvantaged patients.

Gender differences in the association between transitions in depressive symptoms and oral health among older adults with chronic conditions.

BACKGROUND: Oral health influences the quality of life of older adults. Further, depression is negatively associated with oral health. However, little is known about this relationship among older adults with chronic health conditions. Additionally, since oral health and depression differ between genders, this study aimed to investigate the effect of transitions in depressive symptoms on oral health among older adults with chronic health conditions by gender. METHODS: We used data from the Korean Longitudinal Study of Aging (2020-2022). The study sample comprised 2836 older adults (1104 men; 1732 women). We adopted multiple linear regression to examine the association between depressive symptom transitions and oral health by gender. RESULTS: The new onset depression symptoms were significantly associated with the deterioration of oral health in men (ß = -5.4308) and women (ß = -4.8328). Our study showed a gender-specific association between new onset depressive symptoms and particular domains of oral health. For men, the association was slightly more negative in psychosocial function (ß = -2.1177) while women presented lower GOHAI scores in both the physical function domain (ß = -1.8800) and the psychosocial function domain (ß = -1.8801). LIMITATIONS: The data used in this study were self-reported via a survey; thus, self-report bias may be a relevant concern. CONCLUSION: To prevent deterioration in oral health, depressive symptoms must be detected and addressed early among older adults with chronic conditions. This study underscores the importance of interventions that consider gender differences in the association between depressive symptoms and psychosocial and physical functioning.

Patient Perspectives on AI-Driven Predictions of Schizophrenia Relapses: Understanding Concerns and Opportunities for Self-Care and Treatment.

Early detection and intervention for relapse is important in the treatment of schizophrenia spectrum disorders. Researchers have developed AI models to predict relapse from patient-contributed data like social media. However, these models face challenges, including misalignment with practice and ethical issues related to transparency, accountability, and potential harm. Furthermore, how patients who have recovered from schizophrenia view these AI models has been underexplored. To address this gap, we first conducted semi-structured interviews with 28 patients and reflexive thematic analysis, which revealed a disconnect between AI predictions and patient experience, and the importance of the social aspect of relapse detection. In response, we developed a prototype that used patients' Facebook data to predict relapse. Feedback from seven patients highlighted the potential for AI to foster collaboration between patients and their support systems, and to encourage self-reflection. Our work provides insights into human-AI interaction and suggests ways to empower people with schizophrenia.

Novel extracellular matrix architecture on excitatory neurons revealed by HaloTag-HAPLN1.

The brain's extracellular matrix (ECM) regulates neuronal plasticity and animal behavior. ECM staining shows an aggregated pattern in a net-like structure around a subset of neurons and diffuse staining in the interstitial matrix. However, understanding the structural features of ECM deposition across various neuronal types and subcellular compartments remains limited. To visualize the organization pattern and assembly process of the hyaluronan-scaffolded ECM in the brain, we fused a HaloTag to HAPLN1, which links hyaluronan and proteoglycans. Expression or application of the probe enables us to identify spatial and temporal regulation of ECM deposition and heterogeneity in ECM aggregation among neuronal populations. Dual-color birthdating shows the ECM assembly process in culture and in vivo. Sparse expression in vivo reveals novel forms of ECM architecture around excitatory neurons and developmentally regulated dendritic ECM. Overall, our study uncovers extensive structural features of the brain' ECM, suggesting diverse roles in regulating neuronal plasticity.

Prognostic Implications of Early Prediction in Posttraumatic Epilepsy.

Posttraumatic epilepsy (PTE) is a complication of traumatic brain injury that can increase morbidity, but predicting which patients may develop PTE remains a challenge. Much work has been done to identify a variety of risk factors and biomarkers, or a combination thereof, for patients at highest risk of PTE. However, several issues have hampered progress toward fully adapted PTE models. Such issues include the need for models that are well-validated, cost-effective, and account for competing outcomes like death. Additionally, while an accurate PTE prediction model can provide quantitative prognostic information, how such information is communicated to inform shared decision-making and treatment strategies requires consideration of an individual patient's clinical trajectory and unique values, especially given the current absence of direct anti-epileptogenic treatments. Future work exploring approaches integrating individualized communication of prediction model results are needed.

The efficacy of medical management of leiomyoma-associated heavy menstrual bleeding: a mini review.

Leiomyomas, or fibroids, are benign uterine tumors that are commonly associated with abnormal uterine bleeding-L particularly heavy menstrual bleeding (HMB). Treatment options include expectant, medical, image-guided, and surgical. Medical management of HMB is the preferred first-line treatment and includes nonsteroidal anti-inflammatory drugs, contraceptive hormones, tranexamic acid, levonorgestrel intrauterine system, gonadotropin-releasing hormone (GnRH) antagonists and antagonists, selective progesterone receptor modulators, selective estrogen receptor modulators, and aromatase inhibitors. Although alternatives such as vitamins and supplements have been suggested, there is currently a lack of robust evidence of their efficacy. Many of these therapies treat the symptoms rather than the underlying pathology. Progestin-based therapies are the most commonly utilized, although research supporting their effectiveness in the treatment of HMB is modest. Although GnRH agonists and antagonists, which are federal drug administration-approved therapies, provide substantial improvement in abnormal uterine bleeding-L with HMB, the effects typically last for the duration of therapy. Patients may also face financial barriers to GnRH analog therapy. Future studies are required to delineate the nonhormonal treatment options and the long-term management of leiomyoma-associated HMB.

APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aß, through P2RY12.

Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer's disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter. To study microglia surveillance, we imaged microglia baseline motility for 20 min and measured the extension and retraction of processes. We found that APOE4 microglia exhibited significantly less brain surveillance (27%) compared to APOE3 microglia in 6-month-old mice; aging exacerbated this deficit. To measure microglia response to damage, we imaged process motility in response to ATP, an injury-associated signal, for 30 min. We found APOE4 microglia extended their processes significantly slower (0.9 µm/min, p < 0.005) than APOE3 microglia (1.1 µm/min) in 6-month-old animals. APOE-associated alterations in microglia motility were observed in 12- and 21-month-old animals, and this effect was exacerbated with aging in APOE4 microglia. We measured protein and mRNA levels of P2RY12, a core microglial receptor required for process movement in response to damage. We found that APOE4 microglia express significantly less P2RY12 receptors compared to APOE3 microglia despite no changes in P2RY12 transcripts. To examine if the effect of APOE4 on the microglial response to ATP also applied to amyloid ß (Aß), we infused locally Hi-Lyte Fluor 555-labeled Aß in acute brain slices of 6-month-old mice and imaged microglia movement for 2 h. APOE4 microglia showed a significantly slower (p < 0.0001) process movement toward the Aß, and less Aß coverage at early time points after Aß injection. To test whether P2RY12 is involved in process movement in response to Aß, we treated acute brain slices with a P2RY12 antagonist before Aß injection; microglial processes no longer migrated towards Aß. These results provide mechanistic insights into the impact of APOE4 genotype and aging in dynamic microglial behaviors prior to gross Aß pathology and could help explain how APOE4 brains are more susceptible to AD pathogenesis.

Outcomes of Autologous Versus Irradiated Homologous Costal Cartilage Graft in Rhinoplasty.

Background: Autologous costal cartilage (ACC) and irradiated homologous costal cartilage (IHCC) are commonly used in septorhinoplasty when there is insufficient septal cartilage for grafting. Objective: To assess the surgical outcomes of patients who underwent septorhinoplasty with either ACC or IHCC as measured by rates of infection, resorption, warping, and revision rate. Methods: A retrospective analysis of patients who underwent rhinoplasty with ACC or IHCC at a single academic institution was performed. Demographic data, surgical details, antibiotic use, and outcomes, including surgical duration, infection, resorption, warping, and revision rate, were analyzed using Fisher's exact test, chi-squared test, and logistic regression. Results: One hundred forty-three patients were identified. The median age was 48 years (interquartile range: 35-57.5) and 62.2% (n = 89) were female, 61 patients (42.7%) underwent ACC, and 82 (57.3%) IHCC. Revision rate in both groups was similar (ACC = 14.8%, IHCC = 14.6%; p = 0.98). There was no difference in infection rate (ACC = 4.9%, IHCC = 3.7%; p = 0.71). Postoperative deformity and nasal obstruction were the most common indications for revision surgery. Surgical time was shorter with IHCC (p < 0.01). Mean follow-up time was 26.5 months (±25) for ACC, and 16 months (±12) for IHCC. Conclusions: ACC and IHCC are similar in terms of effectiveness and safety in septorhinoplasty.

Bridging the Gap: Exploring Bronchopulmonary Dysplasia through the Lens of Biomedical Informatics.

Bronchopulmonary dysplasia (BPD), a chronic lung disease predominantly affecting premature infants, poses substantial clinical challenges. This review delves into the promise of biomedical informatics (BMI) in reshaping BPD research and care. We commence by highlighting the escalating prevalence and healthcare impact of BPD, emphasizing the necessity for innovative strategies to comprehend its intricate nature. To this end, we introduce BMI as a potent toolset adept at managing and analyzing extensive, diverse biomedical data. The challenges intrinsic to BPD research are addressed, underscoring the inadequacies of conventional approaches and the compelling need for data-driven solutions. We subsequently explore how BMI can revolutionize BPD research, encompassing genomics and personalized medicine to reveal potential biomarkers and individualized treatment strategies. Predictive analytics emerges as a pivotal facet of BMI, enabling early diagnosis and risk assessment for timely interventions. Moreover, we examine how mobile health technologies facilitate real-time monitoring and enhance patient engagement, ultimately refining BPD management. Ethical and legal considerations surrounding BMI implementation in BPD research are discussed, accentuating issues of privacy, data security, and informed consent. In summation, this review highlights BMI's transformative potential in advancing BPD research, addressing challenges, and opening avenues for personalized medicine and predictive analytics.

Personalized mood prediction from patterns of behavior collected with smartphones.

Over the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer depressive mood. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data. Here, we report high-quality longitudinal validated assessments of depressive mood from computerized adaptive testing paired with continuous digital assessments of behavior from smartphone sensors for up to 40 weeks on 183 individuals experiencing mild to severe symptoms of depression. We apply a combination of cubic spline interpolation and idiographic models to generate individualized predictions of future mood from the digital behavioral phenotypes, achieving high prediction accuracy of depression severity up to three weeks in advance (R2 ≥ 80%) and a 65.7% reduction in the prediction error over a baseline model which predicts future mood based on past depression severity alone. Finally, our study verified the feasibility of obtaining high-quality longitudinal assessments of mood from a clinical population and predicting symptom severity weeks in advance using passively collected digital behavioral data. Our results indicate the possibility of expanding the repertoire of patient-specific behavioral measures to enable future psychiatric research.

Randomised, blinded, cross-over evaluation of the palatability of and preference for different potassium binders in participants with chronic hyperkalaemia in the USA, Canada and Europe: the APPETIZE study.

OBJECTIVES: Traditional potassium (K+) binders for treating hyperkalaemia are unpalatable and poorly tolerated. Newer K+ binders are reportedly better tolerated; however, no published data describe their palatability, a determinant of long-term adherence. This study evaluated the palatability of and preference for three K+ binders: sodium and calcium polystyrene sulfonate (S/CPS), sodium zirconium cyclosilicate (SZC) and calcium patiromer sorbitex (patiromer). DESIGN: Phase 4, randomised, participant-blinded, cross-over study. Participants were randomised to one of six taste sequences and, using a 'sip and spit' approach, tasted each K+ binder before completing a survey. SETTING: 17 centres across the USA, Canada and European Union. PARTICIPANTS: 144 participants with chronic kidney disease, hyperkalaemia and no recent use of K+ binders. MAIN OUTCOME MEASURES: For the primary (USA) and key secondary (Canada and European Union) endpoints, participants rated palatability attributes (taste, texture, smell and mouthfeel) and willingness to take each K+ binder on a scale of 0-10 (rational evaluation). Feelings about each attribute, and the idea of taking the product once daily, were evaluated using a non-verbal, visual measure of emotional response. Finally, participants ranked the K+ binders according to palatability. RESULTS: In each region, SZC and patiromer outperformed S/CPS on overall palatability (a composite of taste, texture, smell and mouthfeel), based on rational evaluation and emotional response. Taking the product once daily was more appealing for SZC and patiromer, creating greater receptivity than the idea of taking S/CPS. The emotional response to mouthfeel had the strongest influence on feelings about taking each product. In each region, a numerically greater proportion of participants ranked SZC as the most preferred K+ binder versus patiromer or S/CPS. CONCLUSIONS: Preference for more palatable K+ binders such as SZC and patiromer may provide an opportunity to improve adherence to long-term treatment of hyperkalaemia. TRIAL REGISTRATION NUMBER: NCT04566653.

Almanac - Retrieval-Augmented Language Models for Clinical Medicine.

BACKGROUND: Large language models (LLMs) have recently shown impressive zero-shot capabilities, whereby they can use auxiliary data, without the availability of task-specific training examples, to complete a variety of natural language tasks, such as summarization, dialogue generation, and question answering. However, despite many promising applications of LLMs in clinical medicine, adoption of these models has been limited by their tendency to generate incorrect and sometimes even harmful statements. METHODS: We tasked a panel of eight board-certified clinicians and two health care practitioners with evaluating Almanac, an LLM framework augmented with retrieval capabilities from curated medical resources for medical guideline and treatment recommendations. The panel compared responses from Almanac and standard LLMs (ChatGPT-4, Bing, and Bard) versus a novel data set of 314 clinical questions spanning nine medical specialties. RESULTS: Almanac showed a significant improvement in performance compared with the standard LLMs across axes of factuality, completeness, user preference, and adversarial safety. CONCLUSIONS: Our results show the potential for LLMs with access to domain-specific corpora to be effective in clinical decision-making. The findings also underscore the importance of carefully testing LLMs before deployment to mitigate their shortcomings. (Funded by the National Institutes of Health, National Heart, Lung, and Blood Institute.).

Webbed Neck Deformity Reconstruction in Patients with Turner Syndrome: Technical Considerations in Treating Congenital Pterygium Colli.

Importance: Present an excellent outcome for a rare pterygium colli reconstruction. Objective: Establish techniques that have yielded a successful aesthetic and functional outcome for a patient with pterygium colli in a procedure that lacks consensus. Design, Setting, and Participants: Surgical pearls-description of considerations for a successful reconstruction. An academic practice. Pediatric patient with Turner's syndrome who underwent neck and auricular reconstruction.

Cancer Survivorship at Stanford Cancer Institute.

The Stanford Cancer Survivorship Program is a key initiative of Stanford Cancer Institute. The program's mission is to improve the experience and outcomes of patients and family caregivers throughout all phases of the cancer trajectory by advancing survivorship research, clinical care, and education. The four pillars of the program include clinical care delivery with a focus on primary care-survivorship collaboration and expanding specialty services, education and training of healthcare professionals, transdisciplinary patient-oriented research, and community engagement. Cross-cutting areas of expertise include the following: (a) adolescents and young adults (AYAs), (b) mental health and patient self-management, (c) integration of primary care, and (d) postgraduate medical education. The clinical care model includes embedded survivorship clinics within disease groups in outpatient clinics, novel clinics designed to address unmet needs such as sexual health for women, and primary care-based faculty-led survivorship clinics for patients undergoing active cancer care requiring co-management, those who have completed active therapy and those at high risk for cancer due to genetic risk. Educational initiatives developed to date include an online course and medical textbook for primary care clinicians, a lecture series, monthly research team meetings, and rotations for medical trainees. Patient-facing activities include webinars and a podcast series designed to promote awareness, thus expanding the provision of expert-vetted information. Ongoing research focuses on oncofertility and family building after cancer, improving communication for AYAs, changing mindsets to improve quality of life through targeted digital interventions, increasing capacity to care for cancer survivors, and strengthening collaboration with community partners. IMPLICATIONS FOR CANCER SURVIVORS: Stanford's Cancer Survivorship Program includes a robust transdisciplinary and interdisciplinary research, training and clinical platform that is committed to advancing access and improving care for people living with and beyond cancer, through innovation in design and care delivery.