IL-4-induced SOX9 confers lineage plasticity to aged adult lung stem cells.

Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.

ShinySperm: navigating the sperm proteome landscape.

Context Integrated omics studies hold a crucial role in improving our understanding of reproductive biology. However, the complex datasets so generated are often only accessible via supplementary data files, which lack the capacity for interactive features to allow users to readily interrogate and visualise data of interest. Aims The intent of this technical note was to develop an interactive web-based application that enables detailed interrogation of a representative sperm proteome, facilitating a deeper understanding of the proteins identified, their relative abundance, classifications, functions, and associated phenotypes. Methods We developed a Shiny web application, ShinySperm (https://reproproteomics.shinyapps.io/ShinySperm/ ), utilising R and several complementary libraries for data manipulation (dplyr), interactive tables (DT), and visualisation (ggplot2, plotly). ShinySperm features a responsive user interface, dynamic filtering options, interactive charts, and data export capabilities. Key results ShinySperm allows users to interactively search, filter, and visualise sperm proteomics data based on key features (e.g. protein classification, sperm cell domain, presence, or absence at different maturation stages). This application responds live to filtering options and enables the generation of interactive plots and tables, thus enhancing user engagement and understanding of the data. Conclusions ShinySperm provides a robust platform for the dynamic exploration of epididymal sperm proteome data. It significantly improves accessibility and interpretability of complex datasets, allowing for effective data-driven insights. Implications This technical note highlights the potential of interactive web applications in reproductive biology and provides a plug and play script for the field to produce applications for meaningful researcher interaction with complex omic datasets.

Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity.

Glioblastoma (GBM) is the deadliest form of primary brain tumor with limited treatment options. Recent studies have profiled GBM tumor heterogeneity, revealing numerous axes of variation that explain the molecular and spatial features of the tumor. Here, we seek to bridge descriptive characterization of GBM cell type heterogeneity with the functional role of individual populations within the tumor. Our lens leverages a gene program-centric meta-atlas of published transcriptomic studies to identify commonalities between diverse tumors and cell types in order to decipher the mechanisms that drive them. This approach led to the discovery of a tumor-derived stem cell population with mixed vascular and neural stem cell features, termed a neurovascular progenitor (NVP). Following in situ validation and molecular characterization of NVP cells in GBM patient samples, we characterized their function in vivo. Genetic depletion of NVP cells resulted in altered tumor cell composition, fewer cycling cells, and extended survival, underscoring their critical functional role. Clonal analysis of primary patient tumors in a human organoid tumor transplantation system demonstrated that the NVP has dual potency, generating both neuronal and vascular tumor cells. Although NVP cells comprise a small fraction of the tumor, these clonal analyses demonstrated that they strongly contribute to the total number of cycling cells in the tumor and generate a defined subset of the whole tumor. This study represents a paradigm by which cell type-specific interrogation of tumor populations can be used to study functional heterogeneity and therapeutically targetable vulnerabilities of GBM.

Automated evaluation of diaphragm configuration based on chest CT in COPD patients.

BACKGROUND: Severe chronic obstructive pulmonary disease (COPD) often results in hyperinflation and flattening of the diaphragm. An automated computed tomography (CT)-based tool for quantifying diaphragm configuration, a biomarker for COPD, was developed in-house and tested in a large cohort of COPD patients. METHODS: We used the LungQ platform to extract the lung-diaphragm intersection, as direct diaphragm segmentation is challenging. The tool computed the diaphragm index (surface area/projected surface area) as a measure of diaphragm configuration on inspiratory scans in a COPDGene subcohort. Visual inspection of 250 randomly selected segmentations served as a quality check. Associations between the diaphragm index, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, forced expiratory volume in 1 s (FEV1) % predicted, and CT-derived emphysema scores were explored using analysis of variance and Pearson correlation. RESULTS: The tool yielded incomplete segmentation in 9.2% (2.4% major defect, 6.8% minor defect) of 250 randomly selected cases. In 8431 COPDGene subjects (4240 healthy; 4191 COPD), the diaphragm index was increasingly lower with higher GOLD stages (never-smoked 1.83 ± 0.16; GOLD-0 1.79 ± 0.18; GOLD-1 1.71 ± 0.15; GOLD-2: 1.67 ± 0.16; GOLD-3 1.58 ± 0.14; GOLD-4 1.54 ± 0.11) (p < 0.001). Associations were found between the diaphragm index and both FEV1% predicted (r = 0.44, p < 0.001) and emphysema score (r = -0.36, p < 0.001). CONCLUSION: We developed an automated tool to quantify the diaphragm configuration in chest CT. The diaphragm index was associated with COPD severity, FEV1%predicted, and emphysema score. RELEVANCE STATEMENT: Due to the hypothesized relationship between diaphragm dysfunction and diaphragm configuration in COPD patients, automatic quantification of diaphragm configuration may prove useful in evaluating treatment efficacy in terms of lung volume reduction. KEY POINTS: Severe COPD changes diaphragm configuration to a flattened state, impeding function. An automated tool quantified diaphragm configuration on chest-CT providing a diaphragm index. The diaphragm index was correlated to COPD severity and may aid treatment assessment.

Reproductive morphophysiology of an iteroparous batch spawner fish: from early follicle development to ovulation.

Batch spawner fishes develop successive clutches of oocytes which allows them to participate in many reproductive cycles during their adult life (iteroparous) and spawn in multiple events within each breeding cycle. Here, ovarian follicular development was morpho-functionally analyzed in females of the iteroparous batch spawner fish Gymnocorymbus ternetzi. To obtain better insights into the reproductive morpho-physiology in batch spawners, the objective of this research was to analyze the dynamics of the follicular development, with its hormonal regulation between two active reproduction events. We found that over 16 days, follicles progressed asynchronously to chromatin nucleolus, Primary and Secondary growth stages of oogenesis with progressive secretion of 17ß-estradiol (E2). During the end of secondary growth, the increase in 17α,20ß-dihydroxy-4-pregnen-3-one (17,20ß-p) was measured relative to the maturation process of the ovarian follicles (e.g., nuclear migration and its rupture during the resumption of meiosis). Interestingly, an additional increase in E2 was observed after fish reproduction, probably related to the recruitment of new batch follicles for secondary growth. We also measured the high values of multiple condition factor post-reproduction measurements, reflecting more energy invested during the pre-reproductive process. We also quantified high concentrations of 17,20ß-p, probably related to the recruitment of a new batch of oogonia to meiosis, presumably secreted by post-ovulatory follicles, after fish reproduction. We finally found that fish without exposure to reproductive stimulus developed a regression phase at day 24, characterized by massive follicle atresia, that allow them to recycle energy and constitutive materials of the follicles invested during oogenesis for another reproductive cycle.

Impaired Epithelial CD200L Tolerance Signaling in Irritable Bowel Syndrome Cases With Diarrhea May Be Associated With Recurrent Miscarriages.

PROBLEM: There is a higher incidence of irritable bowel syndrome with miscarriages, and recurrent miscarriages of otherwise normal embryos have been linked to subnormal expression of the immune checkpoint inhibitor CD200L. We sought to determine if alterations in the expression of the CD200 immune checkpoint inhibitor occur in colonic tissue in IBS-D patients. METHOD OF STUDY: Quantitative immunohistochemical staining of biopsies from proximal and distal colon or rectum for the inhibitory CD200L and CD200S molecules was done. CD56 cells were also enumerated as they play a role in recurrent miscarriages and may express CD200S. RESULTS: CD200L was decreased and CD200S was unchanged in epithelium but not stroma of 3 IBS-D cases. One case had an increase in both CD200L and CD200S. CD56 cells were also stained for CD200S. Degranulation was assessed by the percentage of extracellular CD200S that was increased as epithelial CD200L decreased. CONCLUSIONS: This pilot study was promising and warrants a larger sample to determine if a correlation between uterine implantation site CD200L and CD200S expression in normal and failing implantation sites is needed. Colonic epithelial CD200L may then provide useful information about the pathogenesis of the spontaneous miscarriage in individual cases.

Pregnancy and stomas: a 9-year retrospective series at a major metropolitan hospital in Brisbane Queensland.

BACKGROUND: Over 42 000 Australians live with a stoma, and this number increases annually. Pregnancy in stoma patients is a rare but complex condition and there is limited published literature regarding surgical and obstetric complications in pregnant stoma patients. The aim of this paper was to review stoma outcomes, perinatal morbidity and mortality, and early postpartum period in pregnant stoma patients. METHODS: Data was retrospectively obtained on women of childbearing age, with a stoma, who had been pregnant and birthed in the last nine years at the Royal Brisbane and Women's Hospital between January 2014 to December 2022. Data recorded included patient demographics, type of stoma, indication for stoma, need for additional abdominal surgeries, method of conception, pregnancy complications, length of stay, neonatal outcomes and post pregnancy stomal complications. RESULTS: In total, there were 16 births from 13 mothers with stomas. Of 10 births to IBD patients, 40% experienced a serious stomal complication. Caesarean section (CS) rate was 90% for IBD and 83% for non-IBD. In-vitro fertilisation rates were 40% in IBD patients and 0% in non-IBD patients. The average gestational age at delivery was 36 weeks in IBD and 35 weeks non-IBD patients. Neonates delivered to IBD mothers had a birth weight under 2500g in 40% of cases and in non IBD mothers at 33.3% (p = 0.62). Of the sixteen births there was five complications (31.25%) associated with the stoma either during pregnancy or during the sixty-day postpartum period. CONCLUSION: Pregnancy in stoma patients is a rare occurrence and appears to be associated with high rates of CS, preterm delivery, low birth weight and stomal complication.

Empathy and Autism: Establishing the Structure and Different Manifestations of Empathy in Autistic Individuals Using the Perth Empathy Scale.

PURPOSE: There is a common mischaracterisation that autistic individuals have reduced or absent empathy. Measurement issues may have influenced existing findings on the relationships between autism and empathy, and the structure of the empathy construct in autism remains unclear. METHODS: The present study sought to address these gaps by examining the structure and psychometric properties of the Perth Empathy Scale (PES) in autistic individuals (N = 239) compared to non-autistic individuals (N = 690). RESULTS: Our moderated non-linear factor analysis revealed that the multidimensional empathy construct manifested similarly in autistic and non-autistic individuals, with the PES displaying good validity and reliability. Moreover, the results revealed that autistic individuals reported reduced cognitive empathy and reduced affective empathy for positive and negative emotions. However, there was greater heterogeneity of empathic tendencies in the autistic sample, indicating that these mean differences may not be generalisable for all autistic individuals. CONCLUSION: The present study highlights that the PES is suitable for assessing empathy across autistic and non-autistic individuals. This work with the PES also provides greater nuance to our understanding of empathy and autism, and based on these findings, we propose the empathy heterogeneity hypothesis of autism as a new way of describing empathy in autism.

Managing disclosure outcomes in intelligence interviews.

We introduce the disclosure-outcomes management model. The model views disclosure in intelligence interviews as a behaviour interviewees use to profitably navigate self-interest dilemmas. We theorized that interviewees compare the potential outcomes of disclosing to their self-interests. They evaluate the extent to which disclosure will facilitate or impede those self-interests: an interviewee's self-interest dilemma elicits cooperation with respect to some information but not other information. A Preliminary Study (N = 300) supported the model's predictions. We proposed a Replication Study (N = 369) to examine the model further. Participants assumed the role of an intelligence source undergoing an interview. They decided what information to disclose, contending the typical dilemma in an intelligence interview wherein disclosure could jeopardize or advance their self-interests. The results from the Preliminary and Replication studies were broadly in line with our proposition: perceived benefits positively influenced the likelihood of disclosing. However, a negative interaction between costs and benefits observed in the Preliminary Study did not replicate. That finding may be due to power constraints, not evidence against the existence of an interaction effect. Our proposal that-generally speaking-interviewees are likelier to disclose information units that seem less versus more risky requires further examination. Individual-level sensitivity to benefits, costs and their co-occurrence varied substantially in our studies. We discuss avenues for future research.

Exceptions to the rule: When does resistance evolution not undermine antibiotic therapy in human bacterial infections?

The use of antibiotics to treat bacterial infections often imposes strong selection for antibiotic resistance. However, the prevalence of antibiotic resistance varies greatly across different combinations of pathogens and drugs. What underlies this variation? Systematic reviews, meta-analyses, and literature surveys capable of integrating data across many studies have tried to answer this question, but the vast majority of these studies have focused only on cases where resistance is common or problematic. Yet much could presumably be learned from the cases where resistance is infrequent or absent. Here we conducted a literature survey and a systematic review to study the evolution of antibiotic resistance across a wide range of pathogen-by-drug combinations (57 pathogens and 53 antibiotics from 15 drug classes). Using Akaike information criterion-based model selection and model-averaged parameter estimation we explored 14 different factors posited to be associated with resistance evolution. We find that the most robust predictors of high resistance are nosocomial transmission (i.e., hospital-acquired pathogens) and indirect transmission (e.g., vector-, water-, air-, or vehicle-borne pathogens). While the former was to be expected based on prior studies, the positive correlation between high resistance frequencies and indirect transmission is, to our knowledge, a novel insight. The most robust predictor of low resistance is zoonosis from wild animal reservoirs. We also found partial support that resistance was associated with pathogen type, horizontal gene transfer, commensalism, and human-to-human transmission. We did not find support for correlations between resistance and environmental reservoirs, mechanisms of drug action, and global drug use. This work explores the relative explanatory power of various pathogen and drug factors on resistance evolution, which is necessary to identify priority targets of stewardship efforts to slow the spread of drug-resistant pathogens.

Characterization of Olive Oil Phenolic Extracts and Their Effects on the Aggregation of the Alzheimer's Amyloid-ß Peptide and Tau.

The dietary consumption of extra virgin olive oil (EVOO) is believed to slow the progression of Alzheimer's disease (AD) symptoms. Its protective mechanisms are unclear, but specific EVOO phenolic compounds can individually impede the aggregation of amyloid-ß (Aß) peptides and the microtubule-associated protein tau, two important pathological manifestations of AD. It is unknown, however, whether the numerous and variable phenolic compounds that are consumed in dietary EVOO can collectively alter tau and Aß aggregation as effectively as the individual compounds. The activity of these complex mixtures against Aß and tau may be moderated by competition between active and nonactive phenolic components and by extensive derivatizations and isomerization. Here, phenolic mixtures extracted from two different EVOO sources are characterized and tested for how they modulate the aggregation of Aß40 peptide and tau peptides in vitro. The chromatographic and NMR analysis of Greek and Saudi Arabian EVOO phenolic extracts reveals that they have different concentration profiles, and over 30 compounds are identified. Thioflavin T fluorescence and circular dichroism measurements show that relatively low concentrations (<20 µg/mL) of the Greek and Saudi extracts reduce the rate of Aß40 aggregation and fibril mass, despite the extracts having different phenolic profiles. By contrast, the Greek extract reduces the rate of tau aggregation only at very high phenolic concentrations (>100 µg/mL). Most compounds in the extracts bind to preformed Aß40 fibrils and release soluble Aß oligomers that are mildly toxic to SH-SY5Y cells. Much higher (500 µg/mL) extract concentrations are required to remodel tau filaments into oligomers, and a minimal binding of phenolic compounds to the preformed filaments is observed. It is concluded that EVOO extracts having different phenol profiles are similarly capable of modulating Aß40 aggregation and fibril morphology in vitro at relatively low concentrations but are less efficient at modulating tau aggregation. Over 2 M tonnes of EVOO are consumed globally each year as part of the Mediterranean diet, and the results here provide motivation for further clinical interrogation of the antiaggregation properties of EVOO as a potential protective mechanism against AD.

The use of CAMS and DBT to effectively treat patients who are suicidal.

Around the world, suicide ideation, attempts, and deaths pose a major public and mental health challenge for patients (and their loved ones). Accordingly, there is a clear need for effective clinical treatments that reliably reduce suicidal thoughts and behaviors. In this article, we review the Collaborative Assessment and Management of Suicidality (CAMS) and Dialectical Behavior Therapy (DBT), two clinical treatments that rise to the highest levels of empirical rigor. Both CAMS and DBT are now supported by randomized controlled trials (RCTs), with independent replications, and meta-analyses. There are also supportive data related to training clinical providers to use CAMS and DBT with adherence. RCTs that investigate the use of both interventions within clinical trial research designs and the increasing use of these complementary approaches within routine clinical practice are discussed. Future directions for research and clinical use of CAMS and DBT are explored as means to effectively treat suicidal risk.

NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14.

The blood-nerve-barrier (BNB) that regulates peripheral nerve homeostasis is formed by endoneurial capillaries and perineurial cells surrounding the Schwann cell (SC)-rich endoneurium. Barrier dysfunction is common in human tumorigenesis, including in some nerve tumors. We identify barrier disruption in human NF1 deficient neurofibromas, which were characterized by reduced perineurial cell glucose transporter 1 (GLUT1) expression and increased endoneurial fibrin(ogen) deposition. Conditional Nf1 loss in murine SCs recapitulated these alterations and revealed decreased tight junctions and decreased caveolin-1 (Cav1) expression in mutant nerves and in tumors, implicating reduced Cav1-mediated transcytosis in barrier disruption and tumorigenesis. Additionally, elevated receptor tyrosine kinase activity and genetic deletion of Cav1 increased endoneurial fibrin(ogen), and promoted SC tumor formation. Finally, when SC lacked Nf1, genetic loss or pharmacological inhibition of P2RY14 rescued Cav1 expression and barrier function. Thus, loss of Nf1 in SC causes dysfunction of the BNB via P2RY14-mediated G-protein coupled receptor (GPCR) signaling.

Barriers and facilitators to the uptake of electronic collection and use of patient-reported measures in routine care of older adults: a systematic review with qualitative evidence synthesis.

Objective: The aims of this systematic review were to (1) synthesize the available qualitative evidence on the barriers and facilitators influencing implementation of the electronic collection and use of patient-reported measures (PRMs) in older adults' care from various stakeholder perspectives and (2) map these factors to the digital technology implementation framework Non-adoption, Abandonment, challenges to the Scale-up, Spread, Sustainability (NASSS) and behavior change framework Capability, Opportunity, Motivation, Behaviour (COM-B). Materials and Methods: A search of MEDLINE, CINAHL Plus, and Web of Science databases from 1 January 2001 to 27 October 2021 was conducted and included English language qualitative studies exploring stakeholder perspectives on the electronic collection and use of PRMs in older adults' care. Two authors independently screened studies, conducted data extraction, quality appraisal using the Critical Appraisal Skills Programme (CASP), data coding, assessed confidence in review findings using Grading of Recommendations Assessment, Development, and Evaluation Confidence in the Evidence from Reviews of Qualitative Research (GRADE CERQual), and mapped the findings to NASSS and COM-B. An inductive approach was used to synthesize findings describing the stakeholder perspectives of barriers and facilitators. Results: Twenty-two studies were included from the 3368 records identified. Studies explored older adult, caregiver, healthcare professional, and administrative staff perspectives. Twenty nine of 34 review findings (85%) were graded as having high or moderate confidence. Key factors salient to older adults related to clinical conditions and socio-cultural factors, digital literacy, access to digital technology, and user interface. Factors salient to healthcare professionals related to resource availability to collect and use PRMs, and value of PRMs collection and use. Conclusion: Future efforts to implement electronic collection and use of PRMs in older adults' care should consider addressing the barriers, facilitators, and key theoretical domains identified in this review. Older adults are more likely to adopt electronic completion of PRMs when barriers associated with digital technology access, digital literacy, and user interface are addressed. Future research should explore the perspectives of other stakeholders, including those of organizational leaders, digital technology developers and implementation specialists, in various healthcare settings and explore factors influencing implementation of PREMs. PROSPERO registration number: CRD42022295894.

Optimizing Regulatory Reviews for Clinical Protocols that Use Radiopharmaceuticals: Findings of the University of Pennsylvania Radiation Research Safety Committee.

ABSTRACT: Institutional radiation safety committees review research studies with radiation exposure. However, ensuring that the potential patient benefit and knowledge gained merit the radiation risks involved often necessitates revisions that inadvertently delay protocol activations. This quality-improvement study analyzed protocols, identified factors associated with approval time by a radiation safety committee, and developed guidelines to expedite reviews without compromising quality. Clinical protocols submitted to the University of Pennsylvania's Radiation Research Safety Committee (RRSC) for review between 2017 and 2021 were studied. Protocol characteristics, review outcome, stipulations, and approval times were summarized. Statistical analysis (Spearman's rho) was used to investigate stipulations and approval time; rank-sum analysis (Kruskal-Wallis or Wilcoxon) was used to determine whether approval time differed by protocol characteristics. One hundred ten (110) protocols were analyzed. Approximately two-thirds of protocols used approved radiopharmaceuticals to aid investigational therapy trials. Twenty-three percent (23%) of protocols received RRSC approval, and 73% had approval withheld with stipulations, which included requests for edits or additional information. Submissions had a median of three stipulations. Median and mean RRSC approval times were 62 and 80.1 d, and 41% of protocols received RRSC approval after IRB approval. RRSC approval time was positively correlated with stipulations (Spearman's rho = 0. 632, p < 0.001). RRSC approval time was longer for studies using investigational new drugs (median 80 d) than approved radiopharmaceuticals (median 57 d, p = 0.05). The review process is lengthy and may benefit from changes, including publishing standardized radiation safety language and commonly required documents and encouraging timely response to stipulations.

Risk Factors for Dysfunctional Elbow Stiffness following Operative Fixation of Distal Humerus Fractures.

BACKGROUND: Elbow stiffness is one of the most common complications after operative fixation of distal humerus fractures; however, there is relatively limited literature assessing which factors are associated with this problem. The purpose of this study is to identify risk factors associated with dysfunctional elbow stiffness in distal humerus fractures after operative fixation. METHODS: A retrospective review of all distal humerus fractures that underwent operative fixation (AO/OTA 13A-C) at a single level 1 trauma center from November 2014 to October 2021. A minimum six-month follow-up was required for inclusion or the outcome of interest. Dysfunctional elbow stiffness was defined as a flexion-extension arc of less than 100° at latest follow-up or any patient requiring surgical treatment for limited elbow range of motion. RESULTS: A total of 110 patients with distal humerus fractures were included in the study: 54 patients comprised the elbow stiffness group and 56 patients were in the control group. Average follow-up of 343 (59 to 2,079) days. Multiple logistic regression showed that orthogonal plate configuration (aOR: 5.70, 95% CI: 1.91-16.99, p=0.002), and longer operative time (aOR: 1.86, 95% CI: 1.11-3.10, p=0.017) were independently associated with an increased odds of elbow stiffness. OTA/AO 13A type fractures were significantly associated with a decreased odds of stiffness (aOR: 0.16, 95% CI: 0.03-0.80, p=0.026). Among 13C fractures, olecranon osteotomy (aOR: 5.48, 95% CI: 1.08-27.73, p=0.040) was also associated with an increased odds of elbow stiffness. There were no significant differences in injury mechanism, Gustilo-Anderson classification, reduction quality, days to surgery from admission, type of fixation, as well as rates of ipsilateral upper extremity fracture, neurovascular injury, nonunion, or infection between the two groups. CONCLUSION: Dysfunctional elbow stiffness was observed in 49.1% of patients who underwent operative fixation of distal humerus fractures in the present study. Orthogonal plate configuration, olecranon osteotomy, and longer operative time were associated with an increased odds of dysfunctional elbow stiffness; however, 13A type fractures were associated with decreased odds of stiffness. Patients with these injuries should be counseled on their risk of stiffness following surgery, and modifiable risk factors like plate positioning and performing an olecranon osteotomy should be considered by surgeons.

Primary cilia signaling in astrocytes mediates development and regional-specific functional specification.

Astrocyte diversity is greatly influenced by local environmental modulation. Here we report that the majority of astrocytes across the mouse brain possess a singular primary cilium localized to the cell soma. Comparative single-cell transcriptomics reveals that primary cilia mediate canonical SHH signaling to modulate astrocyte subtype-specific core features in synaptic regulation, intracellular transport, energy and metabolism. Independent of canonical SHH signaling, primary cilia are important regulators of astrocyte morphology and intracellular signaling balance. Dendritic spine analysis and transcriptomics reveal that perturbation of astrocytic cilia leads to disruption of neuronal development and global intercellular connectomes in the brain. Mice with primary ciliary-deficient astrocytes show behavioral deficits in sensorimotor function, sociability, learning and memory. Our results uncover a critical role for primary cilia in transmitting local cues that drive the region-specific diversification of astrocytes within the developing brain.

If the peri-operative patient pathway was right, what would it look like?

BACKGROUND: Patients undergoing surgery deserve the best possible peri-operative outcomes. Each stage of the peri-operative patient journey offers opportunities to improve care delivery, with shorter lengths of stay, less complications, reduced costs and better value. METHODS: These opportunities were identified through narrative review of the literature, with consultation and consensus at the hidden pandemic (of postoperative complications) summit 2, July 2023 in Adelaide, Australia RESULTS: Before surgery: Some patients who receive timely alternative treatments may not need surgery at all. The period of waiting after listing should be a time of preparation. Risk assessment at the time of surgical listing facilitates recognition of need for comorbidity optimisation and identifies those who will most benefit from prehabilitation, particularly frail and deconditioned patients. DURING SURGERY: During the surgical admission, ERAS programs result in less postoperative complications, shorter length of stay and better patient experience but require agreement between clinicians, and coordinated monitoring of delivery of the elements in the ERAS bundle of care. AFTER SURGERY: At-risk patients need to have the appropriate levels of monitoring for cardiovascular instability, renal impairment or respiratory dysfunction, to facilitate timely, proactive management if they develop. Access to allied health in the early postoperative period is also critical for promoting mobility, and earlier discharge, particularly after joint surgery. Where appropriate, provision of rehabilitation services at home improves patient experience and adds value. The peri-operative patient journey begins and ends with primary care so there is a need for clear communication, documentation, around sharing of responsibility between practitioners at each stage. CONCLUSION: Identifying and mitigating risk to reduce complications and length of stay in hospital will improve outcomes for patients and deliver the best value for the health system.

Characterizing dog cognitive aging using spontaneous problem-solving measures: development of a battery of tests from the Dog Aging Project.

Companion dogs are a valuable model for aging research, including studies of cognitive decline and dementia. With advanced age, some dogs spontaneously develop cognitive impairments and neuropathology resembling features of Alzheimer's disease. These processes have been studied extensively in laboratory beagles, but the cognitive assays used in that context-which rely on time-consuming operant procedures-are not easily scalable to large samples of community-dwelling companion dogs. We developed a battery of five short-form tasks targeting three aspects of cognition that are impaired in Alzheimer's disease: spatial memory, executive functions, and social cognition. In Experiment 1, we tested a cross-sectional sample of dogs (N = 123) and estimated associations between age and task performance. Older dogs scored lower on measures of spatial learning, memory, and response flexibility, and spent less time near, but more time gazing at, the experimenter. We found no differences in associations between age and performance across dogs of different body masses, a proxy for expected lifespan. In Experiment 2, we demonstrated the feasibility of these measures in clinical settings (N = 35). Dogs meeting clinical criteria for moderate or severe cognitive impairment scored lower, on average, than dogs characterized as mildly impaired and healthy agers, although these distributions overlapped. However, few dogs in our study cohort met the criteria for moderate or severe impairment. The measures presented here show promise for deployment in large-scale longitudinal studies of companion dogs, such as the Dog Aging Project.

Aspirin Use and Incidence of Colorectal Cancer According to Lifestyle Risk.

Importance: Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority. Objective: To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors. Design, Setting, and Participants: A prospective cohort study among women in the Nurses' Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023. Exposures: A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week. Main Outcome and Measures: Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores. Results: The mean (SD) baseline age of the 107 655 study participants (63 957 women from the Nurses' Health Study and 43 698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3 038 215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P < .001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking. Conclusions and Relevance: In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.