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Abstract Metastasis is the leading cause of death in patients with cancer, driving considerable scientific and clinical interest in immunosurveillance of micrometastases. We investigated this process by creating a multiscale mathematical model to study the interactions between the immune system and the progression of micrometastases in general epithelial tissue. We analyzed the parameter space of the model using high-throughput computing resources to generate over 100,000 virtual patient trajectories. We demonstrated that the model could recapitulate a wide variety of virtual patient trajectories, including uncontrolled growth, partial response, and complete immune response to tumor growth. We classified the virtual patients and identified key patient parameters with the greatest effect on the simulated immunosurveillance. We highlight the lessons derived from this analysis and their impact on the nascent field of cancer patient digital twins (CPDTs). While CPDTs could enable clinicians to systematically dissect the complexity of cancer in each individual patient and inform treatment choices, our work shows that key challenges remain before we can reach this vision. In particular, we show that there remain considerable uncertainties in immune responses, unreliable patient stratification, and unpredictable personalized treatment. Nonetheless, we also show that in spite of these challenges, patient-specific models suggest strategies to increase control of clinically undetectable micrometastases even without complete parameter certainty.

Abstract Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton’s tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS. Using a CNS-penetrant BTK inhibitor (BTKi), we demonstrate robust in vivo effects in mouse models of MS. We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation.

Abstract Background Rural populations experience ongoing health inequities with disproportionately high morbidity and mortality rates, but digital health in rural settings is poorly studied. Our research question was: How does digital health influence healthcare outcomes in rural settings? The objective was to identify how digital health capability enables the delivery of outcomes in rural settings according to the quadruple aims of healthcare: population health, patient experience, healthcare costs and provider experience. Methods A multi-site qualitative case study was conducted with interviews and focus groups performed with healthcare staff (n = 93) employed in rural healthcare systems (n = 10) in the state of Queensland, Australia. An evidence-based digital health capability framework and the quadruple aims of healthcare served as classification frameworks for deductive analysis. Theoretical analysis identified the interrelationships among the capability dimensions, and relationships between the capability dimensions and healthcare outcomes. Results Seven highly interrelated digital health capability dimensions were identified from the interviews: governance and management; information technology capability; people, skills, and behaviours; interoperability; strategy; data analytics; consumer centred care. Outcomes were directly influenced by all dimensions except strategy. The interrelationship analysis demonstrated the influence of strategy on all digital health capability dimensions apart from data analytics, where the outcomes of data analytics shaped ongoing strategic efforts. Conclusions The study indicates the need to coordinate improvement efforts targeted across the dimensions of digital capability, optimise data analytics in rural settings to further support strategic decision making, and consider how consumer-centred care could influence digital health capability in rural healthcare services. Digital transformation in rural healthcare settings is likely to contribute to the achievement of the quadruple aims of healthcare if transformation efforts are supported by a clear, resourced digital strategy that is fit-for-purpose to the nuances of rural healthcare delivery.

Abstract Background People experiencing homelessness have increased prevalence, morbidity, and mortality of cardiovascular disease (CVD), attributable to several traditional and non-traditional risk factors. While this burden is well-known, mainstream CVD management plans and healthcare delivery have not been developed with people experiencing homelessness in mind nor tailored to their unique context. The overall objective of this work was to explore and synthesize what is known about CVD management experiences, programs, interventions, and/or recommendations specifically for people experiencing homelessness. Methods We conducted a scoping review to combine qualitative and quantitative studies in a single review using the Arksey and O’Malley framework and lived experience participation. We performed a comprehensive search of OVID Medline, Embase, PsychINFO, CINAHL, Web of Science, Social Sciences Index, Cochrane, and the grey literature with key search terms for homelessness, cardiovascular disease, and programs. All dates, geographic locations, and study designs were included. Articles were analyzed using conventional content analysis. Results We included 37 articles in this review. Most of the work was done in the USA. We synthesized articles’ findings into 1) barriers/challenges faced by people experiencing homelessness and their providers with CVD management and care delivery (competing priorities, lifestyle challenges, medication adherence, access to care, and discrimination), 2) seven international programs/interventions that have been developed for people experiencing homelessness and CVD management with learnings, and 3) practical recommendations and possible solutions at the patient encounter level (relationships, appointment priorities, lifestyle, medication), clinic organization level (scheduling, location, equipment, and multi-disciplinary partnership), and systems level (root cause of homelessness, and cultural safety). Conclusions There is no ‘one-size-fits all’ approach to CVD management for people experiencing homelessness, and it is met with complexity, diversity, and intersectionality based on various contexts. It is clear, however, we need to move to more practically-implemented, community-driven solutions with lived experience and community partnership at the core. Future work includes tackling the root cause of homelessness with affordable housing, exploring ways to bring cardiac specialist care to the community, and investigating the role of digital technology as an avenue for CVD management in the homeless community. We hope this review is valuable in providing knowledge gaps and future direction for health care providers, health services research teams, and community organizations.

Abstract While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8 jck ), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

Behavior problems in children with autism spectrum disorder (ASD) may exacerbate parenting stress. Parenting self-efficacy and family resources may influence this association. We examined cross-sectional statistical mediation effects of parenting self-efficacy on the relationship between child behavior problems and parenting stress and hypothesized that family-level resources moderated this indirect effect. Participants included 132 underserved (Medicaid-eligible) children with ASD (ages 3-13) with racial/ethnic diversity; many (63%) had intellectual disability. Greater externalizing problems were linked with lower parenting self-efficacy, which in turn was associated with increased parenting stress. A larger mediation effect was observed for families with fewer resources. A plausible alternative model (parenting stress mediating parenting self-efficacy) exhibited poorer fit. Implications for family supports and benefits of longitudinal follow-up are discussed.

ABSTRACT: This 42-d study evaluated the effects of phytase, calcium butyrate (CB), and bacitracin methylene disalicylate 50 (BMD) on broiler performance, processing yields, and nutrient digestibility. Ross YPM x 708 male broilers (2,880 total) were distributed in 72 floor pens and assigned to 1 of 9 treatments (8 replicates/treatment) on d of hatch. This experiment was a 2 × 4 + 1 factorial arrangement, including 2 phytase concentrations (500 or 1,500 FTU/kg), 4 microbiota modulating feed additive groups (MMFA; none, CB (0.5 g/kg of diet), BMD (55 mg/kg of diet), or both CB and BMD), and a negative control without feed additives. Broiler performance (d 14, 28, and 42), apparent ileal nutrient digestibility (d 28 and 42), and processing yields (d 43) were determined. Day 14 BW increased with BMD inclusion compared to CB and no MMFA in the 1,500 FTU/kg group but BW were similar between all MMFA combined with 500 FTU/kg (P ≤ 0.05). Supplementing BMD increased d 28 BW and reduced d 1 to 28 feed conversion ratio compared to CB and no MMFA (main effect, P ≤ 0.05). Day 42 BW varied depending on dietary phytase concentrations. When diets contained 500 FTU/kg, broilers fed both CB and BMD had a higher BW than broilers fed only CB. Whereas when the inclusion of phytase was increased to 1,500 FTU/kg, broilers fed diets with only BMD or both CB and BMD had higher BW than broilers fed diets with no MMFA (P ≤ 0.05). Phytase concentrations at 1,500 FTU/kg increased (P ≤ 0.05) digestibility of fat (main effect, d 42), phosphorus (d 28 and 42), and apparent ileal digestible energy (main effect, d 42) compared to 500 FTU/kg. In this study, dietary BMD improved broiler growth compared to CB and no MMFA. However, these observed differences between CB and BMD were dependent on dietary phytase concentrations.

ABSTRACT: Campylobacter jejuni (C. jejuni) is a leading foodborne illness causing bacteria, and poultry is a major reservoir of this pathogen. With the recent increase in broiler production under the “no antibiotics ever” (NAE) system, this study aimed to assess the prevalence, antibiotic resistance, and virulence characteristics of C. jejuni isolated from NAE raised broilers. A total of 270 cloacal swabs were collected from the live-hang areas of 3 commercial processing plants over 9 wk. Each processing plant was visited 3 times at a 1-wk interval, and 30 samples were collected per visit. Among the total 270 cloacal swab samples, C. jejuni was isolated from 44 (16.3%) samples . Of these isolates, 65.9% possessed toxin-producing genes cdtA, cdtB, and cdtC, and invasion gene ciaB. The prevalence of antibioitc resistance genes aph (3′)-IIIa, erm(B) were 59.1%, and 50%, respectively. Nine (20.45%) C. jejuni isolates were identified as multidrug resistant (MDR), and 18 (40.9%) isolates showed resistance to at least 1 tested antibiotic. The highest resistance was observed against tetracycline (29.5%), followed by nalidixic acid (25%), whereas 22.7% of isolates were resistant to 2 clinically important antibiotics, azithromycin and ciprofloxacin. These results suggest that there ishigh prevalence level of multi-drug resistant C. jejuni with toxin producing virulence genes in the NAE-raised broilers sampled in this study, indicating the potential for serious human illnesses if transmitted through the food chain.

ABSTRACT: Salmonella Reading (S. Reading) recently emerged as a foodborne pathogen causing extensive human outbreaks in North America from consuming contaminated poultry products, mostly from turkeys. Understanding the transmission dynamics of this pathogen is crucial for preventing future outbreaks. This study investigated the ability of S. Reading to colonize the tissues and contaminate eggs of broiler breeders. We utilized 2 S. Reading strains, marked with bioluminescence gene: the outbreak strain RS330 and a reference strain RS326. We used 32 commercially sourced broiler breeder hens, 34 wk of age, randomly assigned to the 2 treatments (16 hens per strain). Each hen was intravaginally inoculated with 108 CFU of the respective strain on d 1 and was rechallenged on d 4. Eggs were collected daily postchallenge to recover bioluminescent S. Reading strains from the external eggshell surface and internal egg contents. On d 7 postchallenge, 10 hens from each treatment group were euthanized. Ovaries, oviducts, and ceca were aseptically collected to detect S. Reading colonization. Results showed that 70.5% (36 of 51) and 34.5% (19 of 55) of external eggshell surfaces, and 4.0% (2 of 50) and 1.8% (1 of 54) of the internal egg contents tested positive for the outbreak and nonoutbreak strains. Additionally, 40.0% of ovaries, 70.0% of oviduct, and 70.0% of ceca samples from the outbreak strain group, and 20.0% of ovaries, 70.0% of oviduct, and 80.0% of ceca samples from nonoutbreak strain group were positive. No significant difference (P = 0.05) was observed in all the findings among the strains except for the eggshell surface contamination. These findings suggest that S. Reading can effectively colonize reproductive tissues, translocate to the ceca, and contaminate the eggs of hens. Future research is needed to determine whether S. Reading can remain viable within the eggs throughout incubation and until hatching.

ABSTRACT: The objective of this study was to determine prevalence and perform genomic analysis of Salmonella spp. and Campylobacter spp. isolated from different stages of an integrated NAE broiler complex. Environmental samples were screened with 3M-Molecular Detection System (MDS) and MDS positive samples were further processed for confirmation of results and identification. Core genome-based phylogenies were built for both bacteria isolated from this study along with selected NCBI genomes. The odds ratios and 95% confidence limits were compared among stages and sample types (α < 0.05) using multivariable model. Based on MDS results, 4% and 18% of total samples were positive for Salmonella spp. and Campylobacter spp. respectively. The odds of Salmonella detection in hatchery samples were 2.58 times as likely as compared to its detection in production farms’ samples (P = 0.151) while the odds of Campylobacter detection in production farms’ samples were 32.19 times as likely as its detection in hatchery (P = 0.0015). Similarly, the odds of Campylobacter detection in boot swabs, soil, water, and miscellaneous samples were statistically significant (P < 0.05) as compared with fly paper as reference group. The serovars identified for Salmonella were Typhimurium, Barranquilla, Liverpool, Kentucky, Enteritidis, Luciana, and Rough_O:r:1,5. For Campylobacter, the species identified were Campylobacter jejuni and Campylobacter coli. Phylogeny results show close genetic relatedness among bacterial strains isolated from different locations within the same stage and between different stages. The results show possibility of multiple entry points of such bacteria entering broiler complex and can potentially contaminate the final raw product in the processing plant. It suggests the need for a comprehensive control strategy with strict biosecurity measures and best management practices to minimize or eliminate such pathogens from the poultry food chain.

Summary: Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as “trial-like” based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75ECD, plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL 100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD, and plasma miR-181ab is more limited. Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).

BACKGROUND: Cardiac function of critically ill patients with COVID-19 generally has been reported from clinically obtained data. Echocardiographic deformation imaging can identify ventricular dysfunction missed by traditional echocardiographic assessment. RESEARCH QUESTION: What is the prevalence of ventricular dysfunction and what are its implications for the natural history of critical COVID-19? STUDY DESIGN AND METHODS: This is a multicenter prospective cohort of critically ill patients with COVID-19. We performed serial echocardiography and lower extremity vascular ultrasound on hospitalization days 1, 3, and 8. We defined left ventricular (LV) dysfunction as the absolute value of longitudinal strain of < 17% or left ventricle ejection fraction (LVEF) of < 50%. Primary clinical outcome was inpatient survival. RESULTS: We enrolled 110 patients. Thirty-nine (35.5%) died before hospital discharge. LV dysfunction was present at admission in 38 patients (34.5%) and in 21 patients (36.2%) on day 8 (P = .59). Median baseline LVEF was 62% (interquartile range [IQR], 52%-69%), whereas median absolute value of baseline LV strain was 16% (IQR, 14%-19%). Survivors and nonsurvivors did not differ statistically significantly with respect to day 1 LV strain (17.9% vs 14.4%; P = .12) or day 1 LVEF (60.5% vs 65%; P = .06). Nonsurvivors showed worse day 1 right ventricle (RV) strain than survivors (16.3% vs 21.2%; P = .04). INTERPRETATION: Among patients with critical COVID-19, LV and RV dysfunction is common, frequently identified only through deformation imaging, and early (day 1) RV dysfunction may be associated with clinical outcome.

A randomized controlled trial established initial efficacy of a novel parent training (PT) intervention for improving oral hygiene and oral health in underserved children with ASD (Fenning et al., 2022), a population at risk for unmet dental needs. The present study describes our emic approach to PT development alongside treatment outcome data examining feasibility, acceptability, and engagement. Families with Medicaid-eligible children with ASD ages 3 to 13 years (85% male, 62% with intellectual disability) were assigned to receive PT (n = 60) or a psychoeducational toolkit (n = 59). Results indicate strong retention, fidelity, and adherence, with quantitative and qualitative metrics revealing high treatment satisfaction and utilization. Discussion focuses on implications for individualizing treatment to optimize engagement of underrepresented families.

Abstract Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.

Objective RheumMadness is an online learning collaborative that seeks to actively engage the rheumatology community. The objective of this manuscript is to analyze the educational experience of RheumMadness over two years. Methods Direct measures of participant engagement were obtained using web‐based analytics. An electronic survey was created after the tournament to capture self‐reported engagement and educational experience using the Community of Inquiry framework. Data were analyzed according to the following objectives: (1) compare demographics, engagement, and educational experience of participants between 2021 and 2022; (2) describe the educational experience of those who created scouting reports; (3) explore the impact of RheumMadness on early learners (medical students and residents). Results Compared with 2021, the 2022 tournament had more participants who submitted a bracket, more early learners, and more scouting report creators. Self‐reported engagement and educational experience was high in both years of the tournament among all participants. Over 85% of scouting report creators reported that making a report was a fun and valuable learning experience. Early learners reported significantly higher levels of knowledge integration, sense of belonging in the rheumatology community, social connection, and overall learning experience compared with more advanced participants. Eighty‐five percent of early learners reported that RheumMadness increased their interest in rheumatology. Conclusion RheumMadness expanded from 2021 to 2022, engaging more participants in collaborative learning. Our results demonstrate that RheumMadness is particularly impactful among medical students and residents by helping them explore rheumatology topics and connect with the rheumatology community.

This research employed the Analytical Hierarchy Process (AHP) method to evaluate the performance of the black orchid hydroponic system using Deep Flow Technique (DFT) based on Plant House during the acclimatization phase. The objective of this study was to assess the system's performance considering parameters such as plant height, energy, water requirements, energy costs, nutrient needs, and ease of maintenance. The research methodology combines qualitative and quantitative approaches involving 50 respondents from various orchid communities in several cities in Indonesia. The data were analyzed using AHP to determine the priority weights for the tested alternatives. The results show that plant height holds the highest weight with 0.4394. Comparing the DFT black orchid system with the conventional one reveals differences in performance parameters like energy, water requirements, energy costs, nutrient needs, plant height, and ease of maintenance. The DFT hydroponic system outperforms the conventional system with a total performance index of 0.8832, interpreted as "Excellent," while the conventional system scores a total performance index of 0.5401, interpreted as "Average." The implications of this research suggest that the DFT black orchid system is more suitable for Plant House scale or producing ornamental plants supplied to orchid retailers, enhancing efficiency and productivity in commercial orchid cultivation.

Introducción: La artrodesis tibioastragalina es una opción para tratar la artrosis de tobillo en pacientes que no responden a las medidas conservadoras. Su principal desventaja es el compromiso a mediano y largo plazo de las articulaciones vecinas. Objetivo: Determinar el compromiso de las articulaciones vecinas a mediano y largo plazo, y su impacto sobre los resultados funcionales en los pacientes con artrodesis de tobillo. Materiales y Métodos: Se evaluó a una serie de 11 pacientes (6 mujeres y 5 hombres). El diagnóstico inicial era artrosis postraumática (9 casos), artritis séptica (1 caso) y lesión osteocondral de astrágalo (1 caso). El promedio de edad al operarse era de 50 años. La media de seguimiento fue de 9 años. Se evaluó el compromiso radiográfico de las articulaciones vecinas. La función se valoró mediante la escala analógica visual para dolor, la escala de la AOFAS y un cuestionario simple de satisfacción. Resultados: Diez pacientes (91%) tenían artrosis en alguna de las articulaciones vecinas. El puntaje medio en la escala analógica visual fue de 2,6 y el de la escala de la AOFAS, de 71. Nueve refirieron estar muy satisfechos; uno, medianamente satisfecho y otro se manifestó insatisfecho. Conclusión: El compromiso de las articulaciones vecinas es muy frecuente a largo plazo, pero esto no repercute directamente en los resultados funcionales.