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Abstract Electric grids with buses that are mapped to geographic latitude and longitude are useful for a growing number of applications, such as data visualization, geomagnetically induced current calculations, and multi-energy coupled infrastructure simulations. This paper presents a methodology for validating the quality of geographic coordinates for a power system model, and to assign coordinates to buses with missing or low-quality coordinates. This method takes advantage of geographic indicators already intrinsic to a grid model, such as branch length as implied by impedance and susceptance parameters. The coordinate assignment process uses an approach inspired by graph drawing, that lays out the vertices (buses) and edges (transmission lines), formulated as a nonlinear programming problem with soft edge length constraints. The layout method is very computationally fast and scalable to large power system cases. The method is demonstrated in this paper using a 37-bus test case and a 6717-bus test case, both publicly available, along with a large actual grid model. The results show that, for cases with only a few errors in the coordinates, cases with no coordinates known beforehand, and others in between, this method is able to assign reasonable geographic coordinates to best match known data about the grid.

Abstract Hypersonic vehicles must withstand extreme conditions during flights that exceed five times the speed of sound. These systems have the potential to facilitate rapid access to space, bolster defense capabilities, and create a new paradigm for transcontinental earth-to-earth travel. However, extreme aerothermal environments create significant challenges for vehicle materials and structures. This work addresses the critical need to develop resilient refractory alloys, composites, and ceramics. We will highlight key design principles for critical vehicle areas such as primary structures, thermal protection, and propulsion systems; the role of theory and computation; and strategies for advancing laboratory-scale materials to manufacturable flight-ready components.

313 Background: Advanced molecular PET/CT (mPET) studies are increasingly being utilized in conjunction with multiparametric MRI (mpMRI) to evaluate the burden of radiorecurrent disease in men who develop a biochemical recurrence following definitive radiotherapy (RT) for prostate cancer (PCa). However, radiographic concordance with pathologic confirmation of radiorecurrent disease in this setting is poorly described. We sought to conduct a patient-level analysis comparing concordance of radiographic and pathologic findings between mpMRI and mPET. Methods: Men who had previously undergone definitive RT for PCa and subsequently experienced treatment failure defined by the Phoenix definition were enrolled in a prospective registry study wherein radiographically identified local PCa recurrences were biopsied using mpMRI or mPET fusion (Artemis) with real-time ultrasound. Prior to biopsy, men underwent diagnostic imaging with mpMRI, advanced mPET (68Ga-PSMA-11 or 18F-FACBC), or both in order to identify a biopsy target. At least one imaging modality had to reveal a recurrent lesion based on PIRADS or PROMISE imaging classifications in order to prompt biopsy. Radiographic and pathologic findings were classified as either “treatment effect” or “recurrent disease”. Using biopsy as the reference standard, positive predictive value (PPV) was evaluated for mpMRI and mPET modalities separately. Results: Of 28 patients with radiographic recurrence on mpMRI or mPET, 10/28 (35.7%) exhibited treatment effect without evidence of active cancer on biopsy confirmation. Prostate adenocarcinoma was identified in 17/28 patient biopsies, whereas small cell prostate cancer was present in 1 patient. All 28 men underwent mpMRI prior to biopsy and 23/28 (82.1%) additionally underwent mPET; 19/23 (82.6%) underwent 68Ga-PSMA-11 and 4/23 (17.4%) were imaged with 18F-FACBC. Concordance in the assessment of recurrent disease between mpMRI and mPET was achieved in 12/23 (52.2%) men who underwent both imaging modalities. Among the 28 men who underwent mpMRI, PPV was 0.84, whereas PPV for the 23 men who underwent mPET was 0.70. Conclusions: In patients for whom clinical suspicion of radiorecurrence was high enough to warrant a biopsy, pre-biopsy mpMRI outperforms mPET in terms of PPV for detecting pathologically confirmed locally radiorecurrent PCa. Used in tandem, mpMRI and mPET might better select appropriate candidates for biopsy than either radiographic modality alone. While advanced mPET remains promising for detecting distant recurrences at the time of RT failure, biopsy confirmation following radiographic detection of local radiorecurrence remains essential for evaluating the true burden of local recurrence.

BackgroundMethods for inferring the three-dimensional (3D) configuration of chromatin from conformation capture assays that provide strictly pairwise interactions, notably Hi-C, utilize the attendant contact matrix as input. More recent assays, in particular split-pool recognition of interactions by tag extension (SPRITE), capture multi-way interactions instead of solely pairwise contacts. These assays yield contacts that straddle appreciably greater genomic distances than Hi-C, in addition to instances of exceptionally high-order chromatin interaction. Such attributes are anticipated to be consequential with respect to 3D genome reconstruction, a task yet to be undertaken with multi-way contact data. However, performing such 3D reconstruction using distance-based reconstruction techniques requires framing multi-way contacts as (pairwise) distances. Comparing approaches for so doing, and assessing the resultant impact of long-range and multi-way contacts, are the objectives of this study.ResultsWe obtained 3D reconstructions via multi-dimensional scaling under a variety of weighting schemes for mapping SPRITE multi-way contacts to pairwise distances. Resultant configurations were compared following Procrustes alignment and relationships were assessed between associated Procrustes root mean square errors and key features such as the extent of multi-way and/or long-range contacts. We found that these features had surprisingly limited influence on 3D reconstruction, a finding we attribute to their influence being diminished by the preponderance of pairwise contacts.ConclusionDistance-based 3D genome reconstruction using SPRITE multi-way contact data is not appreciably affected by the weighting scheme used to convert multi-way interactions to pairwise distances.

BackgroundA psychological symptom cluster is the most common cluster identified in oncology patients. Although inflammatory mechanisms are hypothesized to underlie this cluster, epigenetic contributions are unknown.ObjectivesThis study's purpose was to evaluate associations between the occurrence of a psychological symptom cluster and levels of DNA methylation for inflammatory genes in a heterogeneous sample of patients with cancer receiving chemotherapy.MethodsPrior to their second or third cycle of chemotherapy, 1,071 patients reported the occurrence of 38 symptoms using the Memorial Symptom Assessment Scale. A psychological cluster was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using Illumina Infinium 450K and EPIC microarrays. Expression-associated CpG (eCpG) loci in the promoter region of 114 inflammatory genes on the 450K and 112 genes on the EPIC microarray were evaluated for associations with the psychological cluster. Robust rank aggregation was used to identify differentially methylated genes across both samples. Significance was assessed using a false discovery rate of 0.05 under the Benjamini-Hochberg procedure.ResultsCluster of differentiation 40 ( CD40 ) was differentially methylated across both samples. All six promoter eCpGs for CD40 that were identified across both samples were hypomethylated in the psychological cluster group.ConclusionsThis study is the first to suggest associations between a psychological symptom cluster and differential DNA methylation of a gene involved in tissue inflammation and cell-mediated immunity. Our findings suggest that increased CD40 expression through hypomethylation of promoter eCpG loci is involved in the occurrence of a psychological symptom cluster in patients receiving chemotherapy. These findings suggest a direction for mechanistic studies.

BackgroundAdverse childhood experiences (ACEs) can have harmful, long-term health effects. Although primary care providers (PCPs) could help mitigate these effects, no studies have reviewed the impacts of ACE training, screening, and response in primary care.MethodsThis systematic review searched four electronic databases (PubMed, Web of Science, APA PsycInfo, CINAHL) for peer-reviewed articles on ACE training, screening, and/or response in primary care published between Jan 1, 1998, and May 31, 2023. Searches were limited to primary research articles in the primary care setting that reported provider-related outcomes (knowledge, confidence, screening behavior, clinical care) and/or patient-related outcomes (satisfaction, referral engagement, health outcomes). Summary data were extracted from published reports.FindingsOf 6532 records, 58 met inclusion criteria. Fifty-two reported provider-related outcomes; 21 reported patient-related outcomes. 50 included pediatric populations, 12 included adults. A majority discussed screening interventions (n = 40). Equal numbers (n = 25) discussed training and clinical response interventions. Strength of evidence (SOE) was generally low, especially for adult studies. This was due to reliance on observational evidence, small samples, and self-report measures for heterogeneous outcomes. Exceptions with moderate SOE included the effect of training interventions on provider confidence/self-efficacy and the effect of screening interventions on screening uptake and patient satisfaction.InterpretationPrimary care represents a potentially strategic setting for addressing ACEs, but evidence on patient- and provider-related outcomes remains scarce.FundingThe California Department of Health Care Services and the Office of the California Surgeon General.

ObjectivesWhile the gastrointestinal symptom cluster (GISC) is common in patients receiving chemotherapy, limited information is available on its underlying mechanism(s). Emerging evidence suggests a role for inflammatory processes through the actions of the nuclear factor kappa B (NF-κB) signaling pathway. This study evaluated for associations between a GISC and levels of DNA methylation for genes within this pathway.MethodsPrior to their second or third cycle of chemotherapy, 1071 outpatients reported symptom occurrence using the Memorial Symptom Assessment Scale. A GISC was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using EPIC (n = 925) and 450K (n = 146) microarrays. Trans expression-associated CpG (eCpG) loci for 56 NF-κB signaling pathway genes were evaluated. Loci significance were assessed using an exploratory false discovery rate (FDR) of 25% for the EPIC sample. For the validation assessment using the 450K sample, significance was assessed at an unadjusted p-value of 0.05.ResultsFor the EPIC sample, the GISC was associated with increased expression of lymphotoxin beta (LTB) at one differentially methylated trans eCpG locus (cg03171795; FDR = 0.168). This association was not validated in the 450K sample.ConclusionsThis study is the first to identify an association between a GISC and epigenetic regulation of a gene that is involved in the initiation of gastrointestinal immune responses. Findings suggest that increased LTB expression by hypermethylation of a trans eCpG locus is involved in the occurrence of this cluster in patients receiving chemotherapy. LTB may be a potential therapeutic target for this common cluster.

There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.

We conducted a dose-response study of dexamethasone to investigate an optimal dexamethasone suppression test for common marmosets. Twelve marmosets received 0.1, 0.5, or 1.0 mg/kg dexamethasone. Doses of 0.5 and 1.0 mg/kg both suppressed endogenous cortisol for at least 18 h with greater individual variability in the lower 0.5 mg/kg dose.

BackgroundAneurysms are rare anomalies of the portomesenteric venous system. Thrombotic complications of these lesions can lead to mesenteric venous ischemia and bowel infarction, potentially requiring surgical intervention. Herein we describe a case of mesenteric ischemia due to a large thrombosed portomesenteric aneurysm treated with endovascular techniques.Case presentationA 37-year-old previously healthy male who presented with abdominal pain to his local emergency department was found to have a thrombosed 12.0 × 5.1 cm portomesenteric venous aneurysm with evidence of mesenteric ischemia on CT. When conservative management with anticoagulation failed, transhepatic pharmacomechanical thrombolysis was initially performed. This was followed by TIPS placement with additional trans-TIPS thrombectomy to improve sluggish portal outflow and prevent re-thrombosis. The patient's symptoms and imaging findings of ischemia resolved after endovascular therapy. No surgical intervention was required, and the patient was discharged on enoxaparin before being transitioned to apixaban. The TIPS remained patent at 2-year follow-up, with no change in the size of the aneurysm or re-thrombosis noted. The patient's synthetic liver function was preserved with no evidence of hepatic encephalopathy during the follow-up period.ConclusionsEndovascular therapies may be used to manage thrombotic complications of portomesenteric venous aneurysms, obviating the need for surgical intervention in selected patients.

Purpose: To investigate the feasibility and accuracy of 3-dimensional (3D) iPhone scans using commercially available applications compared with computed tomography (CT) for mapping chondral surface topography of the knee. Methods: Ten cadaveric dysplastic trochleae, 16 patellae, and 24 distal femoral condyles (DFCs) underwent CT scans and 3D scans using 3 separate optical scanning applications on an iPhone X. The 3D surface models were compared by measuring surface-to-surface least distance distribution of overlapped models using a validated 3D-3D registration volume merge method. The absolute least mean square distances for the iPhone-generated models from each scanning application were calculated in comparison to CT models using a point-to-surface distance algorithm allowing regional “inside/outside” measurement of the absolute distance between models. Results: Only 1 of the 3 scanning applications created models usable for quantitative analysis. Overall, there was a median absolute least mean square distance between the usable model and CT-generated models of 0.18 mm. The trochlea group had a significantly lower median absolute least mean square distance compared with the DFC group (0.14 mm [interquartile range, 0.13-0.17] vs 0.19 mm [0.17-0.25], P = .002). iPhone models were smaller compared with CT models (negative signed distances) for all trochleae, 83% of DFCs, and 69% of patellae. Conclusions: In this study, we found minimal differences between a 3D iPhone scanning application and conventional CT scanning when analyzing surface topography. Clinical Relevance: Emerging 3D iPhone scanning technology can create accurate, inexpensive, real-time 3D models of the intended target. Surface topography evaluation may be useful in graft selection during surgical procedures such as osteochondral allograft transplantation.

Distributed energy resources, such as rooftop solar, have rapidly expanded in recent years, given declining costs and the desire to reduce carbon emissions. With more energy resources located in the lower-voltage distribution system, it is increasingly helpful to utilize combined transmission and distribution (T&D) system models to analyze interactions between these normally-distinct subsystems. This paper proposes a methodology for creating very large-scale, highly detailed, combined T&D systems that are synthetic—that is, free from non-public data—yet still realistic. The methodology creates very large-scale combined T&D systems by merging the most up-to-date techniques for creating synthetic distribution feeder networks with the latest methods for building synthetic, meshed bulk-power transmission networks. This methodology is demonstrated on a T&D system geolocated in Texas, and benchmarked with co-simulation results. Validation demonstrates that the resulting syn-texas-TDgrid synthetic test system realistically represents characteristics found in actual networks, addressing the lack of available T&D test systems. With over 15,000 feeders and 46 million electrical nodes, this T&D dataset has applications for research in optimal power flow algorithms, voltage control, reconfiguration, and T&D coordination schemes under high adoption of distributed energy resources.

Background: Chondral injuries in the knee are commonly discovered during knee arthroscopy procedures. Due to the poor restoration potential and avascular nature of cartilage, large defects are commonly treated with such surgical procedures. Treatment utilizing an osteochondral allograft (OCA) transplant for symptomatic focal cartilage defects in the patellofemoral joint has demonstrated strong, lasting clinical and radiographic outcomes. Indications: Active and otherwise healthy patients are indicated for surgery when presenting with significant joint-line pain and a large focal chondral defect verified on advanced imaging after an extensive course of nonoperative management. Technique Description: Beginning with diagnostic arthroscopy to confirm the large defect of the medial femoral condyle, we proceeded with OCA transplantation. A small medial peripatellar arthrotomy is performed. The fat pad is removed for visualization and retractors are placed both medially and laterally to appropriately visualize the defect. The defect is then sized according to the appropriate sizing guide. The guide is then placed perpendicular to the defect, and a central guide pin is drilled. A scoring reamer is used to carefully cut the size of the defect followed by a central reamer to prepare the defect. Any debris is removed, and the incision is thoroughly irrigated. The defect is then carefully measured in all four quadrants to match the donor. Any underlying bone is impacted for a stable base. A drill is then used for appropriate marrow venting underneath the defect. The corresponding donor site is selected and reamed with continuous irrigation to prevent thermal necrosis. The plug is removed and carefully measured to match the recipient site. The plug is thoroughly irrigated with pulse lavage to remove marrow elements. The graft is carefully inserted with gentle manual pressure until it is seated perfectly flush with the surrounding cartilage. Results: Clinical research has demonstrated good-to-excellent long-term survivorship of OCA transplantation. Long-term return to sport rates for recreational and competitive athletes are upward of 75%. Discussion/Conclusion: As surgical techniques continue to develop, surgeons should consider utilizing OCA transplants to treat large chondral defects in the patellofemoral joint. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Abstract The monocyte–macrophage system plays an important role in phagocytosis of pathogens and cellular debris following infection or tissue injury in several pathophysiological conditions. We examined ENaC/ASIC subunit transcript expression and the importance of select subunits in migration of bone marrow derived monocytes (freshly isolated) and macrophages (monocytes differentiated in culture). We also examined the effect of select subunit deletion on macrophage phenotype. BM monocytes were harvested from the femurs of male and female WT and KO mice (6–12 weeks of age). Our results show that α, β, γENaC, and ASIC1‐5 transcripts are expressed in BM macrophages and monocytes to varying degrees. At least αENaC, βENaC, and ASIC2 subunits contribute to chemotactic migration responses in BM monocyte–macrophages. Polarization markers (CD86, soluble TNFα) in BM macrophages from mice lacking ASIC2a plus βENaC were shifted towards the M1 phenotype. Furthermore, select M1 phenotypic markers were recovered with rescue of βENaC or ASIC2. Taken together, these data suggest that βENaC and ASIC2 play an important role in BM macrophage migration and loss of βENaC and/or ASIC2 partially polarizes macrophages to the M1 phenotype. Thus, targeting ENaC/ASIC expression in BM macrophages may regulate their ability to migrate to sites of injury.

Background:. This clinical literature systematic review and meta-analysis were performed to assess differences in outcomes between nerves repaired with direct repair (DR) and connector-assisted repair (CAR). Methods:. A systematic literature review for DR and CAR was performed. Studies from 1980 through August 2023 were included if DR or CAR repairs were performed in upper extremities with nerve gaps less than 5 mm and reported sensory Medical Research Council Classification (MRCC) outcomes or equivalent. Comparative analyses were planned for meaningful recovery (MR) rate (at both S3 and S3+ or better), postsurgical neuroma, cold intolerance, altered sensation, pain, and revision rate. Results:. There were significant differences in MR rates for CAR and DR. At the MRCC S3 threshold, 96.1% of CAR and 81.3% of DR achieved MR (P < 0.0001). At the MRCC S3+ threshold, 87.1% of CAR and 54.2% of DR achieved this higher threshold of MR (P < 0.0001). There were no differences in neuroma rate or pain scores in our dataset. Altered sensation (dysesthesia, paresthesia, hyperesthesia, or hypersensitivity) was not discussed in any CAR studies, so no analysis could be performed. The revision rate for both procedures was 0%. The proportion of patients with cold intolerance was 46.2% in the DR studies, which was significantly higher than the 10.7% of patients in the CAR group. Conclusions:. Significantly more patients achieved sensory MR and fewer had cold intolerance when the CAR technique, instead of the DR technique, was performed to repair peripheral nerve injuries.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb−/−), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb−/−mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

Purpose: To use Google trends to explore differences in public interest among types of anterior cruciate ligament (ACL) autografts, specifically quadriceps tendon, patellar tendon, and hamstring tendon autografts, between 2008 and 2019. Methods: Data were obtained by querying Google Trends for key terms and phrases for online search data ranging from January 2008 to December 2019. Relative search volumes were created based on searches related to ACL reconstruction with comparative analysis generated for search terms related to quadriceps ACL, patellar tendon ACL, and hamstring ACL autografts. Statistical analysis included linear regression analysis, comparison of quarterly search volume trends over time, and comparison of cumulative annual search volumes for 2008 versus 2019. Results: Linear models for respective search terms were statistically significant for the quadriceps (P < .001) and patellar (P = .007) tendon autograft groups but not the hamstring group (P = .129). The quadriceps autograft group demonstrated a 12-year search volume trend change of 0.56, which was significantly greater than the hamstring (0.07; P < .001) and patellar tendon (0.168; P < .001) groups. There was no significant difference in the trend change between hamstring and patellar tendon groups (P = .20). Percent change in cumulative relative annual search volumes between 2008 and 2019 was 112% for the quadriceps tendon group, 12.9% for the hamstring group, and 18.6% for the patellar tendon group. Conclusions: This study indicates a consistently increasing public interest in quadriceps tendon autograft for ACL reconstruction. The quadriceps autograft group demonstrated a significantly greater 12-year online search volume, greater linear correlation, and larger percent change between 2008 and 2019 compared with patellar tendon or hamstring autograft groups. Clinical Relevance: Awareness of patient perceptions has value in informing shared decision-making, aligning patient expectations, and guiding areas of future research. Each of these has an impact on patient care. Being aware of patient interest and expectations is particularly important in areas with controversial or emerging research.

Summary: Background: Diarrhoeal disease poses a significant global health challenge, especially in children under three years old. Despite the effectiveness of oral rehydration therapy (ORT), its adoption remains low. Glucose-based ORS (GORS) is the standard, but novel formulations like glucose-free amino acid-based VS002A have emerged as potential alternatives. This study aimed to compare the safety and efficacy of VS002A against the standard WHO-ORS in treating non-cholera acute watery diarrhoea in children. Methods: A triple-blind, randomized trial enrolled 310 male infants and children aged 6–36 months, who were assigned to receive WHO-ORS or VS002A over a 16-month period, from June 2021 to September 2022. Both groups received standard of care, including zinc supplementation. The Primary study outcome measured was the duration of diarrhoea. Secondary outcomes included stool output, treatment failure and adverse events. Exploratory endpoints included urinary output, body weight changes, blood biochemistry, stool microbiology and gut health biomarkers. Findings: Both VS002A and WHO-ORS were well-tolerated with a low adverse event rate. While not different statistically (p = 0.10), duration of diarrhoea was shorter in children treated with VS002A vs. WHO-ORS (65.4 h vs. 72.6 h). Similarly, stool output was also lower vs. WHO-ORS in children treated with VS002A, though not statistically different (p = 0.40). Serum citrulline levels, an indicator of gut health, were higher in the VS002A group at 24 h suggesting a potential protective effect (p = 0.06). Interpretation: The findings of this study support the non-inferiority of VS002A, a glucose-free amino acid-based ORS compared to the WHO-ORS standard of care. VS002A was shown to be safe and effective in treating non-cholera acute watery diarrhoea in young children. VS002A may offer advantages in pathogen-driven diarrhoea, supported by trends toward a lower duration of diarrhoea and stool output within the per protocol group. Furthermore, individuals with prolonged diarrhoea, severe malnutrition, environmental enteric dysfunction or have issues with obesity or insulin resistance, could benefit from a glucose-free ORS. This research contributes to addressing the persistent challenge of childhood diarrhoea by presenting an alternative glucose-free ORS formulation with potential advantages in select scenarios, offering a promising avenue for improving paediatric diarrhoea management worldwide. Funding: The study was funded by Entrinsic Bioscience, LLC., Norwood, MA, USA.

BackgroundInflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate.MethodsUsing clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability.ResultsA higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45 + leukocyte infiltration and elevation of three pro-inflammatory cytokines-TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest.ConclusionsThese data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD.