Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

Virtual Education in Urogynecology: Enhancing Understanding and Management of Pelvic Fistulas.

Introduction: Pelvic fistulas affect a significant number of patients globally, with a relatively low prevalence in the United States. Virtual education offers an effective, scalable solution to bridge this educational gap and lead to a deeper understanding of more common conditions, such as urinary and fecal incontinence. Methods: We developed two virtual cases on rectovaginal and vesicovaginal/ureterovaginal fistulas to enhance medical students' exposure, knowledge, and confidence regarding assessment of pelvic fistulas. The cases could be completed in approximately 30 minutes, asynchronously, and at students' own pace. The cases were integrated into an OB/GYN clerkship. We conducted a survey among students receiving the cases to gather feedback on usability, acceptability, and educational value, which guided subsequent improvements. Results: Forty medical students, ranging from first to third year, participated in the urogynecology elective; 21 (53%) completed the survey. Ninety-one percent agreed or strongly agreed they were satisfied with the cases. All respondents found the format easy to use and appropriate for their level of learning. Most reported the cases improved their confidence in nonsurgical and surgical management options for pelvic fistulas. Discussion: Offering virtual and interactive patient cases on e-learning platforms represents an innovative approach to increasing clinical exposure to urogynecologic disorders. By providing medical students with the opportunity to interact with pelvic fistulas virtually, these cases can help bridge a gap in clinical education. Future exploration is valuable for examining knowledge deficiencies and developing cost-effective, self-paced, easily accessible educational resources to advance medical training and optimize patient care.

Chlorophyll a in lakes and streams of the United States (2005-2022).

The concentration of chlorophyll a in phytoplankton and periphyton represents the amount of algal biomass. We compiled an 18-year record (2005-2022) of pigment data from water bodies across the United States (US) to support efforts to develop process-based, machine learning, and remote sensing models for prediction of harmful algal blooms (HABs). To our knowledge, this dataset of nearly 84,000 sites and over 1,374,000 pigment measurements is the largest compilation of harmonized discrete, laboratory-extracted chlorophyll data for the US. These data were compiled from the Water Quality Portal (WQP) and previously unpublished U.S. Geological Survey's National Water Quality Laboratory (NWQL) data. Data were harmonized for reporting units, pigment type, duplicate values, collection depth, site name, negative values, and some extreme values. Across the country, data show great variation by state in sampling frequency, distribution, and methods. Uses for such data include the calibration of models, calibration of field sensors, examination of relationship to nutrients and other drivers, evaluation of temporal trends, and other applications addressing local to national scale concerns.

Heparin Dose Intensity and Organ Support-Free Days in Patients Hospitalized for COVID-19.

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.

Regulation of vascular endothelial integrity by mesenchymal stem cell extracellular vesicles after hemorrhagic shock and trauma.

BACKGROUND: Patients with hemorrhagic shock and trauma (HS/T) are vulnerable to the endotheliopathy of trauma (EOT), characterized by vascular barrier dysfunction, inflammation, and coagulopathy. Cellular therapies such as mesenchymal stem cells (MSCs) and MSC extracellular vesicles (EVs) have been proposed as potential therapies targeting the EOT. In this study we investigated the effects of MSCs and MSC EVs on endothelial and epithelial barrier integrity in vitro and in vivo in a mouse model of HS/T. This study addresses the systemic effects of HS/T on multiorgan EOT. METHODS: In vitro, pulmonary endothelial cell (PEC) and Caco-2 intestinal epithelial cell monolayers were treated with control media, MSC conditioned media (CM), or MSC EVs in varying doses and subjected to a thrombin or hydrogen peroxide (H2O2) challenge, respectively. Monolayer permeability was evaluated with a cell impedance assay, and intercellular junction integrity was evaluated with immunofluorescent staining. In vivo, a mouse model of HS/T was used to evaluate the effects of lactated Ringer's (LR), MSCs, and MSC EVs on endothelial and epithelial intercellular junctions in the lung and small intestine as well as on plasma inflammatory biomarkers. RESULTS: MSC EVs and MSC CM attenuated permeability and preserved intercellular junctions of the PEC monolayer in vitro, whereas only MSC CM was protective of the Caco-2 epithelial monolayer. In vivo, both MSC EVs and MSCs mitigated the loss of endothelial adherens junctions in the lung and small intestine, though only MSCs had a protective effect on epithelial tight junctions in the lung. Several plasma biomarkers including MMP8 and VEGF were elevated in LR- and EV-treated but not MSC-treated mice. CONCLUSIONS: In conclusion, MSC EVs could be a potential cell-free therapy targeting endotheliopathy after HS/T via preservation of the vascular endothelial barrier in multiple organs early after injury. Further research is needed to better understand the immunomodulatory effects of these products following HS/T and to move toward translating these therapies into clinical studies.

Communicating Alzheimer's biomarker results to cognitively unimpaired research participants: Satisfaction, utility, and impact on research attitudes.

Introduction: Recruitment and retention pose a significant challenge to Alzheimer's disease (AD) research. Returning AD biomarker results to participants has been proposed as a means to improve recruitment and retention. We present findings related to participant satisfaction, utility, and impact on research attitudes from the amyloid positron emission tomography (PET) disclosure sub-study within the Wisconsin Registry for Alzheimer's Prevention (WRAP). Methods: Ninety-nine cognitively unimpaired WRAP participants learned their amyloid PET results (mean age ± SD = 72.0 ± 4.8). Measures of reasons for wanting to learn results, study comprehension, result utility, visit satisfaction, research attitudes, and future study enrollment willingness were collected. Between-group, chi-squared analysis was conducted to determine differences by result type (elevated vs. not elevated amyloid PET result) in study comprehension, result utility, and visit satisfaction. Linear mixed-effects modeling was used to evaluate changes in research attitudes and enrollment willingness as a function of time, amyloid result type (elevated/not elevated), and their interaction. Results: The reasons most frequently endorsed for wanting to learn amyloid PET result was a "desire to contribute to research on Alzheimer's disease dementia" and "to inform preventative measures [one] might take (e.g., change diet, exercise, or other lifestyle changes)." Overall, participants reported understanding the results and found learning them useful. Satisfaction with the study visits was overwhelmingly high, with over 80% agreeing with visit usefulness and their satisfaction. Few differences were found between participants who learned an elevated and not elevated result. Over the course of the study, participants who learned an elevated amyloid PET result reported higher willingness to enroll in drug trials (beta: 0.12, p = 0.01) and lifestyle interventions (beta: 0.10, p = 0.02) compared to participants who learned a not elevated result. Discussion: Formal incorporation of disclosure practices may encourage participant recruitment and retention within AD research. Highlights: Participants wanted to learn their amyloid results to contribute to research.Satisfaction with disclosure and post-disclosure visits was high overall.Returning AD biomarkers can increase willingness to participate in research.

Factors influencing hospital charges for tonsillectomy to treat obstructive sleep apnea in children.

PURPOSE: This study investigates the impact of patient characteristics and demographics on hospital charges for tonsillectomy as a treatment for pediatric obstructive sleep apnea (OSA). The aim is to identify potential disparities in hospital charges and contribute to efforts for equitable access to care. METHODS: Data from the 2016 Healthcare Cost and Utilization Project (HCUP) Kid Inpatient Database (KID) was analyzed. The sample included 3,304 pediatric patients undergoing tonsillectomy ± adenoidectomy for OSA. Variables such as age, race, length of stay, hospital region, residential location, payer information, and median household income were collected. The primary outcome variable was hospital charge. Statistical analyses, including t-tests, ANOVA, and multiple linear regression, were conducted. RESULTS: Among 3,304 pediatric patients undergoing tonsillectomy for OSA. The average total charges for tonsillectomy were $26,400, with a mean length of stay of 1.70 days. Significant differences in charges were observed based on patient race, hospital region, and payer information. No significant differences were found based on gender, discharge quarter, residential location, or median household income. Multiple linear regression showed race, hospital region, and residential location were significant predictors of total hospital charges. CONCLUSION: This study highlights the influence of patient demographics and regional factors on hospital charges for pediatric tonsillectomy in OSA cases. These findings underscore the importance of addressing potential disparities in healthcare access and resource allocation to ensure equitable care for children with OSA. Efforts should be made to promote fair and affordable treatment for all pediatric OSA patients, regardless of their demographic backgrounds.

The effect of anatomic location on porcine models of burn injury and wound healing.

Porcine models are frequently used for burn healing studies; however, factors including anatomic location and lack of standardised wound methods can impact the interpretation of wound data. The objectives of this study are to examine the influence of anatomical locations on the uniformity of burn creation and healing in porcine burn models. To optimise burn parameters on dorsal and ventral surfaces, ex vivo and in situ euthanized animals were first used to examine the location-dependence of the burn depth and contact time relationship. The location-dependent healing in vivo was then examined using burn and excisional wounds at dorsal, ventral, caudal and cranial locations. Lactate dehydrogenase (LDH) and H&E were used to assess burn depth and wound re-epithelialization. We found that burn depth on the ventral skin was significantly deeper than that of the dorsal skin at identical thermal conditions. Compared with burns created ex vivo, burns created in situ immediately post-mortem were significantly deeper in the ventral location. In live animals, 2 out of 12 burn wounds were fully re-epithelialized after 14 days in contrast to complete re-epithelialization of all excisional wounds. Among the burn wounds, those at the cranial-dorsal site exhibited faster healing than at the caudal-dorsal site. This study showed that anatomical location is an important consideration for the consistency of burn depth creation and healing. These data support symmetric localization of treatment and control for comparative assessment of burn healing in porcine models to prevent misinterpretation of results and increase the translatability of findings to humans.

The porcine skin microbiome exhibits broad fungal antagonism.

The skin and its microbiome function to protect the host from pathogen colonization and environmental stressors. In this study, using the Wisconsin Miniature Swine™ model, we characterize the porcine skin fungal and bacterial microbiomes, identify bacterial isolates displaying antifungal activity, and use whole-genome sequencing to identify biosynthetic gene clusters encoding for secondary metabolites that may be responsible for the antagonistic effects on fungi. Through this comprehensive approach of paired microbiome sequencing with culturomics, we report the discovery of novel species of Corynebacterium and Rothia. Further, this study represents the first comprehensive evaluation of the porcine skin mycobiome and the evaluation of bacterial-fungal interactions on this surface. Several diverse bacterial isolates exhibit potent antifungal properties against opportunistic fungal pathogens in vitro. Genomic analysis of inhibitory species revealed a diverse repertoire of uncharacterized biosynthetic gene clusters suggesting a reservoir of novel chemical and biological diversity. Collectively, the porcine skin microbiome represents a potential unique source of novel antifungals.

Reward, relief, and habit drinking profiles in treatment seeking individuals with an AUD.

AIMS: This study aimed to compare reward, relief, and habit treatment-seeking individuals on recent drinking, alcohol use disorder (AUD) phenomenology, and mood. The second aim of the study was to evaluate the predictive validity of reward, relief, and habit profiles. METHOD: Treatment-seeking individuals with an AUD (n = 169) were recruited to participate in a medication trial for AUD (NCT03594435). Reward, relief, and habit drinking groups were assessed using the UCLA Reward Relief Habit Drinking Scale. Group differences at baseline were evaluated using univariate analyses of variance. A subset of participants were enrolled in a 12-week, double-blind, placebo-controlled medication trial (n = 102), and provided longitudinal drinking and phenomenology data. The predictive validity of group membership was assessed using linear regression analyses. RESULTS: At baseline, individuals who drink primarily for relief had higher craving and negative mood than those who drink for reward and habit. Prospectively, membership in the relief drinking group predicted greater alcohol use, greater heavy drinking, and fewer days abstinent compared to those in the reward drinking group. Membership in the relief drinking group also predicted greater alcohol craving, more alcohol-related consequences, and more anxiety symptoms over 12 weeks compared to those in the reward drinking group. CONCLUSIONS: This study provides support for reward and relief drinking motive profiles in treatment-seeking individuals with an AUD. Membership in the relief drinking motive group was predictive of poorer drinking outcomes and more negative symptomology over 12 weeks, indicating that individuals who drink for relief may be a particularly vulnerable sub-population of individuals with AUD.

Bridging the Gap: Integrating Awareness of Polycystic Ovary Syndrome Into Mental Health Practice.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Individuals with PCOS report reduced quality of life compared with those without PCOS, with possible contributing factors including infertility, hirsutism, irregular menses, and weight gain. Recent literature also supports increased associations between PCOS and co-occurring psychiatric conditions, particularly depression, anxiety, bipolar disorder, and eating disorders. It is concerning that a higher prevalence of suicidal ideation has been observed in individuals with PCOS. Given the high rates of psychiatric burden among those with PCOS, psychiatric care providers are well suited to be on the front lines of screening for psychiatric symptoms as well as initiating treatment. Current interventions include lifestyle changes (improving exercise and nutrition), pharmacological treatments (e.g., insulin-sensitizing agents, oral contraceptives, and psychotropic drugs), and psychotherapeutic interventions (e.g., cognitive-behavioral therapy and mindfulness-based therapy). This review provides an overview of recent research on the prevalence of comorbid psychiatric conditions, a foundation in PCOS-specific symptom screening and diagnosis, and an overview of treatments for psychiatric symptoms among individuals with PCOS.

Combined metagenomic- and culture-based approaches to investigate bacterial strain-level associations with medication-controlled mild-moderate atopic dermatitis.

Background: The skin microbiome is disrupted in atopic dermatitis (AD). Existing research focuses on moderate to severe, unmedicated disease. Objective: We sought to investigate metagenomic- and culture-based bacterial strain-level differences in mild, medicated AD and the effects these have on human keratinocytes (HKs). Methods: Skin swabs from anterior forearms were collected from 20 pediatric participants (11 participants with AD sampled at lesional and nonlesional sites and 9 age- and sex-matched controls). Participants had primarily mild to moderate AD and maintained medication use. Samples were processed for microbial metagenomic sequencing and bacterial isolation. Isolates identified as Staphylococcus aureus were tested for enterotoxin production. HK cultures were treated with cell-free conditioned media from representative Staphylococcus species to measure barrier effects. Results: Metagenomic sequencing identified significant differences in microbiome composition between AD and control groups. Differences were seen at the species and strain levels for Staphylococci, with S aureus found only in participants with AD and differences in Staphylococcus epidermidis strains between control and AD swabs. These strains showed differences in toxin gene presence, which was confirmed in vitro for S aureus enterotoxins. The strain from the participant with the most severe AD produced enterotoxin B levels more than 100-fold higher than the other strains (P < .001). Strains also displayed differential effects on HK metabolism and barrier function. Conclusions: Strain-level differences in toxin genes from Staphylococcus strains may explain varying effects on HK, with S aureus and non-aureus strains negatively affecting viability and barrier function. These differences are likely important in AD pathogenesis.

Can behaviorally inhibited preschoolers make friends?

Preschoolers who display extremely inhibited behavior are at risk for the development of anxiety disorders. However, behavioral inhibition (BI) is a multifaceted characteristic. Some children with BI are fearful when confronted by unfamiliar adults, peers, and objects; others are fearful when separated from their parents. In the present study, we examined specific features of BI that predicted observed friendship formation among preschoolers who are behaviorally inhibited. We also examined whether teacher ratings of classroom behaviors predicted friendship formation. Sixty highly inhibited children (35 female, Mage = 52.57 months) were observed during eight weekly free-play sessions with initially unfamiliar inhibited peers. Free-play periods occurred before weekly intervention sessions for children with BI and their parents. An observational protocol was developed to identify children who made a friend during the eight weekly sessions. Before the first session, different subtypes of BI were assessed by parents; preschool teachers assessed the children's classroom behaviors with familiar peers. Twenty-six children met the criteria for having made and kept a friend. Probit regression analyses revealed that parent ratings of BI among unfamiliar peers and teacher ratings of children's social anxiety before the intervention were associated with a decreased probability of making a friend. No evidence was found linking children's responses to the intervention and friendship formation. Results suggest that extremelyinhibited preschoolers are capable of making friends. Implications for future research and intervention efforts that focus on individual differences of children with BI are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Fetal cardiac screening: 1st trimester and beyond.

Congenital heart defects (CHD) are the most common birth defect and a leading cause of infant morbidity and mortality. CHD often occurs in low-risk pregnant patients, which underscores the importance of routine fetal cardiac screening at the time of the 2nd trimester ultrasound. Prenatal diagnosis of CHD is important for counseling and decision-making, focused diagnostic testing, and optimal perinatal and delivery management. As a result, prenatal diagnosis has led to improved neonatal and infant outcomes. Updated fetal cardiac screening guidelines, coupled with technological advancements and educational efforts, have resulted in increased prenatal detection of CHD in both low- and high-risk populations. However, room for improvement remains. In recent years, fetal cardiac screening for specific high-risk populations has started in the 1st trimester, which is a trend that is likely to expand over time. This review discusses fetal cardiac screening throughout pregnancy.

What is slough? Defining the proteomic and microbial composition of slough and its implications for wound healing.

Slough is a well-known feature of non-healing wounds. This pilot study aims to determine the proteomic and microbiologic components of slough as well as interrogate the associations between wound slough components and wound healing. Ten subjects with slow-to-heal wounds and visible slough were enrolled. Aetiologies included venous stasis ulcers, post-surgical site infections and pressure ulcers. Patient co-morbidities and wound healing outcome at 3-months post-sample collection was recorded. Debrided slough was analysed microscopically, through untargeted proteomics, and high-throughput bacterial 16S-ribosomal gene sequencing. Microscopic imaging revealed wound slough to be amorphous in structure and highly variable. 16S-profiling found slough microbial communities to associate with wound aetiology and location on the body. Across all subjects, slough largely consisted of proteins involved in skin structure and formation, blood-clot formation and immune processes. To predict variables associated with wound healing, protein, microbial and clinical datasets were integrated into a supervised discriminant analysis. This analysis revealed that healing wounds were enriched for proteins involved in skin barrier development and negative regulation of immune responses. While wounds that deteriorated over time started off with a higher baseline Bates-Jensen Wound Assessment Score and were enriched for anaerobic bacterial taxa and chronic inflammatory proteins. To our knowledge, this is the first study to integrate clinical, microbiome, and proteomic data to systematically characterise wound slough and integrate it into a single assessment to predict wound healing outcome. Collectively, our findings underscore how slough components can help identify wounds at risk of continued impaired healing and serves as an underutilised biomarker.

Optimal sample size division in two-stage seamless designs.

Inferentially seamless 2/3 designs are increasingly popular in clinical trials. It is important to understand their relative advantages compared with separate phase 2 and phase 3 trials, and to understand the consequences of design choices such as the proportion of patients included in the phase 2 portion of the design. Extending previous work in this area, we perform a simulation study across multiple numbers of arms and efficacy response curves. We consider a design space crossing the choice of a separate versus seamless design with the choice of allocating 0%-100% of available patients in phase 2, with the remainder in phase 3. The seamless designs achieve greater power than their separate trial counterparts. Importantly, the optimal seamless design is more robust than the optimal separate program, meaning that one range of values for the proportion of patients used in phase 2 (30%-50% of the total phase 2/3 sample size) is nearly optimal for a wide range of response scenarios. In contrast, a percentage of patients used in phase 2 for separate trials may be optimal for some alternative scenarios but decidedly inferior for other alternative scenarios. When operationally and scientifically viable, seamless trials provide superior performance compared with separate phase 2 and phase 3 trials. The results also provide guidance for the implementation of these trials in practice.

Upper respiratory microbial communities of healthy populations are shaped by niche and age.

Background: Alterations in upper respiratory microbiomes have been implicated in shaping host health trajectories, including by limiting mucosal pathogen colonization. However, limited comparative studies of respiratory microbiome development and functioning across age groups have been performed. Herein, we perform shotgun metagenomic sequencing paired with pathogen inhibition assays to elucidate differences in nasal and oral microbiome composition and functioning across healthy 24-month-old infant (n=229) and adult (n=100) populations. Results: We find that beta diversity of nasal and oral microbiomes varies with age, with nasal microbiomes showing greater population-level variation compared to oral microbiomes. Infant microbiome alpha diversity was significantly lower across nasal samples and higher in oral samples, relative to adults. Accordingly, we demonstrate significant differences in genus- and species-level composition of microbiomes between sites and age groups. Antimicrobial resistome patterns likewise varied across body sites, with oral microbiomes showing higher resistance gene abundance compared to nasal microbiomes. Biosynthetic gene clusters encoding specialized metabolite production were found in higher abundance across infant oral microbiomes, relative to adults. Investigation of pathogen inhibition revealed greater inhibition of gram-negative and gram-positive bacteria by oral commensals, while nasal isolates had higher antifungal activity. Conclusions: In summary, we identify significant differences in the microbial communities inhabiting nasal and oral cavities of healthy infants relative to adults. These findings inform our understanding of the interactions impacting respiratory microbiome composition and functioning, with important implications for host health across the lifespan.