The acyltransferase Gpc1 is both a target and an effector of the unfolded protein response in Saccharomyces cerevisiae.

The unfolded protein response (UPR) is sensitive to proteotoxic and membrane bilayer stress, both of which are sensed by the ER protein Ire1. When activated, Ire1 splices HAC1 mRNA, producing a transcription factor that targets genes involved in proteostasis and lipid metabolism, among others. The major membrane lipid phosphatidylcholine (PC) is subject to phospholipase-mediated deacylation, producing glycerophosphocholine (GPC), followed by reacylation of GPC through the PC deacylation/reacylation pathway (PC-DRP). The reacylation events occur via a two-step process catalyzed first by the GPC acyltransferase Gpc1, followed by acylation of the lyso-PC molecule by Ale1. However, whether Gpc1 is critical for ER bilayer homeostasis is unclear. Using an improved method for C14-choline-GPC radiolabeling, we first show that loss of Gpc1 results in abrogation of PC synthesis through PC-DRP and that Gpc1 colocalizes with the ER. We then probe the role of Gpc1 as both a target and an effector of the UPR. Exposure to the UPR-inducing compounds tunicamycin, DTT, and canavanine results in a Hac1-dependent increase in GPC1 message. Further, cells lacking Gpc1 exhibit increased sensitivity to those proteotoxic stressors. Inositol limitation, known to induce the UPR via bilayer stress, also induces GPC1 expression. Finally, we show that loss of GPC1 induces the UPR. A gpc1Δ mutant displays upregulation of the UPR in strains expressing a mutant form of Ire1 that is unresponsive to unfolded proteins, indicating that bilayer stress is responsible for the observed upregulation. Collectively, our data indicate an important role for Gpc1 in yeast ER bilayer homeostasis.

Polarized macrophages promote gestational beta cell growth through extracellular signal-regulated kinase 5 signalling.

AIM: To show that depletion of pancreatic macrophages impairs gestational beta cell proliferation and leads to glucose intolerance. MATERIALS AND METHODS: Genetic animal models were applied to study the effects of depletion of pancreatic macrophges on gestational beta-cell proliferaiton and glucose response. The crosstalk between macrophages and beta-cells was studied in vivo using beta-cell-specific extracellular-signal-regulated kinase 5 (ERK5) knockout and epidermal growth receptor (EGFR) knockout mice, and in vitro using a co-culture system. RESULTS: Beta cell-derived placental growth factor (PlGF) recruited naïve macrophages and polarized them towards an M2-like phenotype. These macrophages then secreted epidermal growth factor (EGF), which activated extracellular signal-regulated kinase 5 (ERK5) signalling in beta cells to promote gestational beta cell proliferation. On the other hand, activation of ERK5 signalling in beta cells likely, in turn, enhanced the production and secretion of PlGF by beta cells. CONCLUSIONS: Our study shows a regulatory loop between macrophages and beta cells through PlGF/EGF/ERK5 signalling cascades to regulate gestational beta cell growth.

Amyloid-ß and p-Tau Anti-Threat Response to Herpes Simplex Virus 1 Infection in Primary Adult Murine Hippocampal Neurons.

Alzheimer's Disease (AD) is the sixth leading cause of death in the United States. Recent studies have established a potential link between herpes simplex virus 1 (HSV-1) infection and the development of AD. HSV-1 DNA has been detected in AD amyloid plaques in human brains, and treatment with the antiviral acyclovir (ACV) was reported to block the accumulation of the AD-associated proteins beta-amyloid (Aß) and hyper-phosphorylated tau (p-tau) in Vero and glioblastoma cells. Our goal was to determine whether the accumulation of AD-related proteins is attributable to acute and/or latent HSV-1 infection in mature hippocampal neurons, a region of the brain severely impacted by AD. Primary adult murine hippocampal neuronal cultures infected with HSV-1, with or without antivirals, were assessed for Aß and p-tau expression over 7 days postinfection. P-tau expression was transiently elevated in HSV-1-infected neurons, as well as in the presence of antivirals alone. Infected neurons, as well as uninfected neurons treated with antivirals, had a greater accumulation of Aß42 than uninfected untreated neurons. Furthermore, Aß42 colocalized with HSV-1 latency-associated transcript (LAT) expression. These studies suggest that p-tau potentially acts as an acute response to any perceived danger-associated molecular pattern (DAMP) in primary adult hippocampal neurons, while Aß aggregation is a long-term response to persistent threats, including HSV-1 infection.IMPORTANCE Growing evidence supports a link between HSV-1 infection and Alzheimer's disease (AD). Although AD is clearly a complex multifactorial disorder, an infectious disease etiology provides alternative therapy opportunities for this devastating disease. Understanding the impact that HSV-1 has on mature neurons and the proteins most strongly associated with AD pathology may identify specific mechanisms that could be manipulated to prevent progression of neurodegeneration and dementia.

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.

BACKGROUND: ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. METHODS: In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). RESULTS: ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. CONCLUSION: FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

Children's Conceptions of Ownership for Self and Other: Categorical Ownership Versus Strength of Claim.

Children are capable of viewing object ownership as categorical and exclusive, but ownership claims can also vary by degree. This study investigated how children use these different conceptions of ownership in a giving and a taking task. In two studies, 4- to 7-year olds (N = 105) could give and take craft objects that they or another child had found (weaker claim) and made (stronger claim). In Study 1, no additional ownership information was given, and in Study 2 categorical ownership was stated ("these belong to you"). The results showed that children used categorical ownership for their own objects but used ownership strength for the other child's objects, taking more of the found items.

How children use accuracy information to infer informant intentions and to make reward decisions.

The ability to assess the value of the information one receives and the intentions of the source of that information can be used to establish cooperative relationships and to identify cooperative partners. Across two experiments, 4- to 8-year-old children (N = 204) received a note with correct, incorrect, or no information that affected their efforts on a search task. Children were told that all informants had played the game before and knew the location of the hidden reward. In the no information condition, children were told that the informant needed to leave before finishing the note and, thus, was not intentionally uninformative. Children rated the note with correct information as more helpful than the note with no information; incorrect information was rated least helpful. When asked about the informant's intentions, children attributed positive intentions when the information was correct and when they received unhelpful information but knew the informant was not intentionally uninformative. Children attributed less positive intentions to the informant when they received incorrect information. When given the chance to reward the informant, children rewarded the informant who provided correct information and no information equally; the informant who provided incorrect information received fewer rewards. Combined, these results suggest that young children assume that informants have positive intentions even when they provide no useful information. However, when the information provided is clearly inaccurate, children infer more negative intentions and reward those informants at lower rates. These results suggest that children tend to reward informants more based on their presumed intentions, placing less weight on the value of the information they provide.

AAVMC Internship Program Guidelines 2018.

Veterinary internships are common 1-year post-graduate clinical training programs that are offered both at veterinary colleges and in private practice settings. To promote the quality of these training programs, the American Association of Veterinary Medical Colleges (AAVMC) charged a working group to develop these internship guidelines, which were approved by the AAVMC in 2018 and have also been endorsed by the American Association of Veterinary Clinicians. These guidelines are intended to be applicable to all internships, in both academic and private practice settings, and they place particular emphasis on three aspects of internship training programs: competency-based education, intern well-being, and program outcome.

BRCA1 and MAD2 Are Coexpressed and Are Prognostic Indicators in Tubo-ovarian High-Grade Serous Carcinoma.

OBJECTIVES: The aim of this study was to investigate the relationship between BRCA1 and mitotic arrest deficiency protein 2 (MAD2) protein expression, as determined by immunohistochemistry, and clinical outcomes in epithelial ovarian carcinoma (EOC). METHODS: A tissue microarray consisting of 94 formalin-fixed paraffin-embedded EOC with fully matched clinicopathological data were immunohistochemically stained with anti-BRCA1 and anti-MAD2 antibodies. The cores were scored in a semiquantitative manner evaluating nuclear staining intensity and extent. Coexpression of BRCA1 and MAD2 was evaluated, and patient survival analyses were undertaken. RESULTS: Coexpression of BRCA1 and MAD2 was assessed in 94 EOC samples, and survival analysis was performed on 65 high-grade serous carcinomas (HGSCs). There was a significant positive correlation between BRCA1 and MAD2 expression in this patient cohort (P < 0.0001). Both low BRCA1 and low MAD2 are independently associated with overall survival because of HGSC. Low coexpression of BRCA1 and MAD2 was also significantly associated with overall survival and was driven by BRCA1 expression. CONCLUSION: BRCA1 and MAD2 expressions are strongly correlated in EOC, but BRCA1 expression remains the stronger prognostic factor in HGSC.

Nonsurgical Admissions With Traumatic Injury: Medical Patients Are Trauma Patients Too.

Nontrauma service (NTS) admissions are an increasing problem as ground-level falls in elderly patients become more common. The admission and evaluation of trauma patients to nontrauma services in trauma centers seeking American College of Surgeons (ACS) verification, must follow the ACS mandates for performance improvement requiring some method of evaluating this population when admitted to services other than trauma, orthopedics, and neurosurgery. The purpose of this study and performance improvement project was to improve our process for the definition and evaluation of trauma patients who were being admitted to nontrauma services. We designed an algorithm to evaluate appropriateness of NTS admission and evaluated outcomes for NTS admissions utilizing that algorithm.We created a scoring algorithm and evaluated appropriateness of NTS admission over 2 years in a community-teaching ACS Level II trauma center. We reviewed trauma registry data using χ and Fisher exact tests to determine differences in outcome for NTS versus trauma service (TS) admissions.From December 2014 to December 2016, NTS admission rate fell from maximum of 28% to 4% stabilizing between 8% and 10%. Mortality and overall complication rate between NTS and TS were similar (p = .40 and .66, respectively), but length of stay was lower for TS admissions (p < .0001).A scoring system of algorithm can be used to determine appropriateness of NTS admissions, and validity of the tool can be confirmed using registry-based outcome data for TS versus NTS admissions.

FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis.

OBJECTIVE: The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models. APPROACH AND RESULTS: FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL's critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl(+/-) mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish. CONCLUSIONS: FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes.

Imaging and Clinical Outcomes in 20 Dogs Treated with Thin Film Banding for Extrahepatic Portosystemic Shunts.

OBJECTIVE: To prospectively evaluate the efficacy of thin film band attenuation of congenital extrahepatic portosystemic shunts (CEPSS) in dogs using clinical, biochemical, and imaging-related outcome measures. STUDY DESIGN: Prospective case series. ANIMALS: Dogs with CEPSS (n=20). METHODS: Client-owned dogs with CEPSS were enrolled and thin film banding of the shunting vessel was performed. Before and at least 6 months after surgery, serum bile acids and computed tomography (CT) angiography were performed and owners completed a health questionnaire regarding the dog's clinical signs. Postoperative CT images were assessed for the effectiveness of band closure, change in portal vein/aorta ratio, change in liver volume/weight ratio, and whether the band was placed in the appropriate location. Preoperative and postoperative health questionnaire data and serum bile acids were compared. RESULTS: The band resulted in complete closure of the vessel around which it was placed in 13 dogs. In the remaining 7 dogs, the vessel lumen was narrowed but not completely closed. In 8 dogs the band location was suboptimal, allowing systemic drainage of visceral blood or secondary shunting branches to persist. Liver volume/body weight ratios and portal vein/aorta diameter ratios increased in most dogs. Serum bile acids decreased in all but 1 dog and owners reported improved health in 19 dogs. CONCLUSION: Thin film banding resulted in complete occlusion of many, but not all vessels around which it was placed. Even in dogs with inappropriate band location or with incomplete closure, clinical improvement can be expected based on our results.

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 µg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

Polygenic control of Caenorhabditis elegans fat storage.

Tubby mice and individuals with Bardet-Biedl syndrome have defects in ciliated neuron function and obesity, suggesting an as-yet unknown metabolic signaling axis from ciliated neurons to fat storage tissues. Here we show coordinate regulation of Caenorhabditis elegans fat storage by orthologues of these genes acting in ciliated neurons and by a 3-ketoacyl-coA thiolase (encoded by kat-1) that acts in fat storage tissue. A genetic screen for markedly enhanced fat storage in tub-1 mutants led to the isolation only of kat-1 alleles, which impair fatty acid beta-oxidation. kat-1 acts in the intestine, the major C. elegans fat storage tissue, and is transcriptionally upregulated in animals with high fat storage. A genetic screen for synergistic increase in fat storage of a kat-1 mutant identified bbs-1. bbs-1 acts in 15 ciliated neurons that are poised to sense external and internal nutrient levels, supporting a model in which bbs-1 and tub-1 in ciliated neurons form part of an ancient, conserved neuroendocrine axis. This pathway also includes genes encoding intraflagellar transport proteins and cyclic nucleotide gated channels, demonstrating that C. elegans fat storage is under polygenic control.

Versatility of the Angularis Oris Axial Pattern Flap for Facial Reconstruction.

OBJECTIVE: To describe the versatility of the axial pattern flap based on the cutaneous perforating branch of the angularis oris artery for reconstruction of large facial defects in dogs, including complications and clinical outcomes. STUDY DESIGN: Retrospective clinical case series. ANIMALS: Client-owned dogs (n = 8). METHODS: Facial flaps (n = 9) based at the commissure of the lip with a caudodorsal orientation were utilized, with established anatomical borders. Flaps were elevated deep to the panniculus carnosus in a caudal to rostral direction, preserving the angularis oris artery, its cutaneous perforator, and surrounding cutaneous vasculature. Flaps were rotated dorsally or ventrally to cover the defect. Primary closure of the donor site was by direct apposition in all cases. RESULTS: Angularis oris axial pattern flaps were most commonly used to close large defects of the nasomaxillary area rostral to the eyes (6 dogs), followed by orbital (2) and intermandibular (1) defects. Defects occurred because of tumor resection (6 dogs), trauma (2), and a chronic, non-healing wounding (1). All flaps healed with acceptable functional and cosmetic outcomes without major complications. Followup ranged from 10 days to 16 months. Minor postoperative complications included flap edema (8 dogs), partial incisional dehiscence (3), distal tip necrosis (2), and oroantral fistula recurrence (1). CONCLUSION: Angularis oris axial pattern flaps provided hirsute, full-thickness skin coverage of a variety of large facial defects with minor complications, and should be considered when restructuring large defects of the rostral face or chin.

Anorexigenic effects of central adrenomedullin are associated with hypothalamic changes in juvenile Gallus gallus.

Adrenomedullin (AM), a 52 residue neuropeptide, is associated with anorexia in mammals and has a poorly understood central mechanism of action. Thus, this study focused on elucidating AM's central mechanism of action in an alternative vertebrate model, the chick (Gallus gallus). In Experiment 1, chicks centrally injected with AM dose-dependently reduced food but not water intake. In Experiment 2, those chicks that received central AM had increased c-Fos immunoreactivity in the magnocellular division of the paraventricular nucleus (PaMC), ventromedial hypothalamus (VMH) and doromedial hypothalamus (DM). The lateral hypothalamic area, parvocellular division of the paraventricular hypothalamus and the arcuate nucleus were not affected. In Experiment 3, antagonism of corticotrophin releasing factor (CRF) receptors did not affect AM-associated anorexia. In Experiment 4, a comprehensive behavior analysis was conducted and AM-treated chicks pecked less, moved more, jumped more and spent more time in deep rest. In conclusion, exogenous AM induced anorexia is associated with activation of the PaMC, VMH and DM of the hypothalamus, is not CRF dependent, and affects behaviors unrelated to food intake in chicks.

Inhibitory effect of combinations of caprylic acid and nisin on Listeria monocytogenes in queso fresco.

Queso fresco (QF), a fresh Hispanic cheese has been linked to outbreaks and recalls caused by Listeria contamination. The use antimicrobial treatments may be a potential solution. The goal of this research was to test the addition of nisin (N), caprylic acid (CA) and trans-cinnamaldehyde (CN) as anti-listerial ingredients in QF. QF batches were inoculated with approx. 10(4) CFU/g of 5- or 6-strain mixtures of Listeria monocytogenes and treated with antimicrobials. Samples were stored at 4 °C for three weeks and Listeria counts were determined by plating on PALCAM agar. The impact on the QF's natural indicator microorganisms was also assessed during refrigerated storage. All N and CA combinations (≥0.4 g/kg each) were effective against L. monocytogenes and reduced the final counts by at least 3 log CFU/g after 20 days of storage compared to controls. The levels of most strain mixtures were reduced immediately after treatment and their numbers remained below 10(3) CFU/g during storage. CN (1.2 g/kg) was bacteriostatic against L. monocytogenes, but it did not reduce initial counts. The addition of CN to the combination of N and CA did not enhance their antimicrobial effect. Results indicated that combinations of N and CA could control L. monocytogenes in QF with little impact on the natural flora of the cheese, providing a solution to control post processing L. monocytogenes contamination of QF.

Configural and featural information in facial-composite images.

Eyewitnesses are often invited to construct a facial composite, an image created of the person they saw commit a crime that is used by law enforcement to locate criminal suspects. In the current paper, the effectiveness of composite images was investigated from traditional feature systems (E-FIT and PRO-fit), where participants (face constructors) selected individual features to build the face, and a more recent holistic system (EvoFIT), where they 'evolved' a composite by repeatedly selecting from arrays of complete faces. Further participants attempted to name these composites when seen as an unaltered image, or when blurred, rotated, linearly stretched or converted to a photographic negative. All of the manipulations tested reduced correct naming of the composites overall except (i) for a low level of blur, for which naming improved for holistic composites but reduced for feature composites, and (ii) for 100% linear stretch, for which a substantial naming advantage was observed. Results also indicated that both featural (facial elements) and configural (feature spacing) information were useful for recognition in both types of composite system, but highly-detailed information was more accurate in the feature-based than in the holistic method. The naming advantage of linear stretch was replicated using a forensically more-practical procedure with observers viewing an unaltered composite sideways. The work is valuable to police practitioners and designers of facial-composite systems.

Community Health workers United to Reduce Colorectal cancer and cardiovascular disease among people at Higher risk (CHURCH): study protocol for a randomized controlled trial.

BACKGROUND: Colorectal cancer (CRC) is the second most lethal cancer in the United States (U.S.) with the highest incidence and mortality rates among African Americans (AAs) compared to other racial groups. Despite these disparities, AAs are the least likely to undergo CRC screening, have precancerous colorectal polyps removed, and have CRC detected at stages early enough for curative excision. In addition, compelling evidence links inflammatory dietary patterns to increased CRC and cardiovascular disease risk. Studies show that AA churches can successfully engage in health promotion activities including those related to cancer control. The current study seeks to leverage church-placed Community Health Workers (CHWs) to increase CRC screening and reduce CRC risk. DESIGN AND METHODS: We aim to (1) increase guideline concordant CRC screening uptake using church-placed CHWs trained in screening with a validated instrument, Brief Intervention using Motivational Interviewing, and Referral to Treatment (SBIRT); and (2) reduce dietary risk factors (inflammatory dietary patterns) linked to CRC. The latter will be addressed by culturally adapting an existing, web-based lifestyle program called Alive!. Using a Hybrid Type 1 Implementation-Effectiveness cluster randomized design, we will randomize 22 AA churches into either the dual intervention arm (CHW-led SBIRT intervention plus Alive!) or a usual care arm comprised of CRC prevention educational pamphlets and a list of CRC screening sites. We will recruit 440 subjects and evaluate the effects of both arms on screening uptake (colonoscopy, fecal DNA) (primary outcome) and dietary inflammation score (secondary outcome) at 6-month follow-up, and Life Simple7 (LS7)-a cardiovascular disease (CVD) risk score-at 6 months and 1 year (secondary outcome). Finally, guided by a racism-conscious adaptation of the Consolidated Framework for Implementation Research (CFIR), we will conduct a mixed-methods process evaluation with key stakeholders to understand multi-level influences on CRC screening and CVD risk behaviors. DISCUSSION: Church-placed CHWs are trusted influential connectors between communities and health systems. Studies have shown that these CHWs can successfully implement health prevention protocols in churches, including those related to cancer control, making them potentially important community mediators of CRC screening uptake and CRC/CVD risk reduction. TRIAL REGISTRATION: NCT05174286; clinicaltrials.gov; August 31st, 2023.

Community Health workers United to Reduce Colorectal cancer and cardiovascular disease among people at Higher risk (CHURCH): study protocol for a randomized controlled trial.

Background: Colorectal cancer (CRC) is the second most lethal cancer in the United States (U.S.) with the highest incidence and mortality rates among African Americans (AAs) compared to other racial groups. Despite these disparities, AAs are the least likely to undergo CRC screening, have precancerous colorectal polys removed, and have CRC detected at stages early enough for curative excision. In addition, compelling evidence links inflammatory dietary patterns to increased CRC and cardiovascular disease risk. Studies show that AA churches can successfully engage in health promotion activities including those related to cancer control. The current study seeks to leverage church-placed Community Health Workers (CHWs) to increase CRC screening and reduce CRC risk. Design and Methods: We aim to (1) increase guideline concordant CRC screening uptake using church-placed CHWs trained in screening with a validated instrument, Brief Intervention using Motivational Interviewing, and Referral to Treatment (SBIRT); and (2) reduce dietary risk factors (inflammatory dietary patterns) linked to CRC. The latter will be addressed by culturally adapting an existing, web-based lifestyle program called Alive!. Using a Hybrid Type 1 Implementation-Effectiveness cluster randomized design, we will randomize 22 AA churches into either the dual intervention arm (CHW-led SBIRT intervention plus Alive!) or a usual care arm comprised of CRC prevention educational pamphlets and a list of CRC screening sites. We will recruit 440 subjects and evaluate the effects of both arms on screening uptake (colonoscopy, fecal DNA) (primary outcome) and dietary inflammation score (secondary outcome) at 6-months follow up, and Life Simple7 (LS7) - a cardiovascular disease (CVD) risk score - at 6 months and 1-year (secondary outcome). Finally, guided by a racism-conscious adaptation of the Consolidated Framework for Implementation Research (CFIR), we will conduct a mixed-methods process evaluation with key stakeholders to understand multi-level influences on CRC screening and CVD risk behaviors. Discussion: Church-placed CHWs are trusted influential connectors between communities and health systems. Studies have shown that these CHWs can successfully implement health prevention protocols in churches, including those related to cancer control, making them potentially important community mediators of CRC screening uptake and CRC/CVD risk reduction. Trial registration: NCT05174286.

Evaluation of percutaneously adjustable hydraulic urethral sphincters with and without induced mechanical failure.

OBJECTIVE: To describe (1) the radiographic appearance of intact hydraulic urethral sphincters (HUS) and (2) the success of leak detection using clinically feasible methods. STUDY DESIGN: Prospective, blinded in vitro study. SAMPLE POPULATION: Thirty HUS devices (10 each of 8, 10, and 12 mm diameter sizes). MATERIALS AND METHODS: All devices were inflated with saline (0.9% NaCl) solution to complete occlusion, inspected, and weighed over a 24-hour period for manufacturing defects. HUS phantoms were created to mimic surrounding soft tissues. One randomly selected HUS of each size was evaluated radiographically at different inflation volumes and angles. All HUS systems were then evaluated in random order before and after puncture with volumetry, manometry, radiography, and contrast fluoroscopy. Volumetry was the total volume (mL) retrieved from each HUS system. Manometry was the pressure (cm H2 O) within each HUS system. The HUS devices were filled to a known volume before each measurement. RESULTS: When all HUS sizes were considered, volumetry did not reveal significant differences before and after puncture, but manometry was significantly different (P < .001). Radiography was 63.8% sensitive and 88.3% specific for puncture diagnosis, with inter-observer agreement of 0.58. Contrast fluoroscopy was 78.4% sensitive and 100% specific, with inter-observer agreement of 0.97. CONCLUSIONS: Of those methods tested, contrast fluoroscopy was the most sensitive, specific, and consistent method of leak detection. Manometry was also helpful, but may be difficult to use clinically. Volumetry and radiography were relatively poor indicators of leakage in this model.