QseC inhibition as an antivirulence approach for colitis-associated bacteria.

Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/-Rag2-/- IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.

The Microbiota of Breast Tissue and Its Association with Breast Cancer.

UNLABELLED: In the United States, 1 in 8 women will be diagnosed with breast cancer in her lifetime. Along with genetics, the environment contributes to disease development, but what these exact environmental factors are remains unknown. We have previously shown that breast tissue is not sterile but contains a diverse population of bacteria. We thus believe that the host's local microbiome could be modulating the risk of breast cancer development. Using 16S rRNA amplicon sequencing, we show that bacterial profiles differ between normal adjacent tissue from women with breast cancer and tissue from healthy controls. Women with breast cancer had higher relative abundances of Bacillus, Enterobacteriaceae and Staphylococcus Escherichia coli (a member of the Enterobacteriaceae family) and Staphylococcus epidermidis, isolated from breast cancer patients, were shown to induce DNA double-stranded breaks in HeLa cells using the histone-2AX (H2AX) phosphorylation (γ-H2AX) assay. We also found that microbial profiles are similar between normal adjacent tissue and tissue sampled directly from the tumor. This study raises important questions as to what role the breast microbiome plays in disease development or progression and how we can manipulate this for possible therapeutics or prevention. IMPORTANCE: This study shows that different bacterial profiles in breast tissue exist between healthy women and those with breast cancer. Higher relative abundances of bacteria that had the ability to cause DNA damage in vitro were detected in breast cancer patients, as was a decrease in some lactic acid bacteria, known for their beneficial health effects, including anticarcinogenic properties. This study raises important questions as to the role of the mammary microbiome in modulating the risk of breast cancer development.

Microbiota of human breast tissue.

In recent years, a greater appreciation for the microbes inhabiting human body sites has emerged. In the female mammary gland, milk has been shown to contain bacterial species, ostensibly reaching the ducts from the skin. We decided to investigate whether there is a microbiome within the mammary tissue. Using 16S rRNA sequencing and culture, we analyzed breast tissue from 81 women with and without cancer in Canada and Ireland. A diverse population of bacteria was detected within tissue collected from sites all around the breast in women aged 18 to 90, not all of whom had a history of lactation. The principal phylum was Proteobacteria. The most abundant taxa in the Canadian samples were Bacillus (11.4%), Acinetobacter (10.0%), Enterobacteriaceae (8.3%), Pseudomonas (6.5%), Staphylococcus (6.5%), Propionibacterium (5.8%), Comamonadaceae (5.7%), Gammaproteobacteria (5.0%), and Prevotella (5.0%). In the Irish samples the most abundant taxa were Enterobacteriaceae (30.8%), Staphylococcus (12.7%), Listeria welshimeri (12.1%), Propionibacterium (10.1%), and Pseudomonas (5.3%). None of the subjects had signs or symptoms of infection, but the presence of viable bacteria was confirmed in some samples by culture. The extent to which these organisms play a role in health or disease remains to be determined.

Presence of type 2 diabetes risk factors in children.

This study aimed to identify the prevalence of type 2 diabetes risk factors among elementary school-age children and determine eligibility for type 2 diabetes screening. A cross-sectional review of 971 school-based health clinic medical records of children in grades 1 through 5 was conducted. Relationships of risk factors associated with type 2 diabetes mellitus were examined to determine the prevalence of these risk factors in elementary school-age children. Screening guidelines for type 2 diabetes were applied to determine the prevalence of students meeting criteria for further screening. Almost 40% of the students had a body mass index (BMI) above the 85th percentile for age and gender. Forty-nine percent of the students belonged to a high-risk ethnic group. Acanthosis nigricans, an indicator of insulin resistance, was identified in nearly 27% of the student records. Forty-eight percent of the records identified the student as having a family history of diabetes. Significant correlations were found between the presence of acanthosis nigricans, high BMI, and a family history of diabetes. According to screening guidelines for type 2 diabetes in children, 39.3% of the elementary school children 10 years of age and older were eligible for type 2 diabetes screening. Almost 40% of children younger than 10 years of age had risk factors associated with screening criteria. These findings support the need for early detection of high-risk children and intervention strategies to decrease modifiable risk factors in elementary school-age children. The school nurse is in a pivotal role of identifying such at-risk students during annual, routine health screening practices.

Using unfolding case scenarios to promote clinical reasoning for nurse practitioner students.

ABSTRACT: This article describes how an unfolding case study can be used to promote the development of clinical reasoning through students' self-reported perceptions, although at the same time facilitating collaboration among providers from various specialties. An unfolding case (evolving case) provides sequential information about a patient's illness trajectory as they experience the illness and related symptomology. An unfolding case study was implemented during a college skills laboratory immersion experience for 33 nurse practitioner (NP) students who were in their final year of the NP program. Students were invited per email to complete a confidential REDCap survey after the case presentation and discussion. Twenty-three students completed the survey. More than half of the students (52%) stated the review of the unfolding case offered "significant learning value" and 78% rated the unfolding case as being "very to extremely" helpful in creating opportunities for critical thinking and engagement in clinical reasoning. Implementing unfolding case studies in NP student program curricula promotes critical thinking, clinical reasoning, and allows opportunities to engage in interprofessional collaboration.

Clinical translation of anti-inflammatory effects of Prevotella histicola in Th1, Th2, and Th17 inflammation.

Introduction: EDP1815 is a non-colonizing pharmaceutical preparation of a single stain of Prevotella histicola isolated from the duodenum of a human donor. We report here preclinical and clinical studies showing that the action of EDP1815, an orally delivered and gut restricted single strain of commensal bacteria can regulate inflammatory responses throughout the body. Methods: Supported by evidence for anti-inflammatory activity in three preclinical mouse models of Th1-, TH2-, and Th17-mediated inflammation, EDP1815 was tested clinically in three Phase 1b studies in patients with psoriasis, patients with atopic dermatitis, and healthy volunteers in a KLH skin challenge model. Results: Preclinically, EDP1815 was efficacious in all three mouse models of inflammation, showing reduction in skin inflammation as well as related tissue cytokines. In the Phase 1b studies, EDP1815 was found to be well tolerated by participants, with a safety profile comparable to placebo, including no severe or consistent side-effects reported, and no evidence of immunosuppression with no opportunistic infection occurring in these studies. In psoriasis patients, signs of clinical efficacy were seen after 4 weeks of treatment, which continued beyond the treatment period in the higher-dose cohort. In atopic dermatitis patients, improvements were seen throughout the key physician-and patient-reported outcomes. In a healthy-volunteer study of a KLH-induced skin inflammatory response, consistent anti-inflammatory effects were seen in two cohorts through imaging-based measures of skin inflammation. Discussion: This is the first report demonstrating clinical effects from targeting peripheral inflammation with a non-colonizing gut-restricted single strain of commensal bacteria, providing proof of concept for a new class of medicines. These clinical effects occur without systemic exposure of EDP1815 or modification of the resident gut microbiota, and with placebo-like safety and tolerability. The breadth of these clinical effects of EDP1815, combined with its excellent safety and tolerability profile and oral administration, suggests the potential for a new type of effective, safe, oral, and accessible anti-inflammatory medicine to treat the wide range of diseases driven by inflammation.Clinical Trial Registration: EudraCT # 2018-002807-32; EudraCT # 2018-002807-32; NL8676; https://clinicaltrials.gov/ct2/show/NCT03733353; http://www.trialregister.nl.

Reliability and validity of the acanthosis nigricans screening tool for use in elementary school-age children by school nurses.

The purpose of this study was to test the reliability and validity of an acanthosis nigricans (AN) screening tool for use in elementary school-age children of different ethnic groups. Cross-sectional data were collected via observation of 288, 5- to 12-year-old school-age children. Three nurse clinicians used a 0-4 grade AN screening tool to rate each child's level of AN independently. AN was consistently and appropriately identified in elementary school-age children from different ethnic groups. All clinicians were within one grade 98% of the time. Substantial agreement among raters was found (kappa statistic = .822, p ≤ .001), indicating similar interpretation and reproducibility of the AN screening tool. There was more consistent detection of grade four AN regardless of the children's sex, body mass index, or ethnic group. The AN screening tool is easy to use and reliable for use with elementary school-age children of various ethnic groups.

Neonatal abstinence syndrome: Effectiveness of targeted umbilical cord drug screening.

OBJECTIVE: This study sought to determine if targeted drug screening of newborns was effective in identifying a positive drug test result. STUDY DESIGN: This was a retrospective cross-sectional study. A total of 340 infants met criteria for drug screening. Sensitivity and specificity were used to evaluate each of the potential risk factors in terms of their ability to predict a positive drug test result. Two-sample t-tests were used to compare differences in Finnegan scores between babies with a positive drug test result and those with a negative one. RESULT: The risk factor with the highest sensitivity was maternal history of drug use. The difference in the Finnegan scores between groups was statistically significant. CONCLUSION: The risk factors associated with this study were not very sensitive. The only way to identify all infants at risk of NAS is to standardize the screening process and apply to all infants.

Adapting clinical experiences during a pandemic: One college of nursing's approach.

ABSTRACT: Graduate level nursing programs are having increasing difficulty obtaining clinical sites for their students. Nurse practitioner (NP) students need a minimum of 500 direct care hours in addition to indirect hours. Simulation experiences may not be used as direct patient care hours for NP students, but telehealth experiences may be used if the focus is on obtaining similar competencies to what would be acquired with face-to-face patient experiences. One college of nursing adapted several opportunities for NP students to acquire indirect clinical experiences and specific NP competencies during the coronavirus (COVID-19) pandemic. Several different clinically focused teaching methodologies were planned and implemented. These varied by NP specialty track and included complex case analyses, virtual (Zoom) rounds, well-child cases, and objective structured clinical examinations. These adapted clinical experiences are effective methods of helping students acquire clinical competencies and skills; however, they bring their own challenges. Post-COVID may be a time of new beginnings, moving nursing education forward on finding new and better ways to ensure that students acquire clinical competencies. What the new normal will be for nursing education is yet to be determined, but nursing education will likely never return to where we were before the pandemic.

Strengthening the impact of Doctor of Nursing Practice projects in education and clinical practice.

ABSTRACT: The significance and value of Doctor of Nursing Practice (DNP) projects can be potentiated by collaboration between educators and practice leaders and when students build on previous DNP projects, as demonstrated in this article. Projects can have a longstanding financial, quality, and outcome impact, helping demonstrate the worth and efficacy of the DNP degree.

Faculty and Student Perspectives of a Graduate Online Delivery Model Supported by On-Campus Immersion.

PURPOSE: The purpose of this article is to describe an immersion model implemented in a doctor of nursing practice program with the goal of engaging students and optimizing learning. DESCRIPTION OF THE PROJECT: The immersion model was designed to support learners in an online doctor of nursing practice program to promote self-direction and active involvement in diagnosing, planning, implementing, and evaluating their own learning. The Community of Inquiry framework, based on learning and teaching theory, was used in developing this immersion model. OUTCOME: Students expressed positive opinions about immersion. Students valued simulation and skills practice, peer interaction, engagement with faculty, and the leadership colloquium. Faculty reported value in having group advising meetings and in collaborating across specialty tracks for skills laboratory experiences. CONCLUSION: The immersion model has enhanced student engagement and helped optimize learning outcomes. Students and faculty found the use of the immersion model to be beneficial for practicing skills, use of simulated learning experiences, and student advising.

Proximal splenic artery embolization in the management of splenic rupture.

OBJECTIVE: To report the use of proximal splenic artery embolization for management of spontaneous splenic rupture. DESIGN: Case report and literature review. SETTING: A tertiary pediatric critical care unit in a university teaching hospital. INTERVENTIONS: Proximal splenic artery embolization. MEASUREMENTS AND MAIN RESULTS: An 8-yr-old boy presented with abdominal pain radiating to the left shoulder 9 days after completing induction chemotherapy for acute lymphoblastic leukemia. Imaging revealed a splenic rupture with parenchymal and subcapsular hematomas, with no evidence of active extravasations. The patient was admitted to the pediatric critical care unit for close hemodynamic monitoring and frequent measurements of hemoglobin. His lowest recorded hemoglobin and hematocrit were 63 g/L and 0.19 L/L, respectively. Posttransfusion of packed red blood cells, he was taken to interventional radiology for proximal splenic artery embolization under moderate sedation. Several coils were successfully placed in the proximal splenic arterial system resulting in a marked reduction of splenic blood flow without disruption of collaterals. The patient recovered well from proximal splenic artery embolization in the pediatric critical care unit and experienced short lasting abdominal pain and fever for 1 day. He was discharged home 4 days after the procedure and follow-up imaging showed resolving hematomas with preserved splenic blood flow. CONCLUSION: Proximal splenic artery embolization in children may be a safe therapeutic alternative to either conservative or surgical management in spontaneous splenic rupture. Preservation of splenic tissue with a reduced risk of repeated hemorrhage can be obtained with proximal splenic artery embolization.

Outcomes of extracorporeal, transumbilical versus intracorporeal laparoscopic appendectomy for acute uncomplicated appendicitis in children and adolescents: A retrospective observational cohort study.

BACKGROUND: An extracorporeal (ECA), transumbilical appendectomy has been proposed as a treatment for appendicitis. This study assessed the 30-day perioperative outcomes and cost between ECA and traditional intracorporeal (ICA) techniques for acute uncomplicated appendicitis. METHODS: IRB approval was obtained for this retrospective cohort study of acute uncomplicated appendicitis in children aged 4 to 17 between April 2014 and April 2017. Patients were grouped based on ICA versus ECA. Operative time, length of stay, and complication rates were recorded. RESULTS: A total of 289 patients were included, and of these 217 underwent ICA, and 72 underwent ECA. Median weight-for-age percentile was the only demographic characteristic different between groups (ECA 50 [0.1-100] vs. ICA 71 [0-100]; p < 0.01). Median operative time was significantly shorter in the ECA group (21.0 min [8.0-61.0] vs. 38.0 min [19.0-87.0]; p < 0.0001). Length of stay and complication rates were similar between groups. The median per case cost was significantly lower in the ECA group (CAD$ 593.05 range: 499.70-900.81 vs. CAD$ 858.78 range: 490.36-1106.29; p < 0.001). CONCLUSIONS: Extracorporeal transumbilical laparoscopic appendectomy is associated with shorter operative times and no increased risk of 30-day postoperative complications in children and adolescents. This offers a new operative approach that may reduce hospital cost and resources. LEVEL OF EVIDENCE: III.

Concurrent Neoadjuvant Chemotherapy and Radiation Therapy in Locally Advanced Breast Cancer.

PURPOSE: To evaluate whether concurrent neoadjuvant radiation added to standard chemotherapy could increase the pathologic complete response (pCR) to treatment for locally advanced breast cancer (LABC). METHODS AND MATERIALS: This prospective phase 2 trial recruited 32 LABC patients from 2009 to 2011. Patients received neoadjuvant every-3-weekly 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) for 3 cycles, followed by weekly docetaxel (35 mg/m2) for 9 cycles. Regional radiation (45 Gy/25 plus 5.4 Gy/5) was delivered concurrently with docetaxel, then modified radical mastectomy. Patients were matched post hoc by a blinded statistician to a concurrent cohort treated with neoadjuvant chemotherapy, modified radical mastectomy, and adjuvant regional radiation. RESULTS: Thirty of 32 patients completed treatment. Twenty-seven were successfully matched by propensity score to 81 control patients by age, stage, and molecular subtype. The concurrent chemoradiation produced a significant increase in pCR (14% vs 22%, P<.001) but no statistically significant difference in disease-free and overall survival at 3 years (respectively, 69% vs 81%, P=.186, hazard ratio 0.51; and 74% vs 89%, P=.162, hazard ratio 0.46). Toxicity included 25% of patients with grade 3 pneumonitis and 25% of patients with dermatitis, and 1 death. CONCLUSIONS: Concurrent neoadjuvant radiation added to radiosensitizing chemotherapy significantly improved pCR. A prospective randomized clinical trial is warranted to exploit the improved response seen with concurrent therapy but using another radio-sensitizing taxane, to better minimize treatment-related toxicity and determine its impact on overall survival.

wMel limits zika and chikungunya virus infection in a Singapore Wolbachia-introgressed Ae. aegypti strain, wMel-Sg.

BACKGROUND: Zika (ZIKV) and Chikungunya (CHIKV) viruses are emerging Aedes-borne viruses that are spreading outside their known geographic range and causing wide-scale epidemics. It has been reported that these viruses can be transmitted efficiently by Ae. aegypti. Recent studies have shown that Ae. aegypti when transinfected with certain Wolbachia strains shows a reduced replication and dissemination of dengue (DENV), Chikungunya (CHIKV), and Yellow Fever (YFV) viruses. The aim of this study was to determine whether the wMel strain of Wolbachia introgressed onto a Singapore Ae. aegypti genetic background was able to limit ZIKV and CHIKV infection in the mosquito. METHODOLOGY/PRINCIPAL FINDINGS: Five to seven-day old mosquitoes either infected or uninfected with wMel Wolbachia were orally infected with a Ugandan strain of ZIKV and several outbreak strains of CHIKV. The midgut and salivary glands of each mosquito were sampled at days 6, 9 and 13 days post infectious blood meal to determine midgut infection and salivary glands dissemination rates, respectively. In general, all wild type Ae. aegypti were found to have high ZIKV and CHIKV infections in their midguts and salivary glands, across all sampling days, compared to Wolbachia infected counterparts. Median viral titre for all viruses in Wolbachia infected mosquitoes were significantly lower across all time points when compared to wild type mosquitoes. Most significantly, all but two and one of the wMel infected mosquitoes had no detectable ZIKV and CHIKV, respectively, in their salivary glands at 14 days post-infectious blood meal. CONCLUSIONS: Our results showed that wMel limits both ZIKV and CHIKV infection when introgressed into a Singapore Ae. aegypti genetic background. These results also strongly suggest that female Aedes aegypti carrying Wolbachia will have a reduced capacity to transmit ZIKV and CHIKV.

Insulin resistance syndrome in children.

Insulin resistance, a metabolic dysfunction in glucose metabolism, is associated with numerous physical health findings that have serious health consequences such as obesity, hyperlipidemia, hypertension, cardiovascular disease, and type 2 diabetes. The clustering of these diseases is termed insulin resistance syndrome, previously described as a metabolic condition exclusive to adults. Studies now indicate many of the components associated with insulin resistance syndrome are present in children and adolescents. Identifying children at risk for the development of insulin resistance is important for early prevention and intervention. Detecting early evidence of insulin resistance in children and adolescents can have a preventive effect on the disease components associated with insulin resistance. Primary care providers are in pivotal position for early recognition and treatment of insulin resistance in children.