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Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not biosynthesize purines and rely on purine salvage from the hosts. Protozoan transporters often present different substrate specificities from mammalian transporters, justifying the exploration of nucleoside analogues as therapeutic agents. Previous reports identified nucleosides with potent trypanocidal activity; therefore, two 7-derivatized tubercidins (FH11706, FH10714) and a 3′-deoxytubercidin (FH8513) were assayed against T. cruzi. They were highly potent and selective, and the uptake of the tubercidin analogues appeared to be mediated by the nucleoside transporter TcrNT2. At 10 μM, the analogues reduced parasitemia >90% in 2D and 3D cardiac cultures. The washout assays showed that FH10714 sterilized the infected cultures. Given orally, the compounds did not induce noticeable mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg, 5 days) and presented DNA amplification below the limit of detection. These findings justify further studies with longer treatment regimens, as well as evaluations in combination with nitro drugs, aiming to identify more effective and safer therapies for Chagas disease.

Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

Abstract: The purpose of our integrative review was to synthesize the literature examining relationships between depressive symptoms, silencing the self (STS), sexual relationship power (SRP), and HIV vulnerability among women in the United States. Literature searches were conducted through CINAHL, MEDLINE, PsycINFO, SCOPUS, Sociological Abstracts, and SocINDEX. Integrative review methodology of Whittemore and Knafl guided the review process, and 37 articles met inclusion criteria. The Theory of Gender and Power, modified by Wingood and DiClemente, was the guiding framework to organize and synthesize findings. Primary findings suggest that depressive symptoms, STS, and SRP in relationships may individually influence women's vulnerability for acquiring HIV, yet research lags behind. Evidence documenting relationships between these factors is insufficient to draw generalizable conclusions. Findings suggest that the current literature on this topic does not reflect those women most highly affected by HIV and those who identify as African American or Black in the Southeast region of the United States., (Copyright © 2024 Association of Nurses in AIDS Care.)

Despite recent advances, hypoplastic left heart syndrome (HLHS) patients subsequent to the Fontan still have significant morbidity and mortality. Some require heart transplant due to systemic ventricular dysfunction. Limited data exist on timing for transplant referral. This study aims to correlate systemic ventricular strain by echocardiography to transplant-free survival. HLHS patients who had Fontan palliation at our institution were included. Patients were divided into: 1) Required transplant or experienced mortality (composite end point); 2) Did not require transplant or survived. For those who experienced the composite endpoint, the last echocardiogram prior to the composite outcome was used, while for those who did not experience the composite endpoint the last echocardiogram obtained was used. Several qualitative and quantitative parameters were analyzed with focus on strain parameters. Ninety-five patients with HLHS Fontan palliation were identified. Sixty-six had adequate images and eight (12%) experienced transplant or mortality. These patients had greater myocardial performance index by flow Doppler (0.72 versus 0.53, p = 0.01), higher systolic/diastolic duration ratio (1.51 versus 1.13, p = 0.02), lower fractional area change (17.65 versus 33.99, p < 0.01), lower global longitudinal strain (GLS) (-8.63 versus - 17.99, p < 0.01), lower global longitudinal strain rate (GLSR) (- 0.51 versus - 0.93, p < 0.01), lower global circumferential strain (GCS) (-6.68 versus -18.25, p < 0.01), and lower (GCSR) global circumferential strain rate (-0.45 versus -1.01, p < 0.01). ROC analysis demonstrated predictive value for GLS - 7.6 (71% sensitive, 97% specific, AUC 81%), GLSR -0.58 (71% sensitive, 88% specific, AUC 82%), GCS - 10.0 (86% sensitive, 91% specific, AUC 82%), and GCSR -0.85 (100% sensitive, 71% specific, AUC 90%). GLS and GCS can help predict transplant-free survival in patients with hypoplastic left heart syndrome having undergone Fontan palliation. Higher strain values (closer to zero) may be a helpful tool in determining when transplant evaluation is warranted in these patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study was a randomised, double-blind, placebo-controlled study intended to establish the translatability of the RLS-0071 mechanisms of action from animal disease models to humans by inhibiting neutrophil-mediated inflammation at the tissue level and major inflammatory biomarkers. We hypothesised that RLS-0071 inhibits a temporary neutrophil-mediated inflammation in the lungs induced by inhalation of low-dose lipopolysaccharide (LPS) in healthy participants., Methods: Participants were randomised to one of three arms to receive inhaled LPS followed by three doses of either low-dose (10 mg·kg -1 ) or high-dose (120 mg·kg -1 loading dose followed by two doses of 40 mg·kg -1 ) RLS-0071 i.v. or placebo (saline) every 8 h. Biomarkers evaluating inflammatory responses, with absolute neutrophil counts in induced sputum as the primary end-point, were collected before and at 6 and 24 h after LPS challenge., Results: Active treatment with RLS-0071 showed a similar safety profile to participants receiving placebo. RLS-0071 significantly decreased the numbers of neutrophils in sputum at 6 h post LPS by approximately half (p=0.04). Neutrophil effectors myeloperoxidase, neutrophil elastase and interleukin-1β in sputum were also significantly decreased at 6 h for RLS-0071 compared with placebo. Several biomarkers showed trends suggesting sustained decreases for RLS-0071 versus placebo at 24 h., Conclusion: This clinical trial demonstrated that RLS-0071 was safe and well tolerated and modulated neutrophil-mediated inflammation in humans after inhaled LPS challenge, consistent with results from prior animal model studies., Competing Interests: Conflict of interest: In accordance with our ethical obligation as researchers, we are reporting that J. Goss, P. Hair, U. Thienel and K. Cunnion are employed by ReAlta Life Sciences and receive funding in the form of salaries from ReAlta Life Sciences, a company that may be affected by the research reported in the enclosed paper. J.M. Hohlfeld reports grant support paid to his institution from AltamiraPharma GmbH, Astellas Pharma GmbH, AstraZeneca AB, Bayer AG, Beiersdorf AG, Boehringer Ingelheim Pharma GmbH & Co. KG, CSL Behring GmbH, Desitin Arzneimittel GmbH, EpiEndo Pharmaceuticals, F. Hoffmann-La Roche AG, Genentech, Inc., GlaxoSmithKline GmbH & Co. KG, Janssen Pharmaceutical NV, M&P Pharma AG, Novartis AG, ReAlta Life Sciences, Sanofi-Aventis Deutschland GmbH and UCB Pharma GmbH, personal fees for consultancy from Boehringer Ingelheim Pharma GmbH & Co. KG, Cureteq AG, Merck & Co, Inc., and Roche, personal fees for lectures from HAL Allergy Group and Novartis AG, and personal fees for board service from CSL Behring GmbH and Nocion. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Introduction: In the era of big data, gene-set pathway analyses derived from multi-omics are exceptionally powerful. When preparing and analyzing high-dimensional multi-omics data, the installation process and programing skills required to use existing tools can be challenging. This is especially the case for those who are not familiar with coding. In addition, implementation with high performance computing solutions is required to run these tools efficiently., Methods: We introduce an automatic multi-omics pathway workflow, a point and click graphical user interface to Multivariate Single Sample Gene Set Analysis (MOGSA), hosted on the Cancer Genomics Cloud by Seven Bridges Genomics. This workflow leverages the combination of different tools to perform data preparation for each given data types, dimensionality reduction, and MOGSA pathway analysis. The Omics data includes copy number alteration, transcriptomics data, proteomics and phosphoproteomics data. We have also provided an additional workflow to help with downloading data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium and preprocessing these data to be used for this multi-omics pathway workflow., Results: The main outputs of this workflow are the distinct pathways for subgroups of interest provided by users, which are displayed in heatmaps if identified. In addition to this, graphs and tables are provided to users for reviewing., Conclusion: Multi-omics Pathway Workflow requires no coding experience. Users can bring their own data or download and preprocess public datasets from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium using our additional workflow based on the samples of interest. Distinct overactivated or deactivated pathways for groups of interest can be found. This useful information is important in effective therapeutic targeting., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Community Health Advanced by Medical Practice Superstars is a 1-year, Health Resources and Services Administration (HRSA)-funded fellowship for early career physicians and physician assistants/associates to become primary care transformational leaders. Fellows implement practice-based health care transformation projects in one of the three HRSA priority areas: childhood obesity, mental health, and opioid use disorder. The purpose of these projects is to expand on integrated health in primary care settings where there is a shortage of mental health professionals. The fellows identified areas in which they were able to incorporate mental health care provision to improve diagnostic capacity and whole health delivery, facilitate appropriate behavioral health outcomes, and improve patient physical health outcomes. Project modalities included initiating or increasing behavioral health screenings, aligning screenings with patient outcomes, and coordinating behavioral health care with physical health care. This article describes six mental health-related health care practice transformation projects implemented across rural health care settings, including Federally Qualified Health Centers and academic medical centers. The topics included (a) depression in pregnant and postpartum mothers; (b) adverse childhood experiences screening; (c) depression and chronic disease outcomes, especially diabetes; (d) the use of automated enhancements in patients' electronic medical records for management of clinical depression; (e) improving health outcomes and medication adherence of patients with opioid use disorder; and (f) the (in)adequacy of the Patient Health Questionairre-2 (PHQ-2) for the assessment of depression among patients with diabetes. Clinical specialties included family medicine, pediatrics, and women's health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Despite evidence-based protocols, inappropriate antibiotic use still presents a systemic global threat to health care in nursing homes (NHs). Nursing staff are responsible for recognizing signs and symptoms that may indicate urinary tract infections (UTIs). The current integrative review was designed to examine the state of the literature related to the role of nursing staff in UTI identification and care in NHs. This review, which includes 19 articles published between 2011 and 2020, identified that, although prescribers are the experts in UTI management, nursing staff in NHs were the individuals who recognized changes and communicated residents' needs to prescribers. Further research is required to understand nursing staff's decision making and unique perspectives and determine if evidence-based protocols align with current practice in the NH setting. [ Journal of Gerontological Nursing, 48 (5), 43-50.].

Background: Failure of the pulmonary valve autograft (PVA) after the Ross procedure (RP) has discouraged its widespread use and has led to modifications or alternatives to the procedure. We sought to analyze whether certain technical modifications could improve results of the RP in children., Methods: Sixty-nine patients (median age, 12 years; range, 0.25-17.9) underwent the RP between January 1996 and December 2018. A concomitant Konno procedure was performed on 20 of 69 patients (29%). Prior interventions included balloon valvuloplasty in 30 (44%) and/or surgical valvuloplasty in 39 (57%). Technical modifications included using the native aortic root for external annuloplasty, implanting the autograft using uniplanar horizontal sutures through the aortic wall, normalizing the sinotubular junction, and wrapping the native root remnant around the PVA., Results: Operative mortality was 1 of 69 patients (1.5%), with no late deaths. No patient had neoaortic valvar stenosis and 7 of 68 (10%) had mild regurgitation on discharge echocardiogram. At latest follow-up (median, 9.4 years; range, 0.4-21.3) there was no significant change in Z scores of annulus, sinus, or sinotubular junction diameters when compared with those at discharge. Three patients (4.4%) required late autograft replacement, 2 PVA repair, and 2 resection of a pseudoaneurysm. Actuarial freedom from PVA replacement was 87% at 20 years. Freedom from right ventricular outflow tract catheter reintervention or reoperation was 83% and 80%, respectively., Conclusions: Technical modifications of the RP used in this cohort might successfully prolong the life of the PVA without compromising its growth, an important advantage in pediatric patients., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Tetralogy of Fallot is a congenital heart defect diagnosed in infancy. Assessment of right ventricular size and function is important for evaluation of patients with tetralogy of Fallot, but these quantitative measures are challenging by echocardiography. This study evaluates a semi-automated software (EchoInsight®, Epsilon Imaging) by comparing its measures to manual measures in children with tetralogy of Fallot., Methods: Echocardiographic measurements were performed using manual techniques and semi-automated software. Right ventricular measurements included end-diastolic and end-systolic area, fractional area change, chamber dimensions, and tricuspid annular plane systolic excursion. Reliability, correlation, and agreement between manual and semi-automated measures were assessed., Results: Echocardiograms for 46 patients were analysed. Intra- and inter-observer reliabilities for semi-automated measures were good with intraclass correlation coefficients all over 0.95 and 0.85, respectively. There was high correlation between manual and semi-automated methods for areas and dimensions (r = 0.91-0.98). Tricuspid annular plane systolic excursion measures and fractional area change also correlated, albeit less strongly. The semi-automated measurements of end-systolic and end-diastolic area were a 20 and 47% higher than manual methods, respectively.The semi-automated method yielded a relative 52% lower fractional area change compared to the manual method., Conclusions: The semi-automated software generates quantitative right ventricular measures in children with tetralogy of Fallot with good reliability and good correlation with manual methods for all measures, but with significant difference between manual and semi-automated techniques for area and functional measures. The specific right ventricular geometry in tetralogy of Fallot children may be why, compared to normal anatomy, greater differences were observed between the two techniques.

Aims: Patient satisfaction is paramount to health-related quality of life (HR-QoL) outcomes. High quality, quantitative data from the US describing patients' actual experiences, difficulties, and HR-QoL while on an intermittent self-catheterization (ISC) regimen is very scarce. Our objective was to better understand patient practices with and attitudes towards ISC., Methods: This is a cross-sectional, multi-centered, clinical study of adult men and women performing ISC in the United States. Data collected included demographics, medical history, catheter characteristics, specific self-catheterization habits and two validated HR-QoL questionnaires: The Intermittent Self-Catheterization Questionnaire (ISC-Q) and the Intermittent Catheterization Difficulty Questionnaire (ICDQ)., Results: Two hundred participants were recruited from six sites; 70.0% were male, 73.5% were Caucasian with a median age was 51.0 years (range 19-90 years). The ISC-Q showed that the vast majority of participants reported ease with ISC (82.0% satisfaction score) had confidence in their ability to perform ISC (91.9% satisfaction score); yet, many felt self-conscious about doing so (58.3% satisfaction score) and had concerns about long-term adverse effects (58.1% satisfaction score). The ICDQ indicated little to no difficulty for most participants with all routine ISC practices. A small minority of participants reported some difficulty with a "blocking sensation" during initiation of catheterization, leg spasticity, and painful catheterization. Multivariate linear regression results are also reported., Discussion/conclusion: Participants are confident with ISC and have little overall difficulty, which may be a product of successful education and/or catheter design. urinary tract infections (UTIs) were common (yet variable) and may contribute to the noted long-term ISC concerns. Limitations exist including various selection biases leading to concerns of external validity. Future educational interventions in this population may further improve HR-QoL, optimize UTIs prevention, and diminish concerns with long-term ISC., (© 2021 Wiley Periodicals LLC.)