Co-design of an intervention to optimize mammographic screening participation in women with obesity and/or physical disabilities.

BACKGROUND: Mammographic breast screening/rescreening rates are suboptimal for women with obesity and/or physical disabilities. This study describes development of an intervention framework targeting obesity- and disability-related barriers to improve participation. METHODS: Mixed methods combined a systematic review with first-person perspectives to optimise screening engagement among women with obesity and/or physical disabilities. Phase 1 (systematic review) was conducted following the PRISMA framework. Phase 2 involved in-depth interviews with n = 8 women with lived experience of obesity and/or physical disabilities. An inductive coding approach was applied to the data which was then combined with Phase 1 results to develop the intervention framework. RESULTS: Six studies were included in the systematic review. Tailored education based on individual risk increased willingness to undergo mammographic screening. Recommendations to improve the screening experience included partnerships with consumers, targeted messaging, and enhanced professional development for breast screening staff. Participants also identified strategies to improve the uptake of screening and the experience itself. CONCLUSION: Development and evaluation of interventions informed by frameworks like the one developed in this study are needed to improve engagement in screening to promote regular participation among women with physical disabilities and/or obesity. IMPLICATIONS FOR PRACTICE: Successful implementation of practice interventions co-designed by women with obesity and/or physical disabilities are likely to improve their breast screening participation. Enhanced training of radiographers aimed at upskilling in empathetic communication around required manoeuvring and potentially longer screening times for clients with obesity and/or physical disabilities may encourage more positive client practitioner interactions. Client information aimed at women with obesity should include information on how to prepare for the appointment and explain there may be equipment limitations compromising imaging which may not be completed at an initial appointment.

Demographic Characteristics and Low Iron Status Markers Are Associated with Hemoglobin Levels and Anemia among Children Living at High Elevation in Cusco, Peru.

Anemia is a complex condition associated with diet, chronic infections, and blood loss. Children living at high altitudes have higher absolute hemoglobin levels due to hypoxemia. However, they are exposed to repeated infections and dietary limitations. We conducted a cross-sectional study to identify factors affecting the hemoglobin concentration in children living in high-altitude rural communities in the Anta province of Peru. All children 3-16 years of age attending public schools were invited to participate. We enrolled children 3-16 years old in schools and visited their homes to collect demographic, socioeconomic, medical history, and anthropometric data. Children provided blood and stool samples for complete blood counts, iron status markers, and helminth infection testing. Among the 2,000 children enrolled, the mean age was 9.9 (±3.4) years, 1,004 (50.2%) were female, and the median residence altitude was 3,398 (interquartile range 3,35-3,497) meters. The mean hemoglobin level was 15 (±1.15) mg/dL; 320 (16%) had anemia as defined by WHO. Children with anemia were more likely to have lower serum iron levels (odds ratio [OR] 2.8 [95% CI 2.2-3.6], P <0.001) and serum transferrin saturation (OR 2.8 [95% CI 2-3.9], P <0.001). Younger age (OR 0.85 [95% CI 0.82-0.89], P <0.001), stunting (OR 0.68 [95% CI 0.59-0.79], P <0.001), education of the mother (OR 0.94 [95% CI 0.91-0.98], P <0.005), and low eosinophils (OR 0.49 [95% CI 0.26-0.9], P = 0.022) were associated with anemia. Helminth infections were not associated with anemia. Anemia among children at high altitude is multifactorial, but iron deficiency is a contributing factor. Further studies are needed to evaluate iron status and anemia in children living at high altitudes.

Immune interactions and heterogeneity in transmission drives the pathogen-mediated invasion of grey squirrels in the UK.

Mathematical models highlighted the importance of pathogen-mediated invasion, with the replacement of red squirrels by squirrelpox virus (SQPV) carrying grey squirrels in the UK, a well-known example. In this study, we combine new epidemiological models, with a range of infection characteristics, with recent longitudinal field and experimental studies on the SQPV dynamics in red and grey squirrel populations to better infer the mechanistic basis of the disease interaction. A key finding is that a model with either partial immunity or waning immunity and reinfection, where individuals become seropositive on the second exposure to infection, that up to now has been shown in experimental data only, can capture the key aspects of the field study observations. By fitting to SQPV epidemic observations in isolated red squirrel populations, we can infer that SQPV transmission between red squirrels is significantly (4×) higher than the transmission between grey squirrels and as a result our model shows that disease-mediated replacement of red squirrels by greys is considerably more rapid than replacement in the absence of SQPV. Our findings recover the key results of the previous model studies, which highlights the value of simple strategic models that are appropriate when there are limited data, but also emphasise the likely complexity of immune interactions in wildlife disease and how models can help infer disease processes from field data.

An Update on the Pathogenesis of Fascioliasis: What Do We Know?

Fasciola hepatica is a trematode parasite distributed worldwide. It is known to cause disease in mammals, producing significant economic loses to livestock industry and burden to human health. After ingestion, the parasites migrate through the liver and mature in the bile ducts. A better understanding of the parasite's immunopathogenesis would help to develop efficacious therapeutics and vaccines. Currently, much of our knowledge comes from in vitro and in vivo studies in animal models. Relatively little is known about the host-parasite interactions in humans. Here, we provide a narrative review of what is currently know about the pathogenesis and host immune responses to F. hepatica summarizing the evidence available from the multiple hosts that this parasite infects.

Functional Connectivity Analysis of Visually Evoked ERPs for Mild Cognitive Impairment: Pilot Study.

Mild cognitive impairment (MCI) is considered the early stage of Alzheimer's disease, characterized as mild memory loss. A novel method of functional connectivity (FC) analysis can be used to detect MCI before memory is significantly impaired allowing for preventative measures to be taken. FC examines interactions between EEG channels to grant insight on underlying neural networks and analyze the effects of MCI. Applying FC method of weighted phase lag index (wPLI) to P300 ERPs provided insight on the link between the pathology of Alzheimer's disease and cognitive loss. wPLI was analyzed per frequency band (θ, α, µ, ß) and by channel combination groups (intra-hemispheric short, intra-hemispheric long, inter-hemispheric short, inter-hemispheric long, transverse). MCI was found to have a statistically significant lower ΔwPLIP300 compared to normal controls in the µ intra-hemispheric short (p = 0.0286), µ intra-hemispheric long (p = 0.0477), µ inter-hemispheric short (p = 0.0018) and the α intra-hemispheric short (p = 0.0423). Results indicate a possible deficiency in the dorsal visual processing pathway among MCI subjects as well as an unbalanced coordination between the two hemispheres.

Time-dependent density-functional-theory calculations of the nonlocal electron stopping range for inertial confinement fusion applications.

Nonlocal electron transport is important for understanding laser-target coupling for laser-direct-drive (LDD) inertial confinement fusion (ICF) simulations. Current models for the nonlocal electron mean free path in radiation-hydrodynamic codes are based on plasma-physics models developed decades ago; improvements are needed to accurately predict the electron conduction in LDD simulations of ICF target implosions. We utilized time-dependent density functional theory (TD-DFT) to calculate the electron stopping power (SP) in the so-called conduction-zone plasmas of polystyrene in a wide range of densities and temperatures relevant to LDD. Compared with the modified Lee-More model, the TD-DFT calculations indicated a lower SP and a higher stopping range for nonlocal electrons. We fit these electron SP calculations to obtain a global analytical model for the electron stopping range as a function of plasma conditions and the nonlocal electron kinetic energy. This model was implemented in the one-dimensional radiation-hydrodynamic code lilac to perform simulations of LDD ICF implosions, which are further compared with simulations by the standard modified Lee-More model. Results from these integrated simulations are discussed in terms of the implications of this TD-DFT-based mean-free-path model to ICF simulations.

Simultaneous determination of electrical conductivity and thickness of nonmagnetic metallic foils using two-sided multifrequency eddy current techniques.

In this paper, we describe a simple method for performing multifrequency eddy current characterization of free-standing uniform-thickness metallic foils using a forked inductive coil arrangement. The method involves measuring the mutual inductance between two coils when a foil is present between the coils, and when it is not present; the ratio of these mutual inductances is compared with an analytical solution, and foil conductivity, thickness, and sheet resistance are simultaneously estimated using numerical inversion and least-squares fitting. This method was used to characterize 34 non-ferrous metallic samples with thicknesses between 50 and 640 µm and with conductivities between 0.8 × 107 and 5.8 × 107 S/m. The estimated thicknesses from eddy current characterization agreed well with those measured using confocal optical techniques; the two approaches agreed to within 1 µm for samples that were thinner than 200 µm, and to within 0.5% for samples that had a thickness of 200 µm or greater. The estimated conductivities from eddy current characterization were in close agreement with expected values, given knowledge of the materials used. A particular strength of this approach is that the instrumentation needed is broadly available in research and development laboratories and the associated fixturing is easy to manufacture and assemble. A calibration procedure is described that can be used to reduce errors from geometric uncertainties. This calibration requires a sample that has only a known conductivity or thickness; both do not need to be known. The method described herein is likely extensible to conductivities and thickness well outside the ranges measured as part of this work.

Patterns of Mammography Screening in Women with Breast Cancer in a Kansas Community.

Purpose: The objective of this study was to examine patterns of mammography screening prior to breast cancer diagnosis in all women with breast cancer in a Kansas community. Methods: The study population included 508 women in the Kansas Cancer Registry database diagnosed with breast cancer between 2013-2014 who were patients and residents of a defined area at the time of diagnosis. Screening history within 4 years of diagnosis was obtained. Poisson regression analysis was used to examine the relationship between sociodemographic factors and biennial screening. Results: About 41.5% of women received at least biennial screening, while 22.1% received less than biennial screening and 36.4% had no screening. About 40% of women aged 50-64, 50.4% aged 65-74, and 48.3% aged 75-84 received biennial screening (p=0.002). Women diagnosed with in-situ and localized breast cancers had significantly higher proportions of biennial screening (46.7% and 48.6%, respectively; p < 0.001). Average tumor size was 15.7, 17.4, and 24.4 mm, for women who received at least biennial, some, and no screening, respectively (p < 0.001). Results from Poisson regression analysis showed the adjusted relative risk associated with rural/mixed residence at diagnosis and Medicaid beneficiary was 0.45 and 0.40 (p=0.003 and p=0.032) respectively. Conclusions: Biennial mammography screening was associated with lower breast cancer stage and smaller tumor size, illustrating the importance of screening as early detection. Different outreach strategies may be necessary to reach women within varied age groups or geographical regions to help increase the number of women who remain up-to-date with mammography screening.

Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis.

Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

Improving vitamin D content in pork meat by UVB biofortification.

Vitamin D deficiency is prevalent worldwide and identification of alternative food-based strategies are urgently warranted. In two studies, 12-week old crossbred pigs (Duroc x (Large White x Landrace)) were exposed daily to narrowband UVB radiation for ∼10 weeks or control (no UVB exposure) until slaughter. In Study 1 (n = 48), pigs were exposed to UVB for 2 min and in Study 2 (n = 20), this duration was tripled to 6 min. All pigs were fed the maximum permitted 2000 IU vitamin D3/kg feed. Loin meat was cooked prior to vitamin D LC-MS/MS analysis. In Study 1, pork loin vitamin D3 did not differ between groups. Study 2 provided longer UVB exposure time and resulted in significantly higher loin vitamin D3 (11.97 vs. 6.03 µg/kg), 25(OH)D3 (2.09 vs. 1.65 µg/kg) and total vitamin D activity (22.88 vs. 14.50 µg/kg) concentrations, compared to control (P < 0.05). Pigs remained healthy during both studies and developed no signs of erythema. Biofortification by UVB radiation provides an effective strategy to further safely increase the naturally occurring vitamin D content of pork loin, alongside feed supplementation.

Bioavailability of vitamin D biofortified pork meat: results of an acute human crossover study in healthy adults.

Vitamin D intakes are concerningly low. Food-based strategies are urgently warranted to increase vitamin D intakes and subsequently improve 25-hydroxyvitamin D (25(OH)D) concentrations. This acute randomised three-way crossover study investigated the efficacy of vitamin D biofortified pork derived from pigs exposed to UVB light to increase serum 25(OH)D3 concentrations, compared to a dose-matched vitamin D3 supplement and control pork in adults (n = 14). Blood samples were obtained at baseline and then 1.5, 3, 6, 9 and 24 h postprandially. There was a significant effect of time (p < 0.01) and a significant treatment*time interaction (p < 0.05). UV pork and supplement significantly increased within-group serum 25(OH)D3 concentrations over timepoints (p < 0.05) (max. change 0.9 nmol/L (2.2%) UV pork, 1.5 nmol/L (3.5%) supplement, 0.7 nmol/L (1.9%) control). Vitamin D biofortified pork modestly increased 25(OH)D3 concentrations and produced a similar response pattern as a dose-matched vitamin D supplement, but biofortification protocols should be further optimised to ensure differentiation from standard pork.

Treatment of cryptosporidiosis: nitazoxanide yes, but we can do better.

INTRODUCTION: Cryptosporidiosis was initially recognized as an important cause of diarrhea in AIDS patients. It has been underdiagnosed in other populations. Recent studies have highlighted the importance of Cryptosporidium as a cause of diarrhea and malnutrition in young children in resource-poor countries and an emerging pathogen in organ-transplant recipients. AREAS COVERED: Nitazoxanide is FDA approved for treatment of cryptosporidiosis in immunocompetent people. However, it is less effective in HIV and transplant patients and malnourished children. In transplant recipients, there is emerging data on antiparasitic combinations for cryptosporidiosis, including combinations of nitazoxanide, azithromycin, and in one case rifaximin. High-throughput phenotypic screens have identified some potential treatments. Among them, clofazimine was no better than placebo in a trial in AIDS patients. There have also been efforts to develop drug versus specific parasite targets. However, in part due to safety issues, none of these compounds have advanced into clinical trials. EXPERT OPINION: Development of new and more efficacious therapies for cryptosporidium is imperative. Current approve therapy is far from optimal and lacks efficacy in high-risk populations, such as, patients living with HIV. Additionally, there is limited data on patients with other types of immunosuppression (Transplanted, autoimmune conditions, etc).

Recommendations to improve the patient experience and avoid bias when prenatal screening/testing.

While prenatal screening and testing have expanded substantially over the past decade and provide access to more genetic information, expectant parents are more likely to describe the diagnosis experience as negative than positive. In addition, the conversations that take place during these experiences sometimes reflect unconscious bias against people with disabilities. Consequently, an interdisciplinary committee of experts, including people with disabilities, family members, disability organization leaders, healthcare and genetics professionals, and bioethicists, reviewed selected published and gray literature comparing the current state of the administration of prenatal testing to the ideal state. Subsequently, the interdisciplinary team created recommendations for clinicians, public health agencies, medical organizations, federal agencies, and other stakeholders involved with administering prenatal screening and testing to create better patient experiences; conduct training for healthcare professionals; create, enforce, and fund policies and guidelines; and engage in more robust data collection and research efforts.

Hypogenetic right lung with partial anomalous pulmonary venous return and accessory diaphragm: a case of "scimitar lung".

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital cardiovascular condition in which some of the pulmonary veins drain into the systemic circulation. We report on the cadaveric dissection of a 71-year-old Caucasian male donor who died of chronic obstructive pulmonary disease with hypertension. We noted a faint incisional scar on the thorax extending from the parasternal region at the 4th intercostal level to the midaxillary line. Since the straight-line incision followed the ribs and the scar was quite faint, surgery probably occurred when the donor was young. We also observed numerous surgical interventions of the heart, lungs, and vasculature to correct various defects. The morphology of the heart was normal, but was shifted more to the right side. An atrial septal defect (ASD) was closed with sutures. The right superior pulmonary vein that drained into the superior vena cava (SVC) was ligated close to the SVC and the right inferior, left superior, and inferior pulmonary veins all drained directly into the left atrium. We noticed a dilated coronary sinus entering the right atrium adjacent to the ASD; the ostium of the coronary sinus noticeably lacked the normal valve-like structure. We initially thought the right lung was a "horseshoe" lung, but realised that it was a "hypogenetic" lung with PAPVR and an accessory diaphragm. Compared to the left, the right secondary bronchi were much narrower and branched uncharacteristically, as seen in hypogenetic lung syndrome. The inferior lobe was highly disorganised, severely hypoplastic, and exhibited uncharacteristic morphology. The superior bronchopulmonary segment was markedly hypoplastic. The posterior and medial basal segments were not only hypoplastic and slender, but also extended like a tail to the left pulmonary cavity behind the heart/pericardium and in front of the oesophagus and aorta. The right lung, though hypoplastic, demonstrated patent bronchi and the lobes were inflatable. Based on the hypogenetic lung and PAPVR, we conclude that the donor exhibited 'scimitar' lung.

Gluteal lymphoedema associated with lower extremity lymphoedema: A preliminary study with indocyanine green lymphography and magnetic resonance imaging.

INTRODUCTION: Indocyanine green (ICG) lymphography studies have identified that one in three to five patients with cancer-related lower extremity lymphoedema (LEL) demonstrated dermal backflow extending to the gluteal region. This study aimed to further characterize gluteal lymphoedema using contemporaneous magnetic resonance imaging (MRI). PATIENTS AND METHODS: Twenty-eight patients with unilateral advanced LEL who underwent both ICG lymphography and MRI prior to any surgical procedure were included in this study. The patients were divided into two groups with/without gluteal lymphoedema by the presence of dermal backflow on ICG lymphography. MRI was used to evaluate tissue changes. RESULTS: Ten patients demonstrated gluteal lymphoedema on ICG lymphography and had a higher incidence of skin hypertrophy in the gluteal region. However, no difference in excess leg volume was found between the two groups. A trend of increasing gluteal subcutaneous tissue in the affected side was identified in patients with gluteal lymphoedema with a median increase of 20% compared with an 11% increase in the non-gluteal lymphoedema group. The excess gluteal subcutaneous tissue was positively correlated to ipsilateral excess leg volume. CONCLUSION: The gluteal lymphoedema group on ICG lymphography had skin thickening in the gluteal region and was likely identified in the secondary cancer-related group. Surgical and conservative management options for gluteal lymphoedema need to be considered in advanced LEL.

Validation of the Vanderbilt Responses to Your Child's Speech Rating Scale for Parents of Young Children Who Stutter.

PURPOSE: This study reports the development, refinement, and exploration of the psychometric properties of the Vanderbilt Responses to Your Child's Speech (VRYCS) rating scale, a novel measure designed to assess parents' self-perceived responses to the speech of their children who stutter (CWS). METHOD: Parents of 214 young (ages 2;4[years;months]-5;11) CWS completed the original 40-item version of the VRYCS. Content analyses and an exploratory factor analysis determined the scale's factors and identified specific items corresponding to each. Items that did not load onto the factors were removed and internal consistency was assessed. RESULTS: The final 18-item VRYCS rating scale includes five factors relating to parents' responses to the speech of their CWS including (a) Requesting Change, (b) Speaking for the Child, (c) Supporting Communication, (d) Slowing and Simplifying, and (e) Responding Emotionally. Reliability was demonstrated, responses by parents of CWS were described, and a revised scoring form developed. CONCLUSIONS: The VRYCS is a valid and reliable tool for assessing and exploring parents' perceptions of their own responses to the speech of their CWS for clinical and research purposes. Clinical applications of the VRYCS for assessment and treatment of childhood stuttering are discussed.

Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep.

IGF-1 is a critical fetal growth-promoting hormone. Experimental infusion of an IGF-1 analog, human recombinant LR3 IGF-1, into late gestation fetal sheep increased fetal organ growth and skeletal muscle myoblast proliferation. However, LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), thus reducing physiologic regulation of IGF-1 bioavailability. The peptide sequences for LR3 IGF-1 and sheep IGF-1 also differ. To overcome these limitations with LR3 IGF-1, we developed an ovine (sheep) specific recombinant IGF-1 (oIGF-1) and tested its effect on growth in fetal sheep. First, we measured in vitro myoblast proliferation in response to oIGF-1. Second, we examined anabolic signaling pathways from serial skeletal muscle biopsies in fetal sheep that received oIGF-1 or saline infusion for 2 hours. Finally, we measured the effect of fetal oIGF-1 infusion versus saline infusion (SAL) for 1 week on fetal body and organ growth, in vivo myoblast proliferation, skeletal muscle fractional protein synthetic rate, IGFBP expression in skeletal muscle and liver, and IGF-1 signaling pathways in skeletal muscle. Using this approach, we showed that oIGF-1 stimulated myoblast proliferation in vitro. When infused for 1 week, oIGF-1 increased organ growth of the heart, kidney, spleen, and adrenal glands and stimulated skeletal myoblast proliferation compared to SAL without increasing muscle fractional synthetic rate or hindlimb muscle mass. Hepatic and muscular gene expression of IGFBPs one to three was similar between oIGF-1 and SAL. We conclude that oIGF-1 promotes tissue and organ-specific growth in the normal sheep fetus.

Proper understanding of recurrent stress urinary incontinence treatment in women (PURSUIT): a randomised controlled trial of endoscopic and surgical treatment.

BACKGROUND: Women with stress urinary incontinence (SUI) experience urine leakage with physical activity. Currently, the interventional treatments for SUI are surgical, or endoscopic bulking injection(s). However, these procedures are not always successful, and symptoms can persist or come back after treatment, categorised as recurrent SUI. There are longstanding symptoms and distress associated with a failed primary treatment, and currently, there is no consensus on how best to treat women with recurrent, or persistent, SUI. METHODS: A two-arm trial, set in at least 20 National Health Service (NHS) urology and urogynaecology referral units in the UK, randomising 250 adult women with recurrent or persistent SUI 1:1 to receive either an endoscopic intervention (endoscopic bulking injections) or a standard NHS surgical intervention, currently colposuspension, autologous fascial sling or artificial urinary sphincter. The aim of the trial is to determine whether surgical treatment is superior to endoscopic bulking injections in terms of symptom severity at 1 year after randomisation. This primary outcome will be measured using the patient-reported International Consultation on Incontinence Questionnaire - Urinary Incontinence - Short Form (ICIQ-UI-SF). Secondary outcomes include assessment of longer-term clinical impact, improvement of symptoms, safety, operative assessments, sexual function, cost-effectiveness and an evaluation of patients' and clinicians' views and experiences of the interventions. DISCUSSION: There is a lack of high-quality, randomised, scientific evidence for which treatment is best for women presenting with recurrent SUI. The PURSUIT study will benefit healthcare professionals and patients and provide robust evidence to guide further treatment and improve symptoms and quality of life for women with this condition. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) registry ISRCTN12201059. Registered on 09 January 2020.

Neurocysticercosis: an update on diagnosis, treatment, and prevention.

Neurocysticercosis (NCC) is an important cause of neurological disease worldwide, including imported cases in nonendemic countries. PURPOSE OF REVIEW: The purpose of this review is to update information on diagnosis, management, and prevention of neurocysticercosis. RECENT FINDINGS: WHO and Infectious Diseases Society of America/American Society of Tropical Medicine and Hygiene guidelines emphasize the importance of corticosteroids and antiparasitic drugs for viable parenchymal disease and single enhancing lesions. Subarachnoid NCC is associated with a high fatality rate unless optimally treated. Advances in subarachnoid NCC include use of prolonged antiparasitic and anti-inflammatory courses and the increasing use of antigen-detection and quantitative PCR assays in diagnosis and follow-up. Emerging data support the safety and efficacy of minimally invasive surgery in ventricular cases. Calcified neurocysticercosis continues to be associated with a high burden of disease. Field studies are demonstrating the feasibility of eradication using a combination of mass chemotherapy for human tapeworms and vaccination/treatment of porcine cysticercosis. SUMMARY: NCC remains an important and challenging cause of neurological disease with significant morbidity despite advances in treatment and prevention.

RNA-Based Therapy for Cryptosporidium parvum Infection: Proof-of-Concept Studies.

Cryptosporidium is a leading cause of moderate-to-severe diarrhea in children, which is one of the major causes of death in children under 5 years old. Nitazoxanide is the only FDA-approved treatment for cryptosporidiosis. However, it has limited efficacy in immunosuppressed patients and malnourished children. Therefore, it is urgent to develop novel therapies against this parasite. RNA interference-mediated therapies are emerging as novel approaches for the treatment of infectious diseases. We have developed a novel method to silence essential genes in Cryptosporidium using single-stranded RNA (ssRNA)/Argonaute (Ago) complexes. In this work we conducted proof-of-concept studies to test the anticryptosporidial activity of these complexes by silencing Cryptosporidium parvum nucleoside diphosphate kinase (NDK) using in vitro and in vivo models. We demonstrated that a 3-day treatment with anti-sense NDK ssRNA/Ago decreased parasite burden by ~98% on infected cells. In vivo studies showed that ssRNA/Ago complexes encapsulated in lipid nanoparticles can be delivered onto intestinal epithelial cells of mice treated orally. In addition a cryptosporidiosis-mouse model showed that treatment with NDK ssRNA/Ago complexes reduced oocyst shedding in 4/5 SCID/beige mice during the acute phase of the infection. Our findings highlight the potential use of antisense RNA-based therapy as an alternative approach to cryptosporidiosis treatment.