Natural history of Plasmodium odocoilei malaria infection in farmed white-tailed deer

ABSTRACT White-tailed deer (Odocoileus virginianus), an ecologically and economically important species, are the most widely distributed large animals in North America. A recent study indicated that up to 25% of all white-tailed deer may be infected with Plasmodium odocoilei, a malaria parasite belonging to the distinct clade of ungulate-infecting Plasmodium spp. Because the clinical impact of P. odocoilei on deer health and survival is unknown, we undertook a retrospective longitudinal study of farmed Floridian O. virginianus fawns. We found that a substantial proportion (21%) of fawns acquire malaria infection during the first 8 months of life. Some animals naturally clear P. odocoilei infection, while other animals remain persistently positive. Importantly, we found that animals that acquire malaria parasites very early in life have poor survival compared to animals that remain uninfected. Our report thus provides the first evidence of a clinically significant impact of malaria infection in young deer. IMPORTANCE Malaria parasites of the genus Plasmodium are known to infect a variety of vertebrate hosts, including ungulates (hoofed mammals). A recent study found that up to a quarter of white-tailed deer (Odocoileus virginianus) in North America are infected with the parasite Plasmodium odocoilei. In addition to occupying an important ecological niche, white-tailed deer are popular game animals and deer farming represents a rapidly growing industry. However, the effect of P. odocoilei infection in this ecologically and economically important ungulate species is unknown. Our work is significant because (i) we identified a high prevalence of P. odocoilei in farmed deer and (ii) we found evidence for both cleared and persistent infection, as well as an association with decreased survival of young fawns

Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness

Mutation of the 3β-hydroxysterol Δ7-reductase gene (Dhcr7−/−) results in Smith-Lemli-Opitz syndrome (SLOS). Patients, and genetically altered mice, are unable to produce cholesterol and accumulate 7-dehydrocholesterol (DHC) in serum and tissue. This causes multiple growth and developmental abnormalities as well as immune system anomalies including allergy. Because cholesterol is a key component of liquid-ordered membranes (lipid rafts) and these domains have been implicated in regulating mast cell activation, we examined whether mast cell responsiveness is altered in this model. Mast cells derived from Dhcr7−/− mice (DHCR KO) showed constitutive cytokine production and hyper-degranulation after stimulation of the high affinity IgE receptor (FcɛRI). DHCR KO mast cells, but not wild-type mast cells, accumulated DHC in lipid rafts. DHC partially disrupted lipid raft stability and displaced Lyn kinase protein and activity from lipid rafts. This led to down-regulation of some Lyn-dependent signaling events but increased Fyn kinase activity and Akt phosphorylation. The Lyn-dependent phosphorylation of Csk-binding protein, which negatively regulates Fyn activity, was decreased. This phenotype reproduces some of the characteristics of Lyn-null mast cells, which also demonstrate hyper-degranulation. These findings provide the first evidence of lipid raft dysfunction in SLOS and may explain the observed association of allergy with SLOS

A study of elective genome sequencing and pharmacogenetic testing in an unselected population

BACKGROUND: Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. METHODS: Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. RESULTS: Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty-four participants (85%) were carriers of a recessive or X-linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. CONCLUSION: Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS

Developing a National Implementation Strategy to accelerate Uptake of Evidence-Based Family Caregiver Support in Us Cancer Centers

OBJECTIVE: Characterize key factors and training needs of U.S. cancer centers in implementing family caregiver support services. METHODS: Sequential explanatory mixed methods design consisting of: (1) a national survey of clinicians and administrators from Commission-on-Cancer-accredited cancer centers (N = 238) on factors and training needed for establishing new caregiver programs and (2) qualitative interviews with a subsample of survey respondents (N = 30) to elicit feedback on survey findings and the outline of an implementation strategy to facilitate implementation of evidence-based family caregiver support (the Caregiver Support Accelerator). Survey data was tabulated using descriptive statistics and transcribed interviews were analyzed using thematic analysis. RESULTS: top factors for developing new caregiver programs were that the program be: consistent with the cancer center\u27s mission and strategic plan (87%), supported by clinic leadership (86.5%) and providers and staff (85.7%), and low cost or cost effective (84.9%). top training needs were how to: train staff to implement programs (72.3%), obtain program materials (63.0%), and evaluate program outcomes (62.6%). Only 3.8% reported that no training was needed. Qualitative interviews yielded four main themes: (1) gaining leadership, clinician, and staff buy-in and support is essential; (2) cost and clinician burden are major factors to program implementation; (3) training should help with adapting and marketing programs to local context and culture; and (4) the Accelerator strategy is comprehensive and would benefit from key organizational partnerships and policy standards. CONCLUSION: Findings will be used to inform and refine the Accelerator implementation strategy to facilitate the adoption and growth of evidence-based cancer caregiver support in U.S. cancer centers

Availability of Family Caregiver Programs in Us Cancer Centers

IMPORTANCE: Family caregivers provide the majority of health care to the 18 million patients with cancer in the US. Yet despite providing complex medical and nursing care, a large proportion of caregivers report no formal support or training. In recognition of this gap, many interventions to support cancer caregivers have been developed and tested over the past 2 decades. However, there are few system-level data on whether US cancer centers have adopted and implemented these interventions. OBJECTIVE: to describe and characterize the availability of family caregiver support programs in US cancer centers. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional national survey study was conducted between September 1, 2021, and April 30, 2023. Participants comprised clinical and administrative staff of Commission on Cancer-accredited US cancer centers. Data analysis was performed in May and June 2023. MAIN OUTCOMES AND MEASURES: Survey questions about the availability of 11 types of family caregiver programs (eg, peer mentoring, education classes, and psychosocial programs) were developed after literature review, assessment of similar program evaluation surveys, and discussions among a 13-member national expert advisory committee. Family caregiver programs were defined as structured, planned, and coordinated groups of activities and procedures aimed at specifically supporting family caregivers as part of usual care. Survey responses were tabulated using standard descriptive statistics, including means, proportions, and frequencies. RESULTS: Of the surveys sent to potential respondents at 971 adult cancer centers, 238 were completed (response rate, 24.5%). After nonresponse weight adjustment, most cancer centers (75.4%) had at least 1 family caregiver program; 24.6% had none. The most common program type was information and referral services (53.6%). Cancer centers with no programs were more likely to have smaller annual outpatient volumes (χ2 = 11.10; P = .011). Few centers had caregiver programs on training in medical and/or nursing tasks (21.7%), caregiver self-care (20.2%), caregiver-specific distress screening (19.3%), peer mentoring (18.9%), and children caregiving for parents (8.3%). Very few programs were developed from published evidence in a journal (8.1%). The top reason why cancer centers selected their programs was community members requesting the program (26.3%); only 12.3% of centers selected their programs based on scientific evidence. Most programs were funded by the cancer center or hospital (58.6%) or by philanthropy (42.4%). CONCLUSIONS AND RELEVANCE: In this survey study, most cancer centers had family caregiver programs; however, a quarter had none. Furthermore, the scope of programming was limited and rarely evidence based, with few centers offering caregiving education and training. These findings suggest that implementation strategies are critically needed to foster uptake of evidence-based caregiver interventions

The key glycolytic enzyme phosphofructokinase is involved in resistance to antiplasmodial glycosides

ABSTRACT Plasmodium parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the Plasmodium falciparum glycolytic enzyme, phosphofructokinase (PfPFK9), are associated with in vitro resistance to a primary sulfonamide glycoside (PS-3). Flux through the upper glycolysis pathway was significantly reduced in PS-3-resistant parasites, which was associated with reduced ATP levels but increased flux into the pentose phosphate pathway. PS-3 may directly or indirectly target enzymes in these pathways, as PS-3-treated parasites had elevated levels of glycolytic and tricarboxylic acid (TCA) cycle intermediates. PS-3 resistance also led to reduced MEP pathway intermediates, and PS-3-resistant parasites were hypersensitive to the MEP pathway inhibitor, fosmidomycin. Overall, this study suggests that PS-3 disrupts core pathways in central carbon metabolism, which is compensated for by mutations in PfPFK9, highlighting a novel metabolic drug resistance mechanism in P. falciparum. IMPORTANCE Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway

Changes in Consumer Attitudes toward Broad-Based and Environment-Specific Sodium Policies—SummerStyles 2012 and 2015

We examined temporal changes in consumer attitudes toward broad-based actions and environment-specific policies to limit sodium in restaurants, manufactured foods, and school and workplace cafeterias from the 2012 and 2015 SummerStyle surveys. We used two online, national research panel surveys to conduct a cross-sectional analysis of 7845 U.S. adults. Measures included self-reported agreement with broad-based actions and environment-specific policies to limit sodium in restaurants, manufactured foods, school cafeterias, workplace cafeterias, and quick-serve restaurants. Wald Chi-square tests were used to examine the difference between the two survey years and multivariate logistic regression was used to obtain odds ratios. Agreement with broad-based actions to limit sodium in restaurants (45.9% agreed in 2015) and manufactured foods (56.5% agreed in 2015) did not change between 2012 and 2015. From 2012 to 2015, there was a significant increase in respondents that supported environment-specific policies to lower sodium in school cafeterias (80.0% to 84.9%; p < 0.0001), workplace cafeterias (71.2% to 76.6%; p < 0.0001), and quick-serve restaurants (70.8% to 76.7%; p < 0.0001). Results suggest substantial agreement and support for actions to limit sodium in commercially-processed and prepared foods since 2012, with most consumers ready for actions to lower sodium in foods served in schools, workplaces, and quick-serve restaurants