Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Gaussian versus Non-Gaussian Filtering of Phase-Insensitive Nonclassicality.

Measures of quantum properties are essential to understanding the fundamental differences between quantum and classical systems as well as quantifying resources for quantum technologies. Here, two broad classes of bosonic phase-space functions, which are filtered versions of the Glauber-Sudarshan P function, are compared with regard to their ability to uncover nonclassical effects of light through their negativities. Gaussian filtering of the P function yields the family of s-parametrized quasiprobabilities, while more powerful regularized nonclassicality quasiprobabilities are obtained by non-Gaussian filtering. A method is proposed to directly sample such phase-space functions for the restricted case of phase-independent quantum states from balanced homodyne measurements. This overcomes difficulties of previous approaches that manually append uniformly distributed optical phases to the measured quadrature data. We experimentally demonstrate this technique for heralded single- and two-photon states using balanced homodyne detection with varying efficiency. The s-parametrized quasiprobabilities, which can be directly sampled, are non-negative for detection efficiencies below 0.5. By contrast, we show that significant negativities of non-Gaussian filtered quasiprobabilities uncover nonclassical effects for arbitrarily low efficiencies.

The Funding, Administrative, and Policy Influences on the Evaluation of Primary Prevention Programs in Australia.

Evaluation of primary prevention and health promotion programs contributes necessary information to the evidence base for prevention programs. There is increasing demand for high-quality evaluation of program impact and effectiveness for use in public health decision making. Despite the demand for evidence and known benefits, evaluation of prevention programs can be challenging and organizations face barriers to conducting rigorous evaluation. Evaluation capacity building efforts are gaining attention in the prevention field; however, there is limited knowledge about how components of the health promotion and primary prevention system (e.g., funding, administrative arrangements, and the policy environment) may facilitate or hinder this work. We sought to identify the important influences on evaluation practice within the Australian primary prevention and health promotion system. We conducted in-depth semi-structured interviews with experienced practitioners and managers (n = 40) from government and non-government organizations, and used thematic analysis to identify the main factors that impact on prevention program evaluation. Firstly, accountability and reporting requirements impacted on evaluation, especially if expectations were poorly aligned between the funding body and prevention organization. Secondly, the funding and political context was found to directly and indirectly affect the resources available and evaluation approach. Finally, it was found that participants made use of various strategies to modify the prevention system for more favorable conditions for evaluation. We highlight the opportunities to address barriers to evaluation in the prevention system, and argue that through targeted investment, there is potential for widespread gain through improved evaluation capacity.

Relationship of American Indian blood quantum with osteoporosis risk: a cross-sectional study of American Indian women in Oklahoma.

Information regarding the prevalence and risk of osteoporosis among American Indian (AI) women is limited. This study showed that with increasing AI blood quantum, the prevalence of osteoporosis at the hip based on BMD T-scores decreased and this appeared to be independent of other risk factors. INTRODUCTION: This study was designed to investigate the effects of AI blood quantum (BQ) on osteoporosis prevalence and risk in a cohort of AI women in Oklahoma. METHODS: Women (n = 301), aged 50 years and older, were recruited to participate in the Oklahoma American Indian Women's Osteoporosis Study. Baseline bone density, fracture history, bone biochemical markers, and potential risk factors were assessed. Participants were stratified by AI BQ into BQ1 ≤ 25%, BQ2 = 25-49%, BQ3 = 50-74%, and BQ4 = 75-100%. The effects of BQ on the prevalence and risk of osteoporosis were evaluated. RESULTS: Based on T-scores, one in approximately eight women in the study was osteoporotic at one or more sites. The prevalence of osteoporosis decreased (p < 0.05) with increasing BQ, especially at the hip, trochanteric, and intertrochanter regions. No differences in bone-specific alkaline phosphatase and C-telopeptide were observed across BQ that could account for the differences in bone density. 25-OH vitamin D decreased with increasing BQ, but mean for each BQ1-4 was > 40 ng/mL. Fracture history did not differ across BQ, and though 52% of the population consumed less than the RDA for calcium, no effect of BQ was observed. CONCLUSIONS: In this cohort of women who identified as AI, greater Indian BQ was associated with a decrease in the prevalence of osteoporosis.

Organizational determinants of evaluation practice in Australian prevention agencies.

Program evaluation is essential to inform decision making, contribute to the evidence base for strategies, and facilitate learning in health promotion and disease prevention organizations. Theoretical frameworks of organizational learning, and studies of evaluation capacity building describe the organization as central to evaluation capacity. Australian prevention organizations recognize limitations to current evaluation effectiveness and are seeking guidance to build evaluation capacity. This qualitative study identifies organizational facilitators and barriers to evaluation practice, and explores their interactions in Australian prevention organizations. We conducted semi-structured interviews with 40 experienced practitioners from government and non-government organizations. Using thematic analysis, we identified seven key themes that influence evaluation practice: leadership, organizational culture, organizational systems and structures, partnerships, resources, workforce development and training and recruitment and skills mix. We found organizational determinants of evaluation to have multi-level interactions. Leadership and organizational culture influenced organizational systems, resource allocation and support of staff. Partnerships were important to overcome resource deficits, and systems were critical to embed evaluation within the organization. Organizational factors also influenced the opportunities for staff to develop skills and confidence. We argue that investment to improve these factors would allow organizations to address evaluation capacity at multiple levels, and ultimately facilitate effective evaluation practice.

Plasmid CDS5 influences infectivity and virulence in a mouse model of Chlamydia trachomatis urogenital infection.

The native plasmid of both Chlamydia muridarum and Chlamydia trachomatis has been shown to control virulence and infectivity in mice and in lower primates. We recently described the development of a plasmid-based genetic transformation protocol for Chlamydia trachomatis that for the first time provides a platform for the molecular dissection of the function of the chlamydial plasmid and its individual genes or coding sequences (CDS). In the present study, we transformed a plasmid-free lymphogranuloma venereum isolate of C. trachomatis, serovar L2, with either the original shuttle vector (pGFP::SW2) or a derivative of pGFP::SW2 carrying a deletion of the plasmid CDS5 gene (pCDS5KO). Female mice were inoculated with these strains either intravaginally or transcervically. We found that transformation of the plasmid-free isolate with the intact pGFP::SW2 vector significantly enhanced infectivity and induction of host inflammatory responses compared to the plasmid-free parental isolate. Transformation with pCDS5KO resulted in infection courses and inflammatory responses not significantly different from those observed in mice infected with the plasmid-free isolate. These results indicate a critical role of plasmid CDS5 in in vivo fitness and in induction of inflammatory responses. To our knowledge, these are the first in vivo observations ascribing infectivity and virulence to a specific plasmid gene.

Nonclassical light manipulation in a multiple-scattering medium.

We investigate the possibility of using a scattering medium as a highly multimode platform for implementing quantum walks. We demonstrate the manipulation of a single photon propagating through a strongly scattering medium using wavefront-shaping technique. Measurement of the scattering matrix allows the wavefront of the photon to be shaped to compensate the distortions induced by multiple scattering events. The photon can thus be directed coherently to a specific output mode. Using this approach, we show how entanglement of a single photon across different modes can be manipulated despite the enormous wavefront disturbance caused by the scattering medium.

Effects of dried plum supplementation on bone metabolism in adult C57BL/6 male mice.

Dietary supplementation of dried plum (DP) prevents bone loss and restores bone mass in osteopenic animal models. This study was designed to determine the effects of DP supplementation on bone metabolic activity over time using adult (6-month-old) male C57BL/6 mice (n = 40) receiving control (CON = AIN93 M) or CON+DP 25 % (w/w) diets for 4 or 12 weeks. After 4 weeks of treatment, animals consuming the DP diet had a higher whole-body bone mineral density, vertebral trabecular bone volume (BV/TV), and femoral cortical thickness compared to the CON animals. In the distal metaphysis of the femur, BV/TV was increased in the DP-treated animals, but only after 12 weeks. Bone histomorphometric analyses revealed that DP decreased osteoblast surface (67 %) and osteoclast surface (62 %) at 4 weeks, but these surfaces normalized to the CON animals by 12 weeks. Coincident with these changes, the mineralizing surface (MS/BS) and cancellous bone formation rate (BFR/BS) were reduced at 4 weeks in the DP group compared to the CON, but by 12 weeks of DP supplementation, BFR/BS (~twofold) and MS/BS (~1.7-fold) tended to be increased (p < 0.10). The relative abundance of RNA for key regulators of osteoblast and osteoclast differentiation and indicators of osteoblast activity were reduced in the DP group at 4 weeks with no difference between groups at 12 weeks. These results indicate that supplementing the diet with DP initially suppressed cancellous bone turnover, but a biphasic response occurs over time, resulting in a positive effect on bone mass and structure.

Large-alphabet time-frequency entangled quantum key distribution by means of time-to-frequency conversion.

We introduce a novel time-frequency quantum key distribution (TFQKD) scheme based on photon pairs entangled in these two conjugate degrees of freedom. The scheme uses spectral detection and phase modulation to enable measurements in the temporal basis by means of time-to-frequency conversion. This allows large-alphabet encoding to be implemented with realistic components. A general security analysis for TFQKD with binned measurements reveals a close connection with finite-dimensional QKD protocols and enables analysis of the effects of dark counts on the secure key size.

Development of a method to produce hemoglobin in a bioreactor culture of Escherichia coli BL21(DE3) transformed with a plasmid containing Plesiomonas shigelloides heme transport genes and modified human hemoglobin genes.

We describe a method for production of recombinant human hemoglobin by Escherichia coli grown in a bioreactor. E. coli BL21(DE3) transformed with a plasmid containing hemoglobin genes and Plesiomonas shigelloides heme transport genes reached a cell dry weight of 83.64 g/liter and produced 11.92 g/liter of hemoglobin in clarified lysates.

Ovariectomy and genes encoding core circadian regulatory proteins in murine bone.

SUMMARY: This study investigated the influence of ovarian hormone deficiency on core circadian regulatory protein (CCRP) in the context of bone loss. Our data suggest that ovarian hormone deficiency disrupts diurnal rhythmicity and CCRP expression in bone. Further studies should determine if chronobiology provides a novel therapeutic target for osteoporosis intervention. INTRODUCTION: CCRP synchronize metabolic activities and display an oscillatory expression profile in murine bone. In vitro studies using bone marrow mesenchymal stromal/stem cells have demonstrated that the CCRP is present and can be regulated within osteoblast progenitors. In vivo studies have shown that the CCRP regulates bone mass via leptin/neuroendocrine pathways. The current study used an ovariectomized murine model to test the hypothesis that ovarian hormone deficiency is associated with either an attenuation and/or temporal phase shift of the CCRP oscillatory expression in bone and that these changes are correlated with the onset of osteoporosis. METHODS: Sham-operated controls and ovariectomized female C57BL/6 mice were euthanized at 4-h intervals 2 weeks post-operatively. RESULTS: Ovariectomy attenuated the oscillatory expression of CCRP mRNAs in the femur and vertebra relative to the controls and reduced the wheel-running activity profile. CONCLUSION: Ovarian hormone deficiency modulates the expression profile of the CCRP with potential impact on bone marrow mesenchymal stem cell lineage commitment.

Metal and oxalate contamination in a suburban watershed in the greater Toronto area: the benefits of combining acid leach and selective extraction procedures.

Environmentally available concentrations of Fe, Mn, Zn, Cu, Pb, Cr and Ni in soils and sediments from a small suburban catchment, obtained using an acid leach procedure, are compared to the Ontario Ministry of the Environment lowest effect level (LEL) and severe effect levels (SEL) and to Provincial sediment quality guidelines (PSQG's). These data are then compared to the bioavailability, potential bioavailability and non-bioavailability of the same metals, plus oxalate concentration, identified using a selective extraction procedure. This combination of techniques enhanced analytical interpretation with respect to metal mobility and potential metal contamination. Selective extraction highlighted the presence of oxalate as a potential contaminant, especially in poorly drained valley floor deposits (33,633 mg kg(-1) and 26,284 mg kg(-1)) and lakeshore sediments (27,095 mg kg(-1) and 13,729 mg kg(-1)). These levels are considerably in excess of those previously documented in a similar study from Rio de Janeiro, where contamination of urban sediment by sewage is a recognised environmental problem, and could possibly be used both as an indicator of similar contamination and the identification of those areas that warrant further investigation.

UK B.1.1.7 variant exhibits increased respiratory replication and shedding in nonhuman primates.

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, African green monkeys were infected intranasally with either a contemporary D614G or the UK B.1.1.7 variant. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tract tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases. ONE-SENTENCE SUMMARY: UK B.1.1.7 infection of African green monkeys exhibits increased respiratory replication and shedding but no disease enhancement.

Central melanocortin stimulation increases phosphorylated perilipin A and hormone-sensitive lipase in adipose tissues.

Norepinephrine (NE) released from the sympathetic nerves innervating white adipose tissue (WAT) is the principal initiator of lipolysis in mammals. Central WAT sympathetic outflow neurons express melanocortin 4-receptor (MC4-R) mRNA. Single central injection of melanotan II (MTII; MC3/4-R agonist) nonuniformly increases WAT NE turnover (NETO), increases interscapular brown adipose tissue (IBAT) NETO, and increases the circulating lipolytic products glycerol and free fatty acid. The WAT pads that contributed to this lipolysis were inferred from the increases in NETO. Because phosphorylation of perilipin A (p-perilipin A) and hormone-sensitive lipase are necessary for NE-triggered lipolysis, we tested whether MTII would increase these intracellular markers of lipolysis. Male Siberian hamsters received a single 3rd ventricular injection of MTII or saline. Trunk blood was collected at 0.5, 1.0, and 2.0 h postinjection from excised inguinal, retroperitoneal, and epididymal WAT (IWAT, RWAT, and EWAT, respectively) and IBAT pads. MTII increased circulating glycerol concentrations at 0.5 and 1.0 h, whereas free fatty acid concentrations were increased at 1.0 and 2.0 h. Western blot analysis showed that MTII specifically increased p-perilipin A and hormone-sensitive lipase only in fat pads that previously had MTII-induced increases in NETO. Phosphorylation increased in IWAT at all time points and IBAT at 0.5 h, but not RWAT or EWAT at any time point. These results show for the first time in rodents that p-perilipin A can serve as an in vivo, fat pad-specific indictor of lipolysis and extend our previous findings showing that central melanocortin stimulation increases WAT lipolysis.

Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes.

Kv1.3 potassium channels maintain the membrane potential of effector memory (T(EM)) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of ShK-192 in Kv1.3 shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys(411) of the channel. ShK-192 blocks Kv1.3 with an IC(50) of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 microg/kg, approximately 100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T(EM) cells and suppresses delayed type hypersensitivity when administered at 10 or 100 microg/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T(EM) cells.

BRCA2 alteration is important in clear cell carcinoma of the ovary.

BRCA2 has been shown to play a significant role in hereditary ovarian carcinoma. Several cases of clear cell carcinoma (CCC) of the ovary containing BRCA2 mutations have been identified. We hypothesize that sequence variants of the BRCA2 gene are common in CCC of the ovary. Multiple methods were utilized to detect BRCA2 genetic alterations in a cohort of 13 ovarian CCC. These included an LOH analysis for copy number, real-time and methylation-specific polymerase chain reaction (PCR) to probe for BRCA2 promoter methylation, in addition to protein truncation testing (PTT) gel screening for nonsense BRCA2 mutations, and finally direct gene sequencing to either confirm the nonsense mutations or to detect candidate missense mutations in the remaining tumor samples. Whenever a sequence variation was detected in a tumor sample, the corresponding region was sequenced from a blood sample to determine germline status. Seven BRCA2 sequence variations were identified in 6 of the 13 CCC (46%); three tumors contained an alteration in BRCA2 copy number. Only one subject carried a germline sequence variation that might alter BRCA2 function despite the fact that a family history of breast, ovarian or colon cancer was common in this population. The 5-year disease-specific survival probability for patients with a BRCA2 alteration is 87.5%, compared to only 40% for those patients without a BRCA2 alteration (p = 0.39). Alterations in BRCA2 gene sequence, copy number, or expression are extremely common in CCC and may contribute to a paradoxical better clinical outcome.

Absolute efficiency estimation of photon-number-resolving detectors using twin beams.

A nonclassical light source is used to demonstrate experimentally the absolute efficiency calibration of a photon-number-resolving detector. The photon-pair detector calibration method developed by Klyshko for single-photon detectors is generalized to take advantage of the higher dynamic range and additional information provided by photon-number-resolving detectors. This enables the use of brighter twin-beam sources including amplified pulse pumped sources, which increases the relevant signal and provides measurement redundancy, making the calibration more robust.

General practitioners' perceptions and practices of physical activity counselling: changes over the past 10 years.

OBJECTIVE: In this work, trends in general practitioners' (GP) knowledge, confidence and practices in promoting physical activity to patients over a 10-year period (1997-2007) were studied. DESIGN: Repeated cross-sectional population survey SETTING: General practice in New South Wales (Australia) PARTICIPANTS: 646 (40%), 747 (53%) and 511 (64%) GPs that were registered in a selection of urban and rural divisions in New South Wales participated in 2007, 2000 and 1997, respectively. MAIN OUTCOME MEASURES: Self-report questionnaire on the GP's knowledge, confidence, role perception, attendance of continuous professional development and counselling practice with regard to promoting physical activity in their patients were the main outcome measures. RESULTS: The majority of GPs felt confident in giving physical activity advice and saw it as their role to do so. The proportion of GPs with high confidence and role perception increased between 1997 and 2000 (p<0.001) but remained unchanged thereafter. In 1997, GPs were 0.54 times less likely (95% CI 0.42 to 0.69, p<0.001) to discuss physical activity with more than 10 patients per week than GPs in 2007. However, the percentage of new patients that were asked about their physical activity did not change over the last decade. CONCLUSIONS: Most increases in the proportion of GPs reporting high knowledge, role perception and confidence in giving physical activity advice to patients occurred between 1997 and 2000 and remained unchanged thereafter. In 2007, GPs appeared to give more physical activity advice, but Australian general practice is not yet living up to its potential with regard to physical activity promotion.

Building capacity in local government for integrated planning to increase physical activity: evaluation of the VicHealth MetroACTIVE program.

Integrated planning is a holistic approach to addressing the needs of local communities built on partnerships between those responsible for development, environmental quality and service provision. This study investigated the extent and key influences on the use of integrated planning to promote physical activity among six metropolitan councils in Melbourne Australia, which took part in the MetroACTIVE Project funded by the Victorian Health Promotion Foundation from 2005 to 2007. The evaluation entailed interviews conducted at the mid-term (N = 67) and completion (N = 50) of the project, and the review of relevant documents. Respondents included elected councillors, chief executive officers, officers from different council divisions and the project staff employed in each council. Three councils showed evidence of integrated planning for physical activity, whereas the remainder focused on the delivery of community participation programs. Leadership from senior management and an organizational culture that supported collaboration across council departments were prerequisites for integrated planning. Employment of a dedicated project officer with skills for engaging management and building partnerships within the organization was important. Barriers to integrated planning were a complex organization structure, high demands on the council due to a growing residential population and a poor climate among staff. Overall, integrated planning was found to be a viable approach for developing a coordinated approach to this issue involving the range of council services and functions. Ongoing strategies are needed to facilitate senior management commitment and organizational capacity for integrated planning, with leadership provided by departments responsible for infrastructure or corporate planning.

Providing reviews of evidence to COPD patients: controlled prospective 12-month trial.

The aim of this study was to evaluate a novel patient-held manual designed to reduce the evidence-practice gap in chronic obstructive pulmonary disease (COPD). The intervention manual contained summaries of research evidence. It was developed using current best practice for patient information materials and designed to cause discussion of evidence between patient and doctor. A controlled before-and-after study was employed in two similar but geographically separate regions of metropolitan Adelaide, South Australia. Participants had moderate to severe COPD, with 249 included at baseline and 201 completing the study. Evidence-based COPD management was measured using an indicator with three components: rates of influenza vaccination, bone density testing, and pulmonary rehabilitation. A survey of behavioral steps leading to practice change was conducted with the trial. Analysis, by median split of socioeconomic disadvantage, showed significant difference between study arms for only one component of the indicator of evidence-based practice, enrollment in pulmonary rehabilitation and only for the most socioeconomically disadvantaged stratum. For both socioeconomic strata, more intervention participants than control participants reported remembering being given the information material, reading part or all, and finding it very or quite helpful. Other significant differences were restricted to the stratum of greatest socioeconomic disadvantage: reading all of the material, learning from it, referring back, and talking to a doctor about a topic from the material. Above 90% of all participants who received the manual reported reading from it, 42% reported discussing topics with a doctor, but only 10% reported treatment change attributable to the manual. We have found that people with COPD will read an evidence manual developed using current best practice. However, the study demonstrated improvement for only one of the three components of an indicator of evidence-based disease management for only the most socioeconomically disadvantaged stratum of participants. Future interventions should be designed to better translate reading uptake into evidence-based disease management.