Influenza vaccine allocation in tropical settings under constrained resources.

Influenza virus seasonality, synchronicity, and vaccine supply differ substantially between temperate and tropical settings, and optimal vaccination strategy may differ on this basis. Many national vaccine recommendations focus on high-risk groups, elderly populations, and healthcare workers despite previous analyses demonstrating broad benefits to vaccinating younger high-contact age groups. In this study, we parameterized an age-structured nonseasonal asynchronous epidemiological model of influenza virus transmission for a tropical low-income setting. We evaluated timing and age allocation of vaccines across vaccine supplies ranging from 10 to 90% using decade-based age groups. Year-round vaccination was beneficial when compared with more concentrated annual vaccine distribution. When targeting a single age group for vaccine prioritization, maximum vaccine allocation to the 10-19 high-contact age group minimized annual influenza mortality for all but one vaccine supply. When evaluating across all possible age allocations, optimal strategies always allocated a plurality of vaccines to school-age children (10-19). The converse, however, was not true as not all strategies allocating a plurality to children aged 10-19 minimized mortality. Allocating a high proportion of vaccine supply to the 10-19 age group is necessary but not sufficient to minimize annual mortality as distribution of remaining vaccine doses to other age groups also needs to be optimized. Strategies focusing on indirect benefits (vaccinating children) showed higher variance in mortality outcomes than strategies focusing on direct benefits (vaccinating the elderly). However, the indirect benefit approaches showed a lower mean mortality and a lower minimum mortality than vaccination focused on the elderly.

Nanomechanical footprint of SARS-CoV-2 variants in complex with a potent nanobody by molecular simulations.

Rational design of novel antibody therapeutics against viral infections such as coronavirus relies on surface complementarity and high affinity for their effectiveness. Here, we explore an additional property of protein complexes, the intrinsic mechanical stability, in SARS-CoV-2 variants when complexed with a potent antibody. In this study, we utilized a recent implementation of the GoMartini 3 approach to investigate large conformational changes in protein complexes with a focus on the mechanostability of the receptor-binding domain (RBD) from WT, Alpha, Delta, and XBB.1.5 variants in complex with the H11-H4 nanobody. The analysis revealed moderate differences in mechanical stability among these variants. Also, we identified crucial residues in both the RBD and certain protein segments in the nanobody that contribute to this property. By performing pulling simulations and monitoring the presence of specific native and non-native contacts across the protein complex interface, we provided mechanistic insights into the dissociation process. Force-displacement profiles indicate a tensile force clamp mechanism associated with the type of protein complex. Our computational approach not only highlights the key mechanostable interactions that are necessary to maintain overall stability, but it also paves the way for the rational design of potent antibodies that are mechanostable and effective against emergent SARS-CoV-2 variants.

Psychiatric predictors of quality of life in Parkinson's disease: A three-year longitudinal study.

INTRODUCTION: Parkinson's disease (PD) is associated with worsened quality of life (QOL) over time. Few longitudinal studies exist investigating the relationship of psychiatric comorbidities with QOL in people with PD (PwP). We sought to determine specific psychiatric symptoms associated with decreasing QOL in PwP over time. METHODS: We recruited PwP without dementia from a movement disorders clinic at an academic medical center. Participants were evaluated annually with motor and neuropsychological assessments at each visit. QOL was measured using the Parkinson's Disease Questionnaire-39 (PDQ-39). We assessed psychiatric symptoms, including depression (Beck Depression Inventory II, BDI-II), anxiety (Beck Anxiety Index, BAI), and apathy (Apathy Scale). Psychosis and impulse control disorders (ICDs) were recorded as present or absent. Using random coefficient regression, we analyzed psychiatric features associated with worsened QOL in PwP over three years. RESULTS: From the 105 participants enrolled at baseline, 67 completed three years of follow up. Mean PDQ-39 scores increased from 16.0 at baseline to 19.8 at year three. In multivariate analysis, higher BDI-II scores, BAI scores, and apathy scores were uniquely associated with worsened QOL over time (p < 0.001 for all measures), while presence of ICDs (p = 0.18) or psychosis (p = 0.10) were not. Changes in the BAI score and the BDI-II score exerted similar effects on the overall PDQ-39 score. CONCLUSION: Depression, anxiety, and apathy are all associated with worsening quality of life over time in PwP, while presence of ICDs and psychosis are not. Treatment of these symptoms may lead to improved QOL in PwP.

Polarization-dependent photoemission electron microscopy for domain imaging of inorganic and molecular materials.

Polarization-dependent photoemission electron microscopy (PD-PEEM) exploits spatial variation in the optical selection rules of materials to image domain formation and material organization on the nanoscale. In this Perspective, we discuss the mechanism of PD-PEEM that results in the observed image contrast in experiments and provide examples of a wide range of material domain structures that PD-PEEM has been able to elucidate, including molecular and polymer domains, local electronic structure and defect symmetry, (anti)ferroelectricity, and ferromagnetism. In the end, we discuss challenges and new directions that are possible with this tool for probing domain structure in materials, including investigating the formation of transient ordered states, multiferroics, and the influence of molecular and polymer order and disorder on excited state dynamics and charge transport.

Paradoxical Reaction to Tuberculosis Therapy among HIV-Negative Children: A Systematic Review and Meta-Analysis.

Tuberculosis treatment is sometimes associated with clinical deterioration, referred to as paradoxical reaction (PR), especially in those with HIV coinfection. However, the burden and characteristics of PR in children without HIV coinfection are unclear. We undertook a systematic review to estimate the burden and clinical characteristics of PR in HIV-negative children. We searched PubMed, Embase, Web of Science, CINAHL, Scopus, Cochrane Library, ProQuest, and OpenGrey for studies reporting PR in HIV-negative children (<18 years old). We included observational studies including case series with at least five cases. Data on incidence/prevalence, clinical features, risk factors, management strategies, and outcome of PR were extracted. Risk of bias in the included studies was assessed using the NIH's quality assessment and Joanna Briggs Institute critical appraisal tools. We pooled the prevalence data using random effects meta-analysis. We identified 1,673 studies, of which 10 were eligible for inclusion. They described PR in 133 HIV-negative children. The pooled prevalence was 8.8% (95% CI: 2.9%, 14.6%). Owing to heterogeneity among studies, risk factors for the development of PR could not be identified. Limited data suggested that children developing PR were younger and had neurological or lymph node tuberculosis more often. Most children were treated with corticosteroids, but data were insufficient to identify the optimal management strategy. The review showed that PR affects nearly 1 in 12 HIV-negative children receiving tuberculosis treatment. The paucity of studies emphasizes the need for surveillance/studies to better characterize clinical features, risk factors, appropriate management strategies, and outcome.

Global Genotype by Environment Prediction Competition Reveals That Diverse Modeling Strategies Can Deliver Satisfactory Maize Yield Estimates.

Predicting phenotypes from a combination of genetic and environmental factors is a grand challenge of modern biology. Slight improvements in this area have the potential to save lives, improve food and fuel security, permit better care of the planet, and create other positive outcomes. In 2022 and 2023 the first open-to-the-public Genomes to Fields (G2F) initiative Genotype by Environment (GxE) prediction competition was held using a large dataset including genomic variation, phenotype and weather measurements and field management notes, gathered by the project over nine years. The competition attracted registrants from around the world with representation from academic, government, industry, and non-profit institutions as well as unaffiliated. These participants came from diverse disciplines include plant science, animal science, breeding, statistics, computational biology and others. Some participants had no formal genetics or plant-related training, and some were just beginning their graduate education. The teams applied varied methods and strategies, providing a wealth of modeling knowledge based on a common dataset. The winner's strategy involved two models combining machine learning and traditional breeding tools: one model emphasized environment using features extracted by Random Forest, Ridge Regression and Least-squares, and one focused on genetics. Other high-performing teams' methods included quantitative genetics, classical machine learning/deep learning, mechanistic models, and model ensembles. The dataset factors used, such as genetics; weather; and management data, were also diverse, demonstrating that no single model or strategy is far superior to all others within the context of this competition.

Use of arterial transposition for vascular reconstruction within contaminated or infected abdominal fields.

Intra-abdominal arterial reconstructions in the setting of reoperative, contaminated, or frankly infected fields can be a challenging undertaking for even the most experienced vascular surgeons. Open surgical arterial transpositions have been less commonly performed than other methods of reconstruction in the current era of vascular surgery despite many historical reports of successful outcomes. Autologous artery transpositions represent a viable option in the case of an infected or a contaminated operative field. We have described the cases of three patients treated at our institution who had required intra-abdominal revascularization in a contaminated or frankly infected surgical field. All three patients were successfully treated using open native visceral artery transposition procedures. These cases presented multiple challenges secondary to the ongoing infections, infected operative field, and, sometimes, a history of multiple vascular bypasses involving the aorta and visceral arteries. In such circumstances, we have demonstrated the effectiveness of native visceral arterial transposition as a feasible technique.

The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Exploring the Impact of Folic Acid Supplementation and Vitamin B12 Deficiency on Maternal and Fetal Outcomes in Pregnant Women with Celiac Disease.

Background: Celiac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten, affecting approximately 1% of the global population and two million Americans. An increasing number of studies have identified a link between celiac disease and adverse maternal and fetal outcomes during pregnancy and after birth. Additionally, both celiac disease and pregnancy are associated with an increased risk for nutrient deficiencies, specifically vitamin B12 and folate. Methods: This review examines the current literature related to the folate trap and vitamin B12 deficiency in patients with celiac disease and pregnant women independently and provides rationale for future research to explore the relationship between the folate-to-12 ratio in pregnant women with celiac disease. Results: Deficiencies in vitamin B12 are linked with several negative maternal and fetal health outcomes including pre-eclampsia, gestational diabetes, spontaneous abortion/miscarriage, preterm birth, neural tube defects, intrauterine growth restriction, and low gestational age and birthweight. Conclusions: Folic acid supplementation is widely recommended during pregnancy, but complementary vitamin B12 supplementation is not standard. Physicians should consider celiac disease screening during pregnancy as well as vitamin B12 supplementation.

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms.

Acyl-CoA binding domain-containing proteins (ACBDs) perform diverse but often uncharacterised functions linked to cellular lipid metabolism. Human ACBD4 and ACBD5 are closely related peroxisomal membrane proteins, involved in tethering of peroxisomes to the ER and capturing fatty acids for peroxisomal ß-oxidation. ACBD5 deficiency causes neurological abnormalities including ataxia and white matter disease. Peroxisome-ER contacts depend on an ACBD4/5-FFAT motif, which interacts with ER-resident VAP proteins. As ACBD4/5-like proteins are present in most fungi and all animals, we combined phylogenetic analyses with experimental approaches to improve understanding of their evolution and functions. Notably, all vertebrates exhibit gene sequences for both ACBD4 and ACBD5, while invertebrates and fungi possess only a single ACBD4/5-like protein. Our analyses revealed alterations in domain structure and FFAT sequences, which help understanding functional diversification of ACBD4/5-like proteins. We show that the Drosophila melanogaster ACBD4/5-like protein possesses a functional FFAT motif to tether peroxisomes to the ER via Dm_Vap33. Depletion of Dm_Acbd4/5 caused peroxisome redistribution in wing neurons and reduced life expectancy. In contrast, the ACBD4/5-like protein of the filamentous fungus Ustilago maydis lacks a FFAT motif and does not interact with Um_Vap33. Loss of Um_Acbd4/5 resulted in an accumulation of peroxisomes and early endosomes at the hyphal tip. Moreover, lipid droplet numbers increased, and mitochondrial membrane potential declined, implying altered lipid homeostasis. Our findings reveal differences between tethering and metabolic functions of ACBD4/5-like proteins across evolution, improving our understanding of ACBD4/5 function in health and disease. The need for a unifying nomenclature for ACBD proteins is discussed.

Semi-parametric benchmark dose analysis with monotone additive models.

Benchmark dose analysis aims to estimate the level of exposure to a toxin associated with a clinically significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop a novel approach for calculating benchmark dose lower limits based on an approximate pivot for the nonlinear equation solved by the estimated benchmark dose. The favorable properties of this approach compared to the Delta method and a parameteric bootstrap are discussed. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from six NIH-funded longitudinal cohort studies. Software to reproduce the results in this paper is available online and makes use of the novel semibmd  R package, which implements the methods in this paper.

Radiography managers' perceptions on skills required in public health institutes in Gauteng.

Background: Management of radiography departments requires skilled and competent managers. This task becomes complex if there is no management development and collaborative performance monitoring. Aim: The study aimed to explore and describe the radiography managers' perceptions regarding management training and skills required. Setting: The research was conducted in public health institutions of Gauteng, South Africa. Methods: Qualitative, exploratory and descriptive approach was adopted, and a purposive sampling method was used to select twenty-three (23) managers from the radiography departments; however, data saturation guided the sample size. Data were collected through online focus group discussions (FGDs). Ethical approval was obtained through Departmental Research Committee (DRC) of Medical Imaging and Radiation Sciences (MIRS) department, Higher Degrees Committee (HDC), Research Ethics Committee and Gauteng Department of Health Research Committees. Data trustworthiness was obtained through member checking, data verification and an independent coder to verify the accuracy of the data. Thematic data analysis method was used to analyse the data. Results: Five themes emerged from the thematic analysis and centred on: difficulties in transitioning into management, lack of management support, the need for postgraduate management qualification, coaching and mentoring and required skills for radiography managers. Conclusion: Public health institutions continuously face transitions in service delivery frameworks. This requires competent and skilled radiography managers to survive in this environment. The study revealed that new managers experience difficulties and require management support to succeed in their roles. Contribution: Awareness of managers developmental needs relative to the real-life dynamics of radiography management in Gauteng public health environment.

Biophysical evidence that frostbite is triggered on nanocrystals of biogenic magnetite in garlic cloves (Allium sativum).

Trace levels of biologically precipitated magnetite (Fe3O4) nanocrystals are present in the tissues of many living organisms, including those of plants. Recent work has also shown that magnetite nanoparticles are powerful ice nucleation particles (INPs) that can initiate heterogeneous freezing in supercooled water just below the normal melting temperature. Hence there is a strong possibility that magnetite in plant tissues might be an agent responsible for triggering frost damage, even though the biological role of magnetite in plants is not understood. To test this hypothesis, we investigated supercooling and freezing mortality in cloves of garlic (Allium sativum), a species which is known to have moderate frost resistance. Using superconducting magnetometry, we detected large numbers of magnetite INPs within individual cloves. Oscillating magnetic fields designed to torque magnetite crystals in situ and disturb the ice nucleating process produced significant effects on the temperature distribution of supercooling, thereby confirming magnetite's role as an INP in vivo. However, weak oscillating fields increased the probability of freezing, whereas stronger fields decreased it, a result that predicts the presence of magnetite binding agents that are loosely attached to the ice nucleating sites on the magnetite crystals.

Drivers and mechanisms of harmful algal blooms across hydrologic extremes in hypereutrophic grand lake st marys (Ohio).

Grand Lake St. Marys (GLSM) is a large, shallow, hypereutrophic lake situated in an agricultural watershed with high-nutrient, non-point source runoff. The resulting harmful algal blooms (HABs) are typically dominated by Planktothrix, which can produce microcystin, a potent cyanobacterial toxin that has varied in concentration over the past decade. Some drivers of bloom biomass and toxicity in GLSM are described, but recent years (2019-2022) have exhibited anomalous combinations of winter ice cover and spring runoff, suggesting that additional factors contribute to variability in HAB severity and toxicity. 2020 and 2022 were typical water years, with normal tributary runoff volumes occurring primarily in late winter and spring after either little to no ice cover (2019-2020) or heavy/prolonged ice cover (2021-2022). However, 2021 exhibited prolonged winter ice and low winter/spring runoff. 2020 and 2022 were typical bloom years, with near monoculture, Planktothrix-dominated biomass (11 to 405 µg/L total chlorophyll) and high total concentrations of microcystins (<0.3 to 65 µg/L). However, the first half of 2021 exhibited lower biomass (18 to 65 µg/L chlorophyll a) and toxin concentrations (0.4 to 2.0 µg/L). While biomass returned to bloom levels when external tributary loading increased, ammonium uptake and regeneration rates and microcystin concentrations remained low throughout 2021 (in contrast to other years). Overall, potential ammonium uptake rates strongly correlated with chlorophyll and microcystin concentrations (Bayesian R2 = 0.59; 95% CI = 0.44 to 0.65). Phytoplankton diversity was higher in 2021 than other years, especially in spring/early summer, with increased dinoflagellates and diatoms in spring, followed by a mixed cyanobacterial assemblage in summer. These results suggest that lower external nutrient loads can drive immediate positive impacts on water quality, such as reduced HAB biomass and toxicity and higher phytoplankton diversity, even in hypereutrophic, shallow lakes.

No evidence for an up-regulation of female immune function in response to elevated risk of sexual conflict.

Sexual conflict is widespread among sexually reproducing organisms. Phenotypic plasticity in female resistance traits has the potential to moderate the harm imposed by males during mating, yet female plasticity has rarely been explored. In this experiment, we investigated whether female seed beetles invest more in immunocompetence, measured as phenoloxidase (PO) capacity, when exposed to cues signalling a greater risk of sexual conflict. Risk perception was manipulated by housing focal individuals alone or with a companion as developing larvae, followed by exposure to a mating-free male- or female-biased social environment when adults. We predicted that females exposed to cues of increased sexual conflict would have increased PO capacity. However, PO capacity did not differ between either larval or adult social treatments. Our results suggest that females may not perceive a risk to their fitness on the basis of increased male presence or are unable to adjust this aspect of their phenotype in response to that risk.

Development of a Core Outcome Set for Studies Assessing Interventions for Diabetes-Related Foot Ulceration.

OBJECTIVE: Diabetes affects 537 million people globally, with 34% expected to develop foot ulceration in their lifetime. Diabetes-related foot ulceration causes strain on health care systems worldwide, necessitating provision of high-quality evidence to guide their management. Given heterogeneity of reported outcomes, a core outcome set (COS) was developed to standardize outcome measures in studies assessing treatments for diabetes-related foot ulceration. RESEARCH DESIGN AND METHODS: The COS was developed using Core Outcome Measures in Effectiveness Trials (COMET) methodology. A systematic review and patient interviews generated a long list of outcomes that were rated by patients and experts using a nine-point Likert scale (from 1 [not important] to 9 [critical]) in the first round of the Delphi survey. Based on predefined criteria, outcomes without consensus were reprioritized in a second Delphi round. Critical outcomes and those without consensus after two Delphi rounds were discussed in the consensus meeting where the COS was ratified. RESULTS: The systematic review and patient interviews generated 103 candidate outcomes. The two consecutive Delphi rounds were completed by 336 and 176 respondents, resulting in an overall second round response rate of 52%. Of 37 outcomes discussed in the consensus meeting (22 critical and 15 without consensus after the second round), 8 formed the COS: wound healing, time to healing, new/recurrent ulceration, infection, major amputation, minor amputation, health-related quality of life, and mortality. CONCLUSIONS: The proposed COS for studies assessing treatments for diabetes-related foot ulceration was developed using COMET methodology. Its adoption by the research community will facilitate assessment of comparative effectiveness of current and evolving interventions.