Improving the reading ease of the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR): Development and psychometric properties of an 'Accessible English' version.

Self-report questionnaires are commonly used in depression research with little consideration of their reading ease. This study aimed to increase the reading ease of the commonly-used Quick Inventory of Depressive Symptoms Self Report (QIDS-SR) and assess the impact of the change in wording on the measure's psychometric properties. The study had three phases: 1) Flesh-Kincaid readability statistics of the original and modified wording were compared; 2) a sample of n = 95 participants rated the modified wording for perceived change in meaning and ease of understanding; 3) a second sample of n = 136 participants completed two versions of the QIDS-SR (original, modified, or one of each) alongside the Beck Depression Inventory (BDI). The internal consistency, test-retest reliability and convergent validity of the modified version were assessed. The modified QIDS-SR had significantly higher reading ease, was considered easier to understand and was not perceived to have a significant change in meaning. Its psychometric properties were unaffected. The wording of the questionnaire was successfully simplified to increase its accessibility and this had no notable impact on the psychometric properties of the measure.

In Response to Representativeness of U.S. News & World Report Outcome and Volume Measures for Otolaryngology.

Although outcomes account for 45% of the total ranking score in otolaryngology in the 2023-2024 U.S. News Best Hospitals rankings, little attention has been paid to the representativeness of their outcomes or volume analyses. Through retrospective review of finance data from an academic otolaryngology department, we found the overall 2023-2024 USNWR volume estimate accounted for only 10.0% (n = 2, usw 024/20,334) of all adult admissions and outpatient procedures and did not adequately represent the overall case mix or caseload.

Occurrence and factors associated with Cryptosporidium infection in livestock in three districts of Zambia.

Cryptosporidium is one of the most important enteric diarrhoeal parasites that infect humans and animals worldwide. The current study investigated the occurrence and risk factors associated with Cryptosporidium infection in ruminants aged ≤6 months in Monze, Mumbwa, and Lusaka districts of Zambia. Faecal samples were collected from 328 calves, 190 lambs, and 245 goat kids and analysed for Cryptosporidium oocysts using modified Ziehl Neelsen staining. A closed structured questionnaire was used to obtain epidemiological characteristics and potential risk factors for Cryptosporidium infection. The overall occurrence of Cryptosporidium was 7.9% (60/763), while that in calves, lambs and goat kids was 14.5% (47/328), 5.3% (10/190), and 1.2% (3/245) respectively. Watery/pasty stool and sampling during the rainy season were independently associated with increased risk of infection. In calves, the odds of infection increased during the rainy season, while daily kraal cleaning reduced the infection risk. Lambs showed increased odds of infection with pasty/watery stool and male sex, whereas the wearing of protective clothing by handlers significantly reduced the risk. There were district variations in infection occurrence with Mumbwa district having higher prevalence. The findings of this study show that livestock in Zambia continue to be frequently infected with Cryptosporidium. Protective measures and appropriate farm cleanliness should be implemented in control of this infection. Regional and host-species-specific variations emphasize the need for targeted interventions. These findings, therefore, contribute to effective strategies for Cryptosporidium control, promoting good livestock health and management.

Dark Current in Broadband Perovskite-Organic Heterojunction Photodetectors Controlled by Interfacial Energy Band Offset.

Lead halide perovskite and organic semiconductors are promising classes of materials for photodetector (PD) applications. State-of-the-art perovskite PDs have performance metrics exceeding silicon PDs in the visible. While organic semiconductors offer bandgap tunability due to their chemical design with detection extended into the near-infrared (NIR), perovskites are limited to the visible band and the first fraction of the NIR spectrum. In this work, perovskite-organic heterojunction (POH) PDs with absorption up to 950 nm are designed by the dual contribution of perovskite and the donor:acceptor bulk-heterojunction (BHJ), without any intermediate layer. The effect of the energetics of the donor materials is systematically studied on the dark current (Jd) of the device by using the PBDB-T polymer family. Combining the experimental results with drift-diffusion simulations, it is shown that Jd in POH devices is limited by thermal generation via deep trap states in the BHJ. Thus, the best performance is obtained for the PM7-based POH, which delivers an ultra-low noise current of 2 × 10-14 A Hz-1/2 and high specific detectivity of 4.7 × 1012 Jones in the NIR. Last, the application of the PM7-based POH devices as NIR pulse oximeter with high-accuracy heartbeat monitoring at long-distance of 2 meters is demonstrated.

Current and potential future impacts of food- and water-borne parasites in a changing world: A Norwegian perspective.

In 2021, the Norwegian Scientific Committee for Food and Environment published a multi-criteria risk ranking of 20 potentially food-borne pathogens in Norway. The pathogens ranked included five parasite taxa (3 species, one genus, one family): Toxoplasma gondii, Echinococcus multilocularis, Giardia duodenalis, Cryptosporidium spp., and Anisakidae. Two of these, T. gondii and E. multilocularis, scored very highly (1st and 3rd place, respectively), Cryptosporidium was about midway (9th place), and G. duodenalis and Anisakidae ranked relatively low (15th and 20th place, respectively). Parasites were found, on average, more likely to present an increasing food-borne disease burden in the future than the other pathogens. Here, we review the current impact of these five potentially food-borne parasites in Norway, and factors of potential importance in increasing their future food-borne disease burden. Climate change may affect the contamination of water and fresh produce with transmission stages of the first four parasites, potentially leading to increased infection risk. Alterations in host distribution (potentially due to climate change, but also other factors) may affect the occurrence and distribution of Toxoplasma, Echinococcus, and Anisakidae, and these, coupled with changes in food consumption patterns, could also affect infection likelihood. Transmission of food-borne pathogens is complex, and the relative importance of different pathogens is affected by many factors and will not remain static. Further investigation in, for example, ten-years' time, could provide a different picture of the relative importance of different pathogens. Nevertheless, there is clearly the potential for parasites to exert a greater risk to public health in Norway than currently occurs.

A Novel Macrophage Subpopulation Conveys Increased Genetic Risk of Coronary Artery Disease.

BACKGROUND: Coronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. Although over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types such as macrophages. METHODS: We utilized single-cell RNA-seq and single-cell multiomics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis-the formation of lipid-laden foam cells. The relative genetic contribution to CAD was assessed by partitioning disease heritability across different macrophage subpopulations. Meta-analysis of single-cell RNA-seq data sets from 38 human atherosclerotic samples was conducted to provide high-resolution cross-referencing to macrophage subpopulations in vivo. RESULTS: We identified 18 782 cis-regulatory elements by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD genome-wide association study data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of a novel CD52-hi lipid-handling macrophage subpopulation. These CD52-hi macrophages displayed significantly less lipoprotein accumulation and were also found in human atherosclerotic plaques. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-ß in the causal mechanisms at this locus. CONCLUSIONS: Our results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key subpopulation through which genetic variants operate to influence disease. These findings provide an unbiased framework for functional fine-mapping of genome-wide association study results using single-cell multiomics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

Children and young people's body mass index measures derived from routine data sources: A national data linkage study in Wales.

BACKGROUND: Routine monitoring of Body Mass Index (BMI) in general practice, and via national surveillance programmes, is essential for the identification, prevention, and management of unhealthy childhood weight. We examined and compared the presence and representativeness of children and young people's (CYPs) BMI recorded in two routinely collected administrative datasets: general practice electronic health records (GP-BMI) and the Child Measurement Programme for Wales (CMP-BMI), which measures height and weight in 4-5-year-old school children. We also assessed the feasibility of combining GP-BMI and CMP-BMI data for longitudinal analyses. METHODS: We accessed de-identified population-level GP-BMI data for calendar years 2011 to 2019 for 246,817 CYP, and CMP-BMI measures for 222,772 CYP, held within the Secure Anonymised Information Linkage Databank. We examined the proportion of CYP in Wales with at least one GP-BMI record, its distribution by child socio-demographic characteristics, and trends over time. We compared GP-BMI and CMP-BMI distributions. We quantified the proportion of children with a CMP-BMI measure and a follow-up GP-BMI recorded at an older age and explored the representativeness of these measures. RESULTS: We identified a GP-BMI record in 246,817 (41%) CYP, present in a higher proportion of females (54.2%), infants (20.7%) and adolescents. There was no difference in the deprivation profile of those with a GP-BMI measurement. 31,521 CYP with a CMP-BMI had at least one follow-up GP-BMI; those with a CMP-BMI considered underweight or very overweight were 87% and 70% more likely to have at least one follow-up GP-BMI record respectively compared to those with a healthy weight, as were males and CYP living in the most deprived areas of Wales. CONCLUSIONS: Records of childhood weight status extracted from general practice are not representative of the population and are biased with respect to weight status. Linkage of information from the national programme to GP records has the potential to enhance discussions around healthy weight at the point of care but does not provide a representative estimate of population level weight trajectories, essential to provide insights into factors determining a healthy weight gain across the early life course. A second CMP measurement is required in Wales.

AmiA and AliA peptide ligands, found in Klebsiella pneumoniae, are imported into pneumococci and alter the transcriptome.

Klebsiella pneumoniae releases the peptides AKTIKITQTR and FNEMQPIVDRQ, which bind the pneumococcal proteins AmiA and AliA respectively, two substrate-binding proteins of the ABC transporter Ami-AliA/AliB oligopeptide permease. Exposure to these peptides alters pneumococcal phenotypes such as growth. Using a mutant in which a permease domain of the transporter was disrupted, by growth analysis and epifluorescence microscopy, we confirmed peptide uptake via the Ami permease and intracellular location in the pneumococcus. By RNA-sequencing we found that the peptides modulated expression of genes involved in metabolism, as pathways affected were mostly associated with energy or synthesis and transport of amino acids. Both peptides downregulated expression of genes involved in branched-chain amino acid metabolism and the Ami permease; and upregulated fatty acid biosynthesis genes but differed in their regulation of genes involved in purine and pyrimidine biosynthesis. The transcriptomic changes are consistent with growth suppression by peptide treatment. The peptides inhibited growth of pneumococcal isolates of serotypes 3, 8, 9N, 12F and 19A, currently prevalent in Switzerland, and caused no detectable toxic effect to primary human airway epithelial cells. We conclude that pneumococci take up K. pneumoniae peptides from the environment via binding and transport through the Ami permease. This changes gene expression resulting in altered phenotypes, particularly reduced growth.

CUREs for high-level Galectin-3 expression.

Galectins are a large and diverse protein family defined by the presence of a carbohydrate recognition domain (CRD) that binds ß-galactosides. They play important roles in early development, tissue regeneration, immune homeostasis, pathogen recognition, and cancer. In many cases, studies that examine galectin biology and the effect of manipulating galectins are aided by, or require the ability to express and purify, specific members of the galectin family. In many cases, E. coli is employed as a heterologous expression system, and galectin expression is induced with isopropyl ß-galactoside (IPTG). Here, we show that galectin-3 recognizes IPTG with micromolar affinity and that as IPTG induces expression, newly synthesized galectin can bind and sequester cytosolic IPTG, potentially repressing further expression. To circumvent this putative inhibitory feedback loop, we utilized an autoinduction protocol that lacks IPTG, leading to significantly increased yields of galectin-3. Much of this work was done within the context of a course-based undergraduate research experience, indicating the ease and reproducibility of the resulting expression and purification protocols.

Estimation of diagnostic sensitivity and specificity of abattoir registrations and bulk tank milk ELISA as herd-level tests for Fasciola hepatica using Bayesian latent class modelling.

The common liver fluke, Fasciola hepatica, is a trematode parasite found worldwide, typically with a focal distribution due to its requirement for suitable climatic and environmental conditions to complete its lifecycle. Bovine fasciolosis causes suboptimal production and economic losses, including liver condemnation at slaughter. The lack of reliable diagnostic methods is a disadvantage to the increasing demand for surveillance and control. The aim of this study was to evaluate the diagnostic accuracy of bulk tank milk (BTM) antibody testing and aggregated abattoir registrations (AAR) of liver fluke as herd-level tests for F. hepatica infection using Bayesian latent class models. Data from the abattoirs in 2019-2021 and BTM, sampled in the winter of 2020/2021, were collected from 437 herds on the southwest coast of Norway. The BTM samples were analysed with the SVANOVIR® F. hepatica-Ab ELISA test, with results given as an optical density ratio (ODR), and later dichotomized using the recommended cut-off value from the test manufacturer (ODR ≥0.3). Based on the BTM ELISA test, 47.8% of the herds tested positive. The AAR test was defined as the herd-level proportion of female slaughtered animals registered with liver fluke infection during the study period. For this test, three cut-offs were used (a proportion of 0.05, 0.1 and 0.2). The herds were split into two subpopulations ("Coastal" and "Inland"), which were expected to differ in true prevalence of F. hepatica infection based on climate-related and geographical factors. The diagnostic accuracies of both tests were estimated using Bayesian latent class models with minimally informative priors. Post-hoc analysis revealed that the maximum sum of sensitivity (Se) and specificity (Sp) of the tests was achieved with a herd-level proportion of ≥0.1 registered with liver fluke as the AAR test. Using this cut-off, the median estimate for the diagnostic accuracy of the BTM ELISA was 90.4% (84.0-96.2 95% Posterior Credible Interval (PCI)) for Se and 95.3% (90.6-100% PCI) for Sp, while the median estimate of Se for AAR was 87.5% (81.4-93.1% PCI) and the median estimate of Sp for AAR was 91.0% (85.2-96.5% PCI). The cut-off evaluation of the SVANOVIR® F. hepatica-Ab ELISA test for BTM confirmed the manufacturer's recommended cut-off of ODR ≥0.3 to denote positive and negative herds. This study suggests that AAR and BTM ELISA test can be used as herd-level tools to monitor liver fluke infection, so that appropriate interventions against infection can be implemented as necessary.

Is oncolytic adenoviral-mediated immunotherapy through p53-overexpression the solution to refractory pancreatic ductal adenocarcinoma?

Evaluation of: Araki H, Tazawa H, Kanaya N, et al. Oncolytic virus-mediated p53 overexpression promotes immunogenic cell death and efficacy of PD-1 blockade in pancreatic cancer. Mol Ther Oncolytics. 2022;27:3-13.Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. PDAC has a dense, desmoplastic stroma and immunosuppressive microenvironment, which impedes current treatment options. Immunotherapy delivered via oncolytic virotherapy is one potential solution to these barriers. Immune checkpoint inhibitors may facilitate immunogenic cell death by improving immune cell infiltration in cancer cells. PD-1 blockade shows better clinical outcomes for certain cancers. The addition of p53 to stimulate cell cycle arrest remains a novel field of research. The evaluated article by Araki et al. explores the efficacy of PD-1 blockade with oncolytic adenovirus platforms on immunogenic cell death and the possibility of combining PD-1 blockade and p53-activation. In vitro analysis showed increased cell death in multiple cell lines infected with AdV mediating p53 expression. The underlying process may attribute to apoptosis and autophagy, with evidence of increased immunogenic cell death. In vivo models demonstrated improved efficacy of p53-expressing AdV, particularly with the addition of PD-1 blockade which appears to be related to CD8+ cell infiltration.

Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency.

Several peptide dual agonists of the human glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) are in development for the treatment of type 2 diabetes, obesity and their associated complications. Candidates must have high potency at both receptors, but it is unclear whether the limited experimental data available can be used to train models that accurately predict the activity at both receptors of new peptide variants. Here we use peptide sequence data labelled with in vitro potency at human GCGR and GLP-1R to train several models, including a deep multi-task neural-network model using multiple loss optimization. Model-guided sequence optimization was used to design three groups of peptide variants, with distinct ranges of predicted dual activity. We found that three of the model-designed sequences are potent dual agonists with superior biological activity. With our designs we were able to achieve up to sevenfold potency improvement at both receptors simultaneously compared to the best dual-agonist in the training set.

Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.

Shame, guilt, and drinking motives as mediators between child maltreatment and problematic alcohol use in college students.

Objective: Drinking for emotion regulation may be a concern for college students who have experienced childhood maltreatment, due to high levels of shame and guilt. The present cross-sectional survey study tested how trait shame-proneness, trait guilt-proneness, and trauma-related guilt are differently related to drinking motives and how these pathways mediate the links between maltreatment severity and alcohol outcomes. Participants: Undergraduate student drinkers (n = 464; M age = 19.50, SD = 2.20) from a midsized midwestern University. Methods: Participants completed an online survey inquiring about demographics, childhood maltreatment, shame, guilt, drinking motives, alcohol use, and alcohol-related consequences. Results: There were several significant serial indirect effects of maltreatment on alcohol consumption and related consequences, through trauma-related guilt, shame-proneness, guilt-proneness, drinking-to-cope, and drinking for mood enhancement. Conclusions: On college campuses, to address problematic drinking among childhood maltreatment survivors, interventions may target maladaptive feelings of shame and guilt stemming from trauma exposure.

Characterization of hOAT4 and mOat5 as functional orthologs for renal anion uptake and efflux transport.

Organic anions (OA) are compounds including drugs or toxicants that are negatively charged at physiological pH and are typically transported by Organic Anion Transporters (OATs). Human OAT4 (SLC22A11) is expressed in the apical membrane of renal proximal tubules. Although there is no rodent ortholog of hOAT4, rodents express Oat5 (Slc22a19), an anion exchanger that is also localized to the apical membrane of renal proximal tubule cells. The purpose of this study was to determine the functional similarity between mouse Oat5 and human OAT4. Chinese hamster ovary (CHO) cells expressing SLC22A11 or Slc22a19 were used to assess the transport characteristics of radiolabeled ochratoxin (OTA). We determined the kinetics of OTA transport; the resulting Kt and Jmax values were very similar for both hOAT4 and mOat5: Kt 3.9 and 7.2 µM, respectively, & Jmax 4.4 and 3.9 pmol/cm2, respectively. For the profile of OTA inhibition by OAs, IC50 values were determined for several clinically important drugs and toxicants. The resulting IC50 values ranged from 9 µM for indomethacin to ~600 µM for the diuretic hydrochlorothiazide. We measured the efflux of OTA from preloaded cells; both hOAT4 and mOat5 supported the efflux of OTA. These data support the hypothesis that OAT4 and Oat5 are functional orthologs and share selectivity for OTA both for reabsorption and secretion. Significance Statement This study compares the selectivity profile between human OAT4 and mouse Oat5. Our data revealed a similar selectivity profile for OTA reabsorption and secretion by these two transporters, thereby supporting the hypothesis that hOAT4 and mOat5, while not genetic orthologs, behave as functional orthologs for both uptake and efflux. These data will be instrumental in selecting an appropriate animal model when studying the renal disposition of anionic drugs and toxicants.

Klebsiella pneumoniae peptide hijacks a Streptococcus pneumoniae permease to subvert pneumococcal growth and colonization.

Treatment of pneumococcal infections is limited by antibiotic resistance and exacerbation of disease by bacterial lysis releasing pneumolysin toxin and other inflammatory factors. We identified a previously uncharacterized peptide in the Klebsiella pneumoniae secretome, which enters Streptococcus pneumoniae via its AmiA-AliA/AliB permease. Subsequent downregulation of genes for amino acid biosynthesis and peptide uptake was associated with reduction of pneumococcal growth in defined medium and human cerebrospinal fluid, irregular cell shape, decreased chain length and decreased genetic transformation. The bacteriostatic effect was specific to S. pneumoniae and Streptococcus pseudopneumoniae with no effect on Streptococcus mitis, Haemophilus influenzae, Staphylococcus aureus or K. pneumoniae. Peptide sequence and length were crucial to growth suppression. The peptide reduced pneumococcal adherence to primary human airway epithelial cell cultures and colonization of rat nasopharynx, without toxicity. We identified a peptide with potential as a therapeutic for pneumococcal diseases suppressing growth of multiple clinical isolates, including antibiotic resistant strains, while avoiding bacterial lysis and dysbiosis.