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Antimicrobial resistance is a global threat to human and animal health, with the misuse and overuse of antimicrobials suggested as the main drivers of resistance. Antimicrobial therapy can alter the bacterial community composition and the faecal resistome in cattle. Little is known about the impact of systemic antimicrobial therapy on the faecal microbiome in dairy cows in the presence of disease. Therefore, this study aimed to assess the impact of systemic antimicrobial therapy on the faecal microbiome in dairy cows in the pastoral farm environment, by analysing faecal samples from cattle impacted by several different clinically-defined conditions and corresponding antimicrobial treatments. Analysis at the individual animal level showed a decrease in bacterial diversity and richness during antimicrobial treatment but, in many cases, the microbiome diversity recovered post-treatment when the cow re-entered the milking herd. Perturbations in the microbiome composition and the ability of the microbiome to recover were specific at the individual animal level, highlighting that the animal is the main driver of variation. Other factors such as disease severity, the type and duration of antimicrobial treatment and changes in environmental factors may also impact the bovine faecal microbiome. AmpC-producing Escherichia coli were isolated from faeces collected during and post-treatment with ceftiofur from one cow while no third-generation cephalosporin resistant E. coli were isolated from the untreated cow samples. This isolation of genetically similar plasmid-mediated AmpC-producing E. coli has implications for the development and dissemination of antibiotic resistant bacteria and supports the reduction in the use of critically important antimicrobials.

Our objective was to explore the association between weight status and behavioral problems in children before school age. We examined whether the association between weight status and behavioral problems varied by age and sex.

BackgroundFirearm violence remains a persistent public health threat. Comparing the impact of targeted high-risk versus population-based approaches to prevention may point to efficient and efficacious interventions. We used agent-based modeling to conduct a hypothetical experiment contrasting the impact of high-risk (disqualification) and population-based (price increase) approaches on firearm homicide in New York City (NYC).MethodsWe simulated 800,000 agents reflecting a 15% sample of the adult population of NYC. Three groups were considered and disqualified from all firearm ownership for five years, grouped based on prevalence: low prevalence (psychiatric hospitalization, alcohol-related misdemeanor and felony convictions, 0.23%); moderate prevalence (drug misdemeanor convictions, domestic violence restraining orders, 1.03%); and high prevalence (all other felony/misdemeanor convictions, 2.30%). Population-level firearm ownership was impacted by increasing the price of firearms, assuming 1% price elasticity.ResultsIn this hypothetical scenario, to reduce firearm homicide by 5% in NYC, 25% of the moderate prevalence group, or 12% of the high prevalence group needed to be effectively disqualified; even when all of the low prevalence group was disqualified, homicide did not decrease by 5%. An 18% increase in price similarly reduced firearm homicide by 5.37% (95% CI 4.43-6.31%). Firearm homicide declined monotonically as the proportion of disqualified individuals increased and/or price increased. A combined intervention that both increased price and effectively disqualified "high-risk" groups achieved approximately double the reduction in homicide as any one intervention alone. Increasing illegal firearm ownership by 20%, a hypothetical response to price increases, did not meaningfully change results.ConclusionA key takeaway of our study is that adopting high-risk versus population-based approaches should not be an "either-or" question. When individual risk is variable and diffuse in the population, "high-risk approaches" to firearm violence need to focus on relatively prevalent groups and be highly efficacious in disarming people at elevated risk to achieve meaningful reductions in firearm homicide, though countering issues of social justice and stigma should be carefully considered. Similar reductions can be achieved with population-based approaches, such as price increases, albeit with fewer such countering issues.

Prior to age four, children succeed in non-elicited-response false-belief tasks but fail elicited-response false-belief tasks. To explain this discrepancy, the processing-load account argues that the capacity to represent beliefs emerges in infancy, as indicated by early success on non-elicited-response tasks, but that children's ability to demonstrate this capacity depends on the processing demands of the task and children's processing skills. When processing demands exceed young children's processing abilities, such as in standard elicited-response tasks, children fail despite their capacity to represent beliefs. Support for this account comes from recent evidence that reducing processing demands improves young children's performance: when demands are sufficiently reduced, 2.5-year-olds succeed in elicited-response tasks. Here we sought complementary evidence for the processing-load account by examining whether increasing processing demands impeded children's performance in a non-elicited-response task. 3-year-olds were tested in a preferential-looking task in which they heard a change-of-location false-belief story accompanied by a picture book; across children, we manipulated the amount of linguistic ambiguity in the story. The final page of the book showed two images: one that was consistent with the main character's false belief and one that was consistent with reality. When the story was relatively unambiguous, children looked reliably longer at the false-belief-consistent image, successfully demonstrating their false-belief understanding. When the story was ambiguous, however, this undermined children's performance: looking times to the belief-consistent image were correlated with verbal ability, and only children with verbal skills in the upper quartile of the sample demonstrated a significant preference for the belief-consistent image. These results support the processing-load account by demonstrating that regardless of whether a task involves an elicited response, children's performance depends on the processing demands of the task and their processing skills. These findings also have implications for alternative, deflationary accounts of early false-belief understanding.

Introduced wasps (Vespula germanica and V. vulgaris) are costly invertebrate pests in New Zealand, with large impacts on the local ecology and economy. Wasps eat honeybees (Apis mellifera), which has potentially devastating effects on hive health, as well as agricultural and horticultural industries. Vespex bait, which contains fipronil in a proteinaceous carrier, has recently been introduced for wasp control. In over a decade of reported trials, honeybees have never been observed foraging on Vespex, likely because the bait contains no sugars to serve as a bee food source. However, the potential for the control agent fipronil to enter beehives has not been tested. Therefore, here, we investigated this using a liquid chromatography-mass spectrometry assay of fipronil and two of its environmental breakdown and metabolic derivatives, fipronil desulfinyl and fipronil sulfone. We did not detect fipronil in any of the worker bee, bee larva, honey or pollen samples (n = 120 per product) collected from 30 hives over a 2-year period. Furthermore, although we detected fipronil desulfinyl in one honeybee sample, this is thought to have originated from a single individual, representing a rare occurrence of intoxication, and there was no evidence that Vespex was the toxicant source. There was also no evidence of trophallactic transfer of fipronil or its derivatives in any of the hives sampled. Previous studies have reported the impairment of individual bee performance at fipronil doses similar to the detection limit of our study. However, our results provide confidence that if undetectable intoxication was occurring, it would involve an acute exposure for those few individuals affected, with minimal impairment to colonies. Therefore, we conclude that the use of Vespex in the vicinity of honeybees does not result in significant hive uptake while effectively reducing wasp pressure on honeybee colonies.

BACKGROUND/OBJECTIVES:Our objective was to explore the association between weight status and behavioral problems in children before school age. We examined whether the association between weight status and behavioral problems varied by age and sex. SUBJECTS/METHODS:This study used cross-sectional data from a nationally-representative sample of children and their families in Chile (N = 11,207). These children were selected using a cluster-stratified random sampling strategy. Data collection for this study took place in 2012 when the children were 1.5-6 years of age. We used multivariable analyses to examine the association between weight status and behavioral problems (assessed using the Child Behavior Checklist), while controlling for child's sex, indigenous status, birth weight, and months breastfed; primary caregiver's BMI and education level; and household wealth. RESULTS:Approximately 24% of our sample was overweight or obese. Overweight or obese girls showed more behavioral problems than normal weight girls at age 6 (β = 0.270 SD, 95% CI = 0.047, 0.493, P = 0.018). Among boys age 1 to 5 years, overweight/obesity was associated with a small reduction in internalizing behaviors (β = -0.09 SD, 95% CI = -0.163, -0.006, P = 0.034). CONCLUSIONS:Our data suggest that the associations between weight status and behavioral problems vary across age and sex.

Prior to age four, children succeed in non-elicited-response false-belief tasks but fail elicited-response false-belief tasks. To explain this discrepancy, the processing-load account argues that the capacity to represent beliefs emerges in infancy, as indicated by early success on non-elicited-response tasks, but that children's ability to demonstrate this capacity depends on the processing demands of the task and children's processing skills. When processing demands exceed young children's processing abilities, such as in standard elicited-response tasks, children fail despite their capacity to represent beliefs. Support for this account comes from recent evidence that reducing processing demands improves young children's performance: when demands are sufficiently reduced, 2.5-year-olds succeed in elicited-response tasks. Here we sought complementary evidence for the processing-load account by examining whether increasing processing demands impeded children's performance in a non-elicited-response task. 3-year-olds were tested in a preferential-looking task in which they heard a change-of-location false-belief story accompanied by a picture book; across children, we manipulated the amount of linguistic ambiguity in the story. The final page of the book showed two images: one that was consistent with the main character's false belief and one that was consistent with reality. When the story was relatively unambiguous, children looked reliably longer at the false-belief-consistent image, successfully demonstrating their false-belief understanding. When the story was ambiguous, however, this undermined children's performance: looking times to the belief-consistent image were correlated with verbal ability, and only children with verbal skills in the upper quartile of the sample demonstrated a significant preference for the belief-consistent image. These results support the processing-load account by demonstrating that regardless of whether a task involves an elicited response, children's performance depends on the processing demands of the task and their processing skills. These findings also have implications for alternative, deflationary accounts of early false-belief understanding.

The transcription factor Early Growth Response 3 (Egr3) has been shown to play an important role in negatively regulating T cell activation and promoting T cell anergy in Th1 cells. However, its role in regulating other T helper subsets has yet to be described. We sought to determine the role of Egr3 in a Th17 response using transgenic mice that overexpress Egr3 in T cells (Egr3 TG). Splenocytes from Egr3 TG mice demonstrated more robust generation of Th17 cells even under non-Th17 skewing conditions. We found that while Egr3 TG T cells were not intrinsically more likely to become Th17 cells, the environment encountered by these cells was more conducive to Th17 development. Further analysis revealed a considerable increase in the number of γδ T cells in both the peripheral lymphoid organs and mucosal tissues of Egr3 TG mice, a cell type which normally accounts for only a small fraction of peripheral lymphocytes. Consistent with this marked increase in peripheral γδ T cells, thymocytes from Egr3 TG mice also appear biased toward γδ T cell development. Coculture of these Egr3-induced γδ T cells with wildtype CD4+ T cells increases Th17 differentiation, and Egr3 TG mice are more susceptible to bleomycin-induced lung inflammation. Overall our findings strengthen the role for Egr3 in promoting γδ T cell development and show that Egr3-induced γδ T cells are both functional and capable of altering the adaptive immune response in a Th17-biased manner. Our data also demonstrates that the role played by Egr3 in T cell activation and differentiation is more complex than previously thought.

The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce apoptosis in non-tumorigenic cells via mitochondrial dysfunction, independent of FASN inhibition.

Embden-Meyerhof pathway (EMP) in tandem with 2-C-methyl-D-erythritol 4-phosphate pathway (MEP) is commonly used for isoprenoid biosynthesis in E. coli. However, this combination has limitations as EMP generates an imbalanced distribution of pyruvate and glyceraldehyde-3-phosphate (G3P). Herein, four glycolytic pathways-EMP, Entner-Doudoroff Pathway (EDP), Pentose Phosphate Pathway (PPP) and Dahms pathway were tested as MEP feeding modules for isoprene production. Results revealed the highest isoprene production from EDP containing modules, wherein pyruvate and G3P were generated simultaneously; isoprene titer and yield were more than three and six times higher than those of the EMP module, respectively. Additionally, the PPP module that generates G3P prior to pyruvate was significantly more effective than the Dahms pathway, in which pyruvate production precedes G3P. In terms of precursor generation and energy/reducing-equivalent supply, EDP+PPP was found to be the ideal feeding module for MEP. These findings may launch a new direction for the optimization of MEP-dependent isoprenoid biosynthesis pathways.

Genetic approaches (e.g. mutation, RNA interference) in model organisms, particularly the nematode Caenorhabditis elegans, have yielded a wealth of information on cellular processes that can influence lifespan. Although longevity mutants discovered in the lab are instructive of cellular physiology, lab studies might miss important genes that influence health and longevity in the wild. C. elegans has relatively low natural genetic variation and high levels of linkage disequilibrium, and thus is not optimal for studying natural variation in longevity. In contrast, its close relative C. remanei possesses very high levels of molecular genetic variation and low levels of linkage disequilibrium. To determine whether C. remanei may be a good model system for the study of natural genetic variation in aging, we evaluated levels of quantitative genetic variation for longevity and resistance to oxidative, heat and UV stress. Heritability (and the coefficient of additive genetic variation) was high for oxidative and heat stress resistance, low (but significant) for longevity, and essentially zero for UV stress response. Our results suggest that C. remanei may be a powerful system for studying natural genetic variation for longevity and oxidative and heat stress response, as well as an informative model for the study of functional relationships between longevity and stress response.

Embden-Meyerhof pathway (EMP) in tandem with 2-C-methyl-D-erythritol 4-phosphate pathway (MEP) is commonly used for isoprenoid biosynthesis in E. coli. However, this combination has limitations as EMP generates an imbalanced distribution of pyruvate and glyceraldehyde-3-phosphate (G3P). Herein, four glycolytic pathways—EMP, Entner-Doudoroff Pathway (EDP), Pentose Phosphate Pathway (PPP) and Dahms pathway were tested as MEP feeding modules for isoprene production. Results revealed the highest isoprene production from EDP containing modules, wherein pyruvate and G3P were generated simultaneously; isoprene titer and yield were more than three and six times higher than those of the EMP module, respectively. Additionally, the PPP module that generates G3P prior to pyruvate was significantly more effective than the Dahms pathway, in which pyruvate production precedes G3P. In terms of precursor generation and energy/reducing-equivalent supply, EDP+PPP was found to be the ideal feeding module for MEP. These findings may launch a new direction for the optimization of MEP-dependent isoprenoid biosynthesis pathways. [ABSTRACT FROM AUTHOR]

: Genetic approaches (e.g. mutation, RNA interference) in model organisms, particularly the nematode Caenorhabditis elegans, have yielded a wealth of information on cellular processes that can influence lifespan. Although longevity mutants discovered in the lab are instructive of cellular physiology, lab studies might miss important genes that influence health and longevity in the wild. C. elegans has relatively low natural genetic variation and high levels of linkage disequilibrium, and thus is not optimal for studying natural variation in longevity. In contrast, its close relative C. remanei possesses very high levels of molecular genetic variation and low levels of linkage disequilibrium. To determine whether C. remanei may be a good model system for the study of natural genetic variation in aging, we evaluated levels of quantitative genetic variation for longevity and resistance to oxidative, heat and UV stress. Heritability (and the coefficient of additive genetic variation) was high for oxidative and heat stress resistance, low (but significant) for longevity, and essentially zero for UV stress response. Our results suggest that C. remanei may be a powerful system for studying natural genetic variation for longevity and oxidative and heat stress response, as well as an informative model for the study of functional relationships between longevity and stress response. [ABSTRACT FROM AUTHOR]

: Genetic approaches (e.g. mutation, RNA interference) in model organisms, particularly the nematode Caenorhabditis elegans, have yielded a wealth of information on cellular processes that can influence lifespan. Although longevity mutants discovered in the lab are instructive of cellular physiology, lab studies might miss important genes that influence health and longevity in the wild. C. elegans has relatively low natural genetic variation and high levels of linkage disequilibrium, and thus is not optimal for studying natural variation in longevity. In contrast, its close relative C. remanei possesses very high levels of molecular genetic variation and low levels of linkage disequilibrium. To determine whether C. remanei may be a good model system for the study of natural genetic variation in aging, we evaluated levels of quantitative genetic variation for longevity and resistance to oxidative, heat and UV stress. Heritability (and the coefficient of additive genetic variation) was high for oxidative and heat stress resistance, low (but significant) for longevity, and essentially zero for UV stress response. Our results suggest that C. remanei may be a powerful system for studying natural genetic variation for longevity and oxidative and heat stress response, as well as an informative model for the study of functional relationships between longevity and stress response. [ABSTRACT FROM AUTHOR]

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks' relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded "yes" or "no" to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions, including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus.

Embden-Meyerhof pathway (EMP) in tandem with 2-C-methyl-D-erythritol 4-phosphate pathway (MEP) is commonly used for isoprenoid biosynthesis in E. coli. However, this combination has limitations as EMP generates an imbalanced distribution of pyruvate and glyceraldehyde-3-phosphate (G3P). Herein, four glycolytic pathways—EMP, Entner-Doudoroff Pathway (EDP), Pentose Phosphate Pathway (PPP) and Dahms pathway were tested as MEP feeding modules for isoprene production. Results revealed the highest isoprene production from EDP containing modules, wherein pyruvate and G3P were generated simultaneously; isoprene titer and yield were more than three and six times higher than those of the EMP module, respectively. Additionally, the PPP module that generates G3P prior to pyruvate was significantly more effective than the Dahms pathway, in which pyruvate production precedes G3P. In terms of precursor generation and energy/reducing-equivalent supply, EDP+PPP was found to be the ideal feeding module for MEP. These findings may launch a new direction for the optimization of MEP-dependent isoprenoid biosynthesis pathways. [ABSTRACT FROM AUTHOR]

Adults listen to music for an average of 18 hours a week (with some people reaching more than double that). With rapidly changing technology, music collections have become overwhelmingly digital ushering in changes in listening habits, especially when it comes to listening on personal devices. By using interactive visualizations, descriptive analysis and thematic analysis, this project aims to explore why people download and listen to music and which aspects of the music listening experience are prioritized when people talk about tracks on their device. Using a newly developed data collection method, Shuffled Play, 397 participants answered open-ended and closed research questions through a short online questionnaire after shuffling their music library and playing two pieces as prompts for reflections. The findings of this study highlight that when talking about tracks on their personal devices, people prioritise characterizing them using sound and musical features and associating them with the informational context around them (artist, album, and genre) over their emotional responses to them. The results also highlight that people listen to and download music because they like it-a straightforward but important observation that is sometimes glossed over in previous research. These findings have implications for future work in understanding music, its uses and its functions in peoples' everyday lives.

Shiga toxin-producing Escherichia coli (STEC) are a leading cause of foodborne outbreaks of human disease, but they reside harmlessly as an asymptomatic commensal in the ruminant gut. STEC serogroup O145 are difficult to isolate as routine diagnostic methods are unable to distinguish non-O157 serogroups due to their heterogeneous metabolic characteristics, resulting in under-reporting which is likely to conceal their true prevalence. In light of these deficiencies, the purpose of this study was a twofold approach to investigate enhanced STEC O145 diagnostic culture-based methods: firstly, to use a genomic epidemiology approach to understand the genetic diversity and population structure of serogroup O145 at both a local (New Zealand) (n = 47) and global scale (n = 75) and, secondly, to identify metabolic characteristics that will help the development of a differential media for this serogroup. Analysis of a subset of E. coli serogroup O145 strains demonstrated considerable diversity in carbon utilisation, which varied in association with eae subtype and sequence type. Several carbon substrates, such as D-serine and D-malic acid, were utilised by the majority of serogroup O145 strains, which, when coupled with current molecular and culture-based methods, could aid in the identification of presumptive E. coli serogroup O145 isolates. These carbon substrates warrant subsequent testing with additional serogroup O145 strains and non-O145 strains. Serogroup O145 strains displayed extensive genetic heterogeneity that was correlated with sequence type and eae subtype, suggesting these genetic markers are good indicators for distinct E. coli phylogenetic lineages. Pangenome analysis identified a core of 3,036 genes and an open pangenome of >14,000 genes, which is consistent with the identification of distinct phylogenetic lineages. Overall, this study highlighted the phenotypic and genotypic heterogeneity within E. coli serogroup O145, suggesting that the development of a differential media targeting this serogroup will be challenging.

Biological and bioinspired polymer microparticles have broad biomedical and industrial applications, including drug delivery, tissue engineering, surface modification, environmental remediation, imaging, and sensing. Full realization of the potential of biopolymer microparticles will require methods for rigorous characterization of particle sizes, morphologies, and dynamics, so that researchers may correlate particle characteristics with synthesis methods and desired functions. Toward this end, we evaluated biopolymer microparticles using flow imaging microscopy. This technology is widely used in the biopharmaceutical industry but is not yet well-known among the materials community. Our polymer, a genetically engineered elastin-like polypeptide (ELP), self-assembles into micron-scale coacervates. We performed flow imaging of ELP coacervates using two different instruments, one with a lower size limit of approximately 2 microns, the other with a lower size limit of approximately 300 nanometers. We validated flow imaging results by comparison with dynamic light scattering and atomic force microscopy analyses. We explored the effects of various solvent conditions on ELP coacervate size, morphology, and behavior, such as the dispersion of single particles versus aggregates. We found that flow imaging is a superior tool for rapid and thorough particle analysis of ELP coacervates in solution. We anticipate that researchers studying many types of microscale protein or polymer assemblies will be interested in flow imaging as a tool for quantitative, solution-based characterization.

Background: Frequent hemodialysis provided more than three times per week may lower mortality and improve health-related quality of life. Yet, the evidence is inconclusive. We evaluated the benefits and harms of frequent hemodialysis in people with kidney failure compared with standard hemodialysis., Methods: We performed a systematic review of randomized controlled trials including adults on hemodialysis with highly sensitive searching in MEDLINE, Embase, CENTRAL, and Google Scholar on 3 January 2024. Data were pooled using random-effects meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. We adjudicated evidence certainty using GRADE., Results: From 11,142 unique citations, only seven studies involving 518 participants proved eligible. The effects of frequent hemodialysis on physical and mental health were imprecise due to few data. Frequent hemodialysis probably had uncertain effect on death from all cause compared with standard hemodialysis (relative risk 0.79, 95% confidence interval 0.33-1.91, low certainty evidence). Data were not reported for death from cardiovascular causes, major cardiovascular events, fatigue or vascular access., Conclusion: The evidentiary basis for frequent hemodialysis is incomplete due to clinical trials with few or no events reported for mortality and cardiovascular outcome measures and few participants in which patient-reported outcomes including health-related quality of life and symptoms were reported., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Natale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Efforts to develop a range of HIV prevention products that can serve as behaviorally congruent viable alternatives to consistent condom use and oral pre-exposure prophylaxis (PrEP) remain crucial. MTN-035 was a randomized crossover trial seeking to evaluate the safety, acceptability, and adherence to three placebo modalities (insert, suppository, enema) prior to receptive anal intercourse (RAI). If participants had no RAI in a week, they were asked to use their assigned product without sex. We hypothesized that the modalities would be acceptable and safe for use prior to RAI, and that participants would report high adherence given their behavioral congruence with cleansing practices (e.g., douches and/or enemas) and their existing use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. Participants (N = 217) were sexual and gender minorities enrolled in five different countries (Malawi, Peru, South Africa, Thailand, and the United States of America). Mean age was 24.9 years (range 18-35 years). 204 adverse events were reported by 98 participants (45.2%); 37 (18.1%) were deemed related to the study products. The proportion of participants reporting "high acceptability" was 72% (95%CI: 65% - 78%) for inserts, 66% (95%CI: 59% - 73%) for suppositories, and 73% (95%CI: 66% - 79%) for enemas. The proportion of participants reporting fully adherent per protocol (i.e., at least one use per week) was 75% (95%CI: 69% - 81%) for inserts, 74% (95%CI: 68% - 80%) for suppositories, and 83% (95%CI: 77% - 88%) for enemas. Participants fully adherent per RAI-act was similar among the three products: insert (n = 99; 58.9%), suppository (n = 101; 58.0%) and enema (n = 107; 58.8%). The efficacy and effectiveness of emerging HIV prevention drug depends on safe and acceptable delivery modalities that are easy to use consistently. Our findings demonstrate the safety and acceptability of, and adherence to, enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide., Competing Interests: AL has received funding for investigator sponsored research projects from Gilead Sciences and ViiV Healthcare. Gilead Sciences donated study drug to studies led by AL. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Psychological factors link the co-occurrence of tinnitus-related distress and pain perceptions in patients with chronic tinnitus., Objective: This study examines, if treatment-related changes in these factors ameliorate both tinnitus-related distress and pain perceptions in a sample of patients with chronic tinnitus., Methods: N = 1238 patients with chronic tinnitus provided pre- and post-treatment ratings of tinnitus-related distress and affective or sensory pain perceptions alongside measures of depressive symptoms and perceived stress. Treatment comprised an intensive tinnitus-specific multimodal treatment program. Using serial indirect-effects analyses, we examined association patterns between baseline values and change rates of those variables that were found to respond to treatment., Results: Small effect sizes emerged for changes in tinnitus-related distress, affective (but not sensory) pain perceptions, depressive symptoms, emotional tension and worry. At pre- or post-treatment respectively, baseline values and change rates intercorrelated. Across timepoints, (1) baseline tinnitus-related distress and affective pain perceptions were positively associated with improvements in tinnitus-related distress, affective pain perceptions and depressive symptoms. (2) Baseline depressive symptoms or emotional tension mediated positive associations between baseline tinnitus-related distress and improvement in affective pain perceptions. (3) Change in depressive symptoms mediated the effect of baseline tinnitus-related distress on change in affective pain perceptions-partly through associated change in emotional tension or worry. Mood-independent aspects of emotional tension were negatively associated with improvement in affective pain perceptions., Conclusions: Depressive symptoms, emotional tension and worry emerge as key predictors of treatment response and transdiagnostic treatment targets for alleviating tinnitus-related distress and functionally associated affective pain perceptions., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the co-occurrence of tinnitus-related distress and pain experiences alongside psychological factors that may underlie their association., Method: Patients with chronic tinnitus (N = 1238) completed a questionnaire battery examining tinnitus-related distress and affective and sensory pain perceptions. A series of simple, parallel- and serial multiple mediator models examined indirect effects of psychological comorbidities as well as -process variables including depressivity, perceived stress and coping attitudes. Moderator and moderated mediation analyses examined differential relational patterns in patients with decompensated vs. compensated tinnitus., Results: There were significant associations between tinnitus-related distress and pain perceptions. These were partially mediated by most specified variables. Psychological comorbidities appeared to influence tinnitus-pain associations through their impact on depressivity, perceived stress, and coping attitudes. Some specific differences in affective vs. sensory pain perception pathways emerged. Patients with decompensated tinnitus yielded significantly higher symptom burden across all measured indices. Tinnitus decompensation was associated with heightened associations between [1] tinnitus-related distress and pain perceptions, depressivity and negative coping attitudes; and [2] most psychological comorbidities and sensory, but not affective pain perception. Moderated mediation analyses revealed stronger indirect effects of depressivity and anxiety in mediating affective-, and anxiety in mediating sensory pain perception in patients with decompensated tinnitus., Conclusion: Psychological constructs mediate the co-occurrence of tinnitus- and pain-related symptoms across different levels of tinnitus-related distress. Psychological treatment approaches should conceptualize and address individualised interactions of common cognitive-emotional processes in addressing psychosomatic symptom clusters across syndromatic patients with varying distress levels., Competing Interests: The authors have declared that no competing interests exist.

Background: Cognitive impairment affects up to 80 percent of the stroke population, however, both the available evidence about post-stroke cognition and the measures used to evaluate it longitudinally have not been well described. The aims of this systematic scoping review were: to identify and characterize studies evaluating cognition longitudinally after stroke; to summarize the cognitive instruments used and the domains they target; and to organize cognitive domains assessed using the International Classification of Functioning, Disability and Health (ICF)., Methods: We used a systematic scoping approach to search for peer-reviewed articles involving adults with stroke that evaluated cognition longitudinally. Screening of titles, abstracts, and full reports was completed independently by two reviewers, across six electronic databases (PubMed, PsycInfo, Medline, Cinahl Plus, Embase, and Web of Science). Cognitive domains were mapped to an ICF function independently by the same two reviewers, using a previously tested, standardized approach., Results: A total of 5,540 records were found; 257 were included, representing a total pooled sample of 120,860 stroke survivors. Of these studies, 200 (78%) provided specific cognitive outcomes from the longitudinal evaluations, 57 (22%) reported model predictions, and 77 (30%) included interventions. Cognition was evaluated with 356 unique instruments, targeting 95 distinct cognitive domains, and 17 mental functions from the ICF. The Mini-Mental State Examination was the most frequently used instrument (117 reports, 46%). Other tools used longitudinally were the Trail Making Test (17% of reports), tests of verbal fluency (14%), the Functional Independence Measure (14%), the Montreal Cognitive Assessment (13%), the Digit Span (11%), and the Stroop test (10%). Global cognition was evaluated in 170 reports (66%), followed by higher-level cognitive functioning (29%), memory (28%), language (21%), attention (21%), and perceptual skills (14%). Studies using functional (or performance-based) cognitive assessments over time were scarce (< 1%)., Conclusion: Our findings indicate that whilst there is a substantial number of studies available that report longitudinal evaluations of cognition after stroke, there is large variability in the measures used and the cognitive domains they target. Nonetheless, the available data for evaluation of cognition over time after stroke can be organized and described systematically., Competing Interests: The authors have declared that no competing interests exist.

The exclusive role of the medial temporal lobe in explicit memory has been questioned by several studies reporting medial temporal lobe involvement during implicit learning. Prior studies have demonstrated that hippocampal engagement is present during the implicit learning of perceptual associations, however, it is absent during learning response-related associations. Therefore, it was hypothesized that the function of the medial temporal lobe during implicit learning is related to the extraction of perceptual associations in general. While in most implicit learning tasks visual stimuli were used, the aim of the current functional magnetic resonance imaging (fMRI) study was to detect whether activations within medial temporal lobe structures are also found during implicit learning of auditory associations. In a modified version of the classical serial reaction time task, participants reacted to the presentation of five different tones. Unbeknownst to the participants, the tones were presented with an underlying sequential regularity that could be learned. To avoid an influence of response learning on acoustic associative learning, response buttons were remapped in every trial. After learning, two different tests were used to measure participants' conscious knowledge about the underlying sequence in order to assess the amount of implicit memory and to exclude participants with explicit knowledge acquired during learning. fMRI results revealed hippocampal activations for implicit learning of the acoustic sequence. When detecting a relation between implicit learning of acoustic associations and hippocampal activations, this study indicated a relation between hippocampal activations and memory formation of perceptual-based relational representation regardless of explicit knowledge. Thus, present findings suggest a general functional role for the formation of sequenced perceptual associations independent of the involvement of awareness., Competing Interests: The authors have declared that no competing interests exist.

During incidental learning statistical regularities are extracted from the environment without the intention to learn. Acquired implicit memory of these regularities can affect behavior in the absence of awareness. However, conscious insight in the underlying regularities can also develop during learning. Such emergence of explicit memory is an important learning mechanism that is assumed to involve prediction errors in the striatum and to be dopamine-dependent. Here we directly tested this hypothesis by manipulating dopamine levels during incidental learning in a modified serial reaction time task (SRTT) featuring a hidden regular sequence of motor responses in a placebo-controlled between-group study. Awareness for the sequential regularity was subsequently assessed using cued generation and additionally verified using free recall. The results demonstrated that dopaminergic modulation nearly doubled the amount of explicit sequence knowledge emerged during learning in comparison to the placebo group. This strong effect clearly argues for a causal role of dopamine-dependent processing for the development of awareness for sequential regularities during learning., Competing Interests: The authors have declared that no competing interests exist.

Using a standardized instrument to evaluate patients' stress reactions has become more important in daily clinical routines. Different signs or symptoms of stress are often unilaterally explored: the physiological, psychological or social aspects of stress disorders are each viewed on a single dimension. However, all dimensions afflict patients who have persistent health problems due to chronic stress. Therefore, it is important to use a multidimensional approach to acquire data. The 'Psycho-Physiological-Stress-Test' (PPST) was established to achieve a comprehensive understanding of stress and was further developed at the Charité-Universitätsmedizin Berlin in collaboration with the Psychological Department of Freie Universität Berlin. The PPST includes a series of varying stress phases, embedded in two periods of rest. Physiological and psychological parameters are simultaneously measured throughout the test session. Specifically, the PPST activates the sympathetic stress axis, which is measured by heart rate, blood pressure, respiration depth and rate, electro dermal activation and muscle tension (frontalis, masseter, trapezius). Psychological data are simultaneously collected, and include performance, motivation, emotion and behavior. After conducting this diagnostic test, it is possible to identify individual stress patterns that can be discussed with the individual patient to develop and recommend (outpatient) treatment strategies. This paper introduces the PPST as a standardized way to evaluate stress reactions by presenting the results from a sample of psychosomatic inpatients (n = 139) who were treated in Charité-Universitätsmedizin Berlin, Germany. We observed that the varying testing conditions provoked adjusted changes in the different physiological parameters and psychological levels.

Mouse models show that experimental stress mimicking prolonged life-stress exposure enhances neurogenic inflammation, induces adaptive immunity cytokine-imbalance characterized by a shift to Type 1 T-helper cell cytokines and increases apoptosis of epithelial cells. This affects hair growth in otherwise healthy animals. In this study, we investigate whether a prolonged naturalistic life-stress exposure affects cytokine balance and hair parameters in healthy humans. 33 (18 exam, 15 comparison) female medical students with comparable sociobiological status were analyzed during a stressful final examination period, at three points in time (T) 12 weeks apart. T1 was before start of the learning period, T2 between the three-day written exam and an oral examination, and T3 after a 12 week rest and recovery from the stress of the examination period. Assessments included: self-reported distress and coping strategies (Perceived Stress Questionnaire [PSQ], Trier Inventory for the Assessment of Chronic Stress [TICS]), COPE), cytokines in supernatants of stimulated peripheral blood mononucleocytes (PBMCs), and trichogram (hair cycle and pigmentation analysis). Comparison between students participating in the final medical exam at T2 and non-exam students, revealed significantly higher stress perception in exam students. Time-wise comparison revealed that stress level, TH1/TH2 cytokine balance and hair parameters changed significantly from T1 to T2 in the exam group, but not the control. However, no group differences were found for cytokine balance or hair parameters at T2. The study concludes that in humans, naturalistic stress, as perceived during participation in a major medical exam, has the potential to shift the immune response to TH1 and transiently hamper hair growth, but these changes stay within a physiological range. Findings are instructive for patients suffering from hair loss in times of high stress. Replication in larger and more diverse sample populations is required, to assess suitability of trichogram analysis as biological outcome for stress studies.

The Health Literacy Questionnaire (HLQ), developed in Australia in 2012 using a 'validity-driven' approach, has been rapidly adopted and is being applied in many countries and languages. It is a multidimensional measure comprising nine distinct domains that may be used for surveys, needs assessment, evaluation and outcomes assessment as well as for informing service improvement and the development of interventions. The aim of this paper is to describe the German translation of the HLQ and to present the results of the validation of the culturally adapted version. The HLQ comprises 44 items, which were translated and culturally adapted to the German context. This study uses data collected from a sample of 1,058 persons with chronic conditions. Statistical analyses include descriptive and confirmatory factor analyses. In one-factor congeneric models, all scales demonstrated good fit after few model adjustments. In a single, highly restrictive nine-factor model (no cross-loadings, no correlated errors) replication of the original English-language version was achieved with fit indices and psychometric properties similar to the original HLQ. Reliability for all scales was excellent, with a Cronbach's Alpha of at least 0.77. High to very high correlations between some HLQ factors were observed, suggesting that higher order factors may be present. Our rigorous development and validation protocol, as well as strict adaptation processes, have generated a remarkable reproduction of the HLQ in German. The results of this validation provide evidence that the HLQ is robust and can be recommended for use in German-speaking populations., Trial Registration: German Clinical Trial Registration (DRKS): DRKS00000584. Registered 23 March 2011.

Recently, elevated ongoing pre-stimulus beta power (13-17 Hz) at encoding has been associated with subsequent memory formation for visual stimulus material. It is unclear whether this activity is merely specific to visual processing or whether it reflects a state facilitating general memory formation, independent of stimulus modality. To answer that question, the present study investigated the relationship between neural pre-stimulus oscillations and verbal memory formation in different sensory modalities. For that purpose, a within-subject design was employed to explore differences between successful and failed memory formation in the visual and auditory modality. Furthermore, associative memory was addressed by presenting the stimuli in combination with background images. Results revealed that similar EEG activity in the low beta frequency range (13-17 Hz) is associated with subsequent memory success, independent of stimulus modality. Elevated power prior to stimulus onset differentiated successful from failed memory formation. In contrast, differential effects between modalities were found in the theta band (3-7 Hz), with an increased oscillatory activity before the onset of later remembered visually presented words. In addition, pre-stimulus theta power dissociated between successful and failed encoding of associated context, independent of the stimulus modality of the item itself. We therefore suggest that increased ongoing low beta activity reflects a memory promoting state, which is likely to be moderated by modality-independent attentional or inhibitory processes, whereas high ongoing theta power is suggested as an indicator of the enhanced binding of incoming interlinked information., Competing Interests: The authors have declared that no competing interests exist.

Individuals who initiate substance use before high school are at higher risk of negative outcomes. Eighty-six young adults between the ages of 18 and 28 participated in semi-structured qualitative interviews focused on the circumstances surrounding participants' first use of substances and their pattern of use in the year following initiation in order to investigate similarities and differences between early versus later initiators. Initiation and use among early initiators were more likely to be encouraged by poor parental monitoring or active facilitation of use by parents. Early initiators were more likely to report risky patterns of use such as daily use and using alone. The data suggest that interventions targeting this population should focus on improving parental monitoring and decreasing positive parental attitudes toward adolescent substance use and efforts to increase identification and intervention by middle school staff to reach youth from high-risk families., Competing Interests: The authors have declared that no competing interests exist.

Vibroacoustic stimulation by a Body Monochord can induce relaxation states of various emotional valence. The skin conductance level (SCL) of the tonic electrodermal activity is an indicator of sympathetic arousal of the autonomic nervous system and thus an indicator of the relaxation response. Salivary cortisol is considered to be a stress indicator of the HPA-axis. The effects of the treatment with a Body Monochord and listening to relaxation music (randomized chronological presentation) on SCL and salivary cortisol in relation to the emotional valence of the experience were examined in patients with psychosomatic disorders (N = 42). Salivary cortisol samples were collected immediately before and after the expositions. Subjective experience was measured via self-rating scales. Overall, both the exposure to the Body Monochord as well as the exposure to the relaxation music induced an improvement of patients' mood and caused a highly significant reduction of SCL. A more emotionally positive experience of relaxation correlated with a slightly stronger reduction of the SCL. Both treatment conditions caused a slight increase in salivary cortisol, which was significant after exposure to the first treatment. The increase of salivary cortisol during a relaxation state is contrary to previous findings. It is possible that the relaxation state was experienced as an emotional challenge, due to inner images and uncommon sensations that might have occurred., Competing Interests: The authors have declared that no competing interests exist.

The superoxide dismutase mimetic manganese [III] tetrakis [5,10,15,20]-benzoic acid porphyrin (MnTBAP) is a potent antioxidant compound that has been shown to limit weight gain during short-term high fat feeding without preventing insulin resistance. However, whether MnTBAP has therapeutic potential to treat pre-existing obesity and insulin resistance remains unknown. To investigate this, mice were treated with MnTBAP or vehicle during the last five weeks of a 24-week high fat diet (HFD) regimen. MnTBAP treatment significantly decreased body weight and reduced white adipose tissue (WAT) mass in mice fed a HFD and a low fat diet (LFD). The reduction in adiposity was associated with decreased caloric intake without significantly altering energy expenditure, indicating that MnTBAP decreases adiposity in part by modulating energy balance. MnTBAP treatment also improved insulin action in HFD-fed mice, a physiologic response that was associated with increased protein kinase B (PKB) phosphorylation and expression in muscle and WAT. Since MnTBAP is a metalloporphyrin molecule, we hypothesized that its ability to promote weight loss and improve insulin sensitivity was regulated by heme oxygenase-1 (HO-1), in a similar fashion as cobalt protoporphyrins. Despite MnTBAP treatment increasing HO-1 expression, administration of the potent HO-1 inhibitor tin mesoporphyrin (SnMP) did not block the ability of MnTBAP to alter caloric intake, adiposity, or insulin action, suggesting that MnTBAP influences these metabolic processes independent of HO-1. These data demonstrate that MnTBAP can ameliorate pre-existing obesity and improve insulin action by reducing caloric intake and increasing PKB phosphorylation and expression.

Objective: NUCB2/nesfatin-1 is an anorexigenic hormone with elevated levels in obese and decreased levels in anorexia nervosa (AN) patients. Moreover, a role in the regulation of stress and emotions was suggested by several rodent and preliminary human studies. Since anxiety and depression are common comorbidities in AN, we investigated the association of NUCB2/nesfatin-1 with anxiety, depression and perceived stress in AN., Methods: We analyzed circulating NUCB2/nesfatin-1 levels in 64 female inpatients diagnosed with anorexia nervosa (body mass index, BMI; mean±SD, 14.7±2.3 kg/m2). At the same time anxiety (GAD-7), depression (PHQ-9), stress (PSQ-20) and disordered eating (EDI-2) were measured psychometrically., Results: No correlation was observed between NUCB2/nesfatin-1 and BMI (r = 0.06, p = 0.70). The study population was divided in patients with low anxiety (n = 32, GAD-7 scores, mean±SD, 7.5±3.3) and high anxiety (n = 32, 16.0±3.0, p<0.001). Patients with high anxiety scores displayed 65% higher NUCB2/nesfatin-1 levels (p = 0.04). This was reflected by a positive correlation of GAD-7 and NUCB2/nesfatin-1-levels (r = 0.32, p = 0.04). Scores of PSQ-20 (73.3±14.3 vs. 48.6±17.2) and PHQ-9 (18.8±5.0 vs. 10.3±5.1) were higher in the high anxiety group (p<0.001) but did not correlate with NUCB2/nesfatin-1 (p>0.05). EDI-2 total score was also higher in the high anxiety group (52.3±14.1 vs. 40.2±16.0, p = 0.02), while no correlations of EDI-2-scores with plasma NUCB2/nesfatin-1 were observed (p>0.05)., Conclusions: Circulating NUCB2/nesfatin-1 levels correlated positively with perceived anxiety, whereas no association with BMI or eating disorder symptoms was observed. NUCB2/nesfatin-1 might be primarily involved in the modulation of anxiety and subsequently in the regulation of eating habits and body weight in AN.