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The ability of Mycobacterium tuberculosis (Mtb) to persist in its host may enable an evolutionary advantage for drug resistant variants to emerge. A potential strategy to prevent persistence and gain drug efficacy is to directly target the activity of enzymes that are crucial for persistence. We present a method for expedited discovery and structure-based design of lead compounds by targeting the hypoxia-associated enzyme L-alanine dehydrogenase (AlaDH). Biochemical and structural analyses of AlaDH confirmed binding of nucleoside derivatives and showed a site adjacent to the nucleoside binding pocket that can confer specificity to putative inhibitors. Using a combination of dye-ligand affinity chromatography, enzyme kinetics and protein crystallographic studies, we show the development and validation of drug prototypes. Crystal structures of AlaDH-inhibitor complexes with variations at the N6 position of the adenyl-moiety of the inhibitor provide insight into the molecular basis for the specificity of these compounds. We describe a drug-designing pipeline that aims to block Mtb to proliferate upon re-oxygenation by specifically blocking NAD accessibility to AlaDH. The collective approach to drug discovery was further evaluated through in silico analyses providing additional insight into an efficient drug development strategy that can be further assessed with the incorporation of in vivo studies.

[This corrects the article DOI: 10.1371/journal.pone.0245064.].

Ecological restoration frequently involves the addition of native plants, but the effectiveness (in terms of plant growth, plant survival, and cost) of using seeds versus container plants has not been studied in many plant communities. It is also not known if plant success would vary by species or based on functional traits. To answer these questions, we added several shrub species to a coastal sage scrub restoration site as seeds or as seedlings in a randomized block design. We measured percent cover, density, species richness, size, survival, and costs. Over the two years of the study, shrubs added to the site as seeds grew more and continued to have greater density than plants added from containers. Seeded plots also had greater native species richness than planted plots. However, shrubs from containers had higher survival rates, and percent cover was comparable between the planted and seeded treatments. Responses varied by species depending on functional traits, with deep-rooted evergreen species establishing better from container plants. Our cost analysis showed that it is more expensive to use container plants than seed, with most of the costs attributed to labor and supplies needed to grow plants. Our measurements of shrub density, survival, species richness, and growth in two years in our experimental plots lead us to conclude that coastal sage scrub restoration with seeds is optimal for increasing density and species richness with limited funds, yet the addition of some species from container plants may be necessary if key species are desired as part of the project objectives.

SARS-CoV-2 has infected nearly 3.7 million and killed 61,722 Californians, as of May 22, 2021. Non-pharmaceutical interventions have been instrumental in mitigating the spread of the coronavirus. However, as we ease restrictions, widespread implementation of COVID-19 vaccines is essential to prevent its resurgence. In this work, we addressed the adequacy and deficiency of vaccine uptake within California and the possibility and severity of resurgence of COVID-19 as restrictions are lifted given the current vaccination rates. We implemented a real-time Bayesian data assimilation approach to provide projections of incident cases and deaths in California following the reopening of its economy on June 15, 2021. We implemented scenarios that vary vaccine uptake prior to reopening, and transmission rates and effective population sizes following the reopening. For comparison purposes, we adopted a baseline scenario using the current vaccination rates, which projects a total 11,429 cases and 429 deaths in a 15-day period after reopening. We used posterior estimates based on CA historical data to provide realistic model parameters after reopening. When the transmission rate is increased after reopening, we projected an increase in cases by 21.8% and deaths by 4.4% above the baseline after reopening. When the effective population is increased after reopening, we observed an increase in cases by 51.8% and deaths by 12.3% above baseline. A 30% reduction in vaccine uptake alone has the potential to increase cases and deaths by 35% and 21.6%, respectively. Conversely, increasing vaccine uptake by 30% could decrease cases and deaths by 26.1% and 17.9%, respectively. As California unfolds its plan to reopen its economy on June 15, 2021, it is critical that social distancing and public behavior changes continue to be promoted, particularly in communities with low vaccine uptake. The Centers for Disease Control and Prevention (CDC) recommendation to ease mask-wearing for fully vaccinated individuals despite major inequities in vaccine uptake in counties across the state highlights some of the logistical challenges that society faces as we enthusiastically phase out of this pandemic.

BackgroundThe COVID-19 pandemic led to important indirect health and social harms in addition to deaths and morbidity due to SARS-CoV-2 infection. These indirect impacts, such as increased depression and substance abuse, can have persistent effects over the life course. Estimated health and cost outcomes of such conditions and mitigation strategies may guide public health responses.MethodsWe developed a cost-effectiveness framework to evaluate societal costs and quality-adjusted life years (QALYs) lost due to six health-related indirect effects of COVID-19 in California. Short- and long-term outcomes were evaluated for the adult population. We identified one evidence-based mitigation strategy for each condition and estimated QALYs gained, intervention costs, and savings from averted health-related harms. Model data were derived from literature review, public data, and expert opinion.ResultsPandemic-associated increases in prevalence across these six conditions were estimated to lead to over 192,000 QALYs lost and to approach $7 billion in societal costs per million population over the life course of adults. The greatest costs and QALYs lost per million adults were due to adult depression. All mitigation strategies assessed saved both QALYs and costs, with five strategies achieving savings within one year. The greatest net savings over 10 years would be achieved by addressing depression ($242 million) and excessive alcohol use ($107 million).DiscussionThe COVID-19 pandemic is leading to significant human suffering and societal costs due to its indirect effects. Policymakers have an opportunity to reduce societal costs and health harms by implementing mitigation strategies.

IntroductionCoronary heart disease (CHD) is the most common cardiovascular disease in the United States and heart disease is the leading cause of death in North Dakota. Although obesity is a major risk factor for CHD, some studies have reported an inverse relationship between body mass index (BMI) and CHD outcomes. Understanding the epidemiology of CHD among individuals with and without obesity is essential to guide health planning. Therefore, the objectives of this study were to estimate the prevalence and identify predictors of CHD among North Dakota adults with and without obesity.MethodsBehavioral Risk Factor Surveillance System data from 2017 to 2021 were provided by the North Dakota Department of Health and Human Services. Weighted prevalence estimates and 95% confidence intervals (CIs) were computed for CHD and potential risk factors among respondents with and without obesity (BMI ≥30 kg/m2). Multivariable logistic regression was used to identify significant predictors of CHD in both groups.ResultsA total of 17,092 respondents were included in the study. Respondents with obesity had a higher prevalence of CHD (4.7%, 95% CI: 4.2-5.4) than those without obesity (3.0%, 95% CI: 2.7-3.4). Predictors of CHD among both groups included age, sex, self-reported general health, high blood pressure, high cholesterol, chronic obstructive pulmonary disease, and diabetes. Having a personal doctor (Odds Ratio [OR] = 1.91, 95% CI: 1.13-3.23) and arthritis (OR = 1.72, 95% CI: 1.34-2.22) were significant predictors of CHD among respondents without obesity, but not among those without obesity.ConclusionWhile the prevalence of CHD was significantly higher among adults with obesity compared to those without obesity, the findings of the stratified analysis indicated that predictors of the condition tended to be similar for the two groups. This study provides useful information to guide health planning and control programs that aim to reduce the burden of CHD in North Dakota.

BackgroundEvidence suggests that some infectious diseases, such as herpes zoster (HZ), are associated with elevated risk of subsequent dementia, while certain anti-viral medications are associated with lower risk. We sought to evaluate associations between HZ diagnosis and treatment with incident dementia in a large, retrospective matched cohort.MethodsUsing ICD-9 and ICD-10 diagnosis codes in electronic medical records, we identified members of Kaiser Permanente Northwest age 50 and older from 2000-2019 with a HZ diagnosis during this period. A comparison group without HZ diagnosis was individually matched 3:1 on age at HZ diagnosis date (index date), sex, and membership length prior to index date. We excluded subjects with dementia diagnosed before the index date. Antiherpetic medication was identified using pharmacy fills 1 month before to 12 months after the index date. We employed survival analysis to examine the associations between dementia and HZ diagnosis and antiherpetic medication, adjusting multivariable models for demographic and clinical factors. We stratified on age and sex and conducted a sensitivity analysis with a 5-year lag period.ResultThe study included 101,328 persons, 25,332 with HZ. Over a median follow-up of 4.8 years, 6,000 developed dementia. HZ diagnosis was not associated with higher hazard of dementia (hazard ratio (HR) = 0.99, 95% CI 0.93-1.05) in the primary analysis. Among persons with HZ diagnoses, the HR for receipt of any antiherpetic medication was 0.79 (95% CI 0.70-0.90) in univariate analysis and 0.88 (95% CI 0.77-1.00) after adjustment for demographic and clinical factors. Dementia was not associated with trends in duration of medication use or cumulative dose.ConclusionsWe found little evidence for an association between HZ diagnosis and dementia overall. Antiherpetic medication prescribed around the time of HZ diagnosis was statistically associated with lower risk of subsequent dementia in some but not all analyses and subgroups.

BackgroundTransitions of care after cancer treatment pose a major challenge for patient safety as adverse events and unplanned healthcare utilization occur frequently. At this point, patient and family engagement (PFE) is particularly valuable since patients and their families experience various challenges along this pathway, such as changing roles and recurrent needs to navigate across structural gaps between different services. However, there is currently a lack of evidence on the impact of PFE on patient safety in transitions after cancer treatment.ObjectiveTo systematically review and synthesize evidence on effects of different PFE interventions on patient safety in the transition of care after cancer treatment.MethodsThis protocol for a systematic review with meta-analysis follows PRISMA-P guidelines. A comprehensive database search will be conducted in MEDLINE, EMBASE, CENTRAL, CINAHL, and APA PsycInfo. Trial registries and grey literature will be searched, forward and backward citation tracking will be performed. Trials with prospective, longitudinal, interventional study designs will be included if they evaluate PFE interventions on patient safety outcomes (primary outcomes: healthcare utilization, patient harm, adherence, patient experience; secondary: quality of life, distress); eligible studies need to survey patients with any oncological disease during or after transition following cancer treatment. Results will be synthesized narratively and meta-analytically using a random-effects model. Risk of bias will be assessed using the Cochrane RoB-2 and revised JBI critical appraisal tool. The certainty of evidence will be judged according to the GRADE approach.DiscussionRobust evidence of effectiveness is needed to establish PFE interventions for patient safety in care transitions for oncological patients. This review will allow evidence-based conclusions about types and effects of different PFE interventions for transitional safety in oncology care and inform stakeholders in designing sustainable PFE activities.Trial registrationPROSPERO (CRD42024546938), OSF (doi.org/10.17605/OSF.IO/9XAMU).

Alzheimer's disease (AD) imposes a major burden on affected individuals, their caregivers and health-care systems alike. Though quite many risk factors for disease progression have been identified, there is a lack of prospective studies investigating the interplay and predictive value of a wide variety of patient variables associated with cognitive deterioration (defined as key feature of AD progression). Study participants were patients with probable and possible AD, that were assessed at four time points over a period of two years (T1-T4). The main results were threefold: (i) over time, significant changes were observed regarding patients' cognitive functioning, activities of daily living and caregiver load (but not depression, pain, neuropsychiatric symptoms); (ii) intercorrelations between caregiver load and patients' cognitive and functional variables were high, correlation patterns remaining rather stable across time; (iii) cognitive functioning at T4 was best predicted by patients' age, sex, atrial fibrillation and activities of daily living at T1; and (iv) across all four assessment points, cognitive functioning was best predicted by time (i.e., disease duration), age, sex, activities of daily living and depression. Overall, even in early stages of AD and during a short two-year period, functional changes were significant and tightly intertwined with caregiver load, thus stressing the need to consider caregiver load when diagnosing and treating patients with AD. A novel and clinically relevant finding is that even in early stages of AD, cognitive deterioration was best predicted by a combination of patients' demographic, somatic and functional variables.

[This corrects the article DOI: 10.1371/journal.pone.0264826.].

BackgroundCommunity engagement (CE) is pertinent to ethically and scientifically rigorous infectious disease clinical trials in sub-Saharan Africa (SSA). However, there are critiques that CE is not properly embedded in research processes and that there is uncertainty about what CE entails. The aim of this study was to gain an understanding of CE in infectious disease clinical trials in SSA, specifically factors affecting CE and existing strategies for engaging with communities.MethodsSemi-structured telephone interviews were conducted with 20 community and clinical trial (CT) stakeholders who worked in SSA. The audio-recorded interviews were transcribed verbatim and analysed inductively using thematic analysis.ResultsThemes are as follows: 1) Communities are abandoned research-entities-a disconnect between scientific teams and communities was observed and knowledge translation was not prioritised at the community-level. 2) Us and them: community engagement teams vs investigators-CE teams expressed that researchers did not account for CE processes and often did not involve CE staff in their planning, and felt that their roles were not valued. 3) Ethical considerations: concerns and gaps-there were concerns that procedures were not standardised and that ethics processes were not adhered to. 4) Opportunities for improved CE practices-training needs were expressed, including for standardised practices, ethics, and for developing a holistic understanding of collaborating with communities.ConclusionCE role players require intensive training to ensure ethical CE and that communities are treated with dignity. This includes 1) using collaborative strategies involving research and CE staff, 2) protocol-adherence that recognises CE as pertinent, 3) viewing communities as complex and building relationships that are sustainable, and 4) ensuring that knowledge translation is considered at a community-level. Further research is necessary to investigate potential training programmes that integrate these elements.

BackgroundAfter traumatic brain injury (TBI), individuals can experience changes to quality of life (QOL). Despite understanding the factors that impact QOL after TBI, there is limited patient-oriented research to understand the subjective priorities for QOL after TBI. This study aims to understand the priorities for QOL after TBI using a group consensus building method.MethodsThe Technique for Research of Information by Animation of a Group of Experts (TRIAGE) method was used to determine priorities for QOL after TBI. In phase one, expert participants were consulted to understand the context of QOL after TBI. In phase two, participants with TBI completed a questionnaire to broadly determine the factors that contributed to their QOL. In phase three, a portion of participants from phase two engaged in focus groups to identify the most relevant priorities. Data was analyzed thematically. In phase four, expert participants were consulted to finalize the priorities.ResultsPhase one included three expert participants who outlined the complexity and importance of QOL after TBI. Phase two included 34 participants with TBI who described broad priorities for QOL including social support, employment, and accessible environments. Phase three included 13 participants with TBI who identified seven priorities for QOL: ensuring basic needs are met, participating in everyday life, trusting a circle of care, being seen and accepted, finding meaning in relationships, giving back and advocating, and finding purpose and value. In phase four, four expert participants confirmed the QOL priorities.InterpretationsFindings emphasize the critical need to address priorities for QOL after TBI to ensure improved health outcomes.

BackgroundDespite the importance of labour market participation and the high number of people with disabilities in rural Africa who rely on subsistence agriculture to survive, very few studies have documented labour market outcomes among farmers with and without disabilities in Africa.ObjectiveWe examined how labour market participation differed by disability and other factors among smallholder farmers in Western Kenya.MethodsWe use cross-sectional data collected between January and April 2022 from sorghum farmers enrolled in a trial evaluating the impact of a programme designed to improve labour market participation among sorghum farmers in rural Western Kenya. Disability and Labour market outcomes were assessed using questions from the Washington Group /ILO Labor Force Survey Disability Module the ILO Labour Force Survey module respectively. Univariate and multiple regression analyses were conducted to identify socio-demographic characteristics and other related factors associated with labour market participation.ResultsAmong 4459 participants, disability was reported by 20.3% of women and 12.3% of men. Labour market participation was reported by 77.1% and 81.3% of women and men, respectively. Adjusting for demographic confounders, having a disability was associated with a lower likelihood of labour market participation (odds ratio 0.59, 95% confidence interval, 0.42-0.83, P = 0.001). These findings were similar in a modified model that looked at functional difficulties separately from anxiety and depression. Women, older participants, and those who were dependent on others were also more likely not to report participation in the labour market.ConclusionsIncreased recognition and understanding of functional limitations among smallholder farmers is vital for the success of economic empowerment programmes aimed at increasing labour market participation among the most vulnerable populations.

This in-vitro study aimed to analyse the effect of brushing and different brushing parameters (kind of toothpaste, kind of toothbrush, brushing force) on erosive tooth wear of primary bovine enamel and dentin. Specimens were prepared from primary bovine enamel or dentin (each group n = 12) and cyclically eroded (6 × 60 s/d, citric acid, pH 2.4) and brushed with children's toothbrushes (2 × 15 s/d) over 5 days. The brushing parameters under investigation were: toothpaste (fluoridated, fluoride-free), toothbrush (manual; rotating-oscillating and sonic, each at two different activation modes) and brushing force (1 N, 2 N). Specimens that were only eroded and not brushed served as controls. Enamel and dentin wear was quantified using widefield confocal microscopy. Statistical analysis was performed using three- and one-way ANOVAs followed by Scheffe's (enamel) or Tamhane's (dentin) post-hoc tests (p < 0.05). Brushing with the fluoridated toothpaste was able to significantly reduce erosive wear in enamel (by 15 to 37%, 6 of 10 groups) and in dentin (by 58 to 72%, all groups), while brushing with the fluoride-free toothpaste was not different from the controls. Considering the kind of toothpaste and brushing force, slight differences between the toothbrushes were observed in enamel, but not in dentin. Within the same toothbrush and activation mode, almost no differences between 1 and 2 N brushing force were detected. In conclusion, erosive tooth wear on primary bovine dental hard tissue mainly depends on the kind of toothpaste, rather than on the kind of toothbrush and the brushing force.

The one-sample log-rank test is the preferred method for analysing the outcome of single-arm survival trials. It compares the survival distribution of patients with a prefixed reference survival curve that usually represents the expected outcome under standard of care. However, classical one-sample log-rank tests assume that the reference curve is known, ignoring that it is frequently estimated from historical data and therefore susceptible to sampling error. Neglecting the variability of the reference curve can lead to an inflated type I error rate, as shown in a previous paper. Here, we propose a new survival test that allows to account for the sampling error of the reference curve without knowledge of the full underlying historical survival time data. Our new test allows to perform a valid historical comparison of patient survival times when only a historical survival curve rather than the full historic data is available. It thus applies in settings where the two-sample log-rank test is not applicable as method of choice due to non-availability of historic individual patient survival time data. We develop sample size calculation formulas, give an example application and study the performance of the new test in a simulation study.

PurposeTo determine the prevalence and causes of blindness and visual impairment among adults in Kogi, Nigeria.MethodsA Rapid assessment of avoidable blindness (RAAB) protocol was used with additional tools measuring disability and household wealth to measure the prevalence of blindness and visual impairment (VI) and associations with sex, disability, wealth, cataract surgical coverage and its effectiveness.ResultsAge- and sex-adjusted all-cause prevalence of bilateral blindness was 3.6% (95%CI 3.0-4.2%), prevalence of blindness among people living with additional, non-visual disabilities was 38.3% (95% CI 29.0-48.6%) compared to 1.6% (95%CI 1.2-2.1%; [Formula: see text] = 771.9, p6/18) was seen in 61 eyes (52.6%) increasing to 71 (61.2%) eyes with best correction. Cost was identified as the main barrier to surgery.ConclusionFindings suggest there exists inequalities in eye care with women, poorer people and people with disabilities having a lower Cataract Surgical Coverage, thereby, underscoring the importance of eye care programs to address these inequalities.

Psychopathy is a severe personality disorder marked by a wide range of emotional deficits, including a lack of empathy, emotion dysregulation, and alexithymia. Previous research has largely examined these emotional impairments in isolation, ignoring their influence on each other. Thus, we examined the concurrent interrelationship between emotional impairments in psychopathy, with a particular focus on the mediating role of alexithymia. Using path analyses with cross-sectional data from a community sample (N = 315) and a forensic sample (N = 50), our results yielded a statistically significant mediating effect of alexithymia on the relationship between psychopathy and empathy (community and forensic) and between psychopathy and emotion dysregulation (community). Moreover, replacing psychopathy with its three dimensions (i.e., meanness, disinhibition, and boldness) in the community sample revealed that boldness may function as an adaptive trait, with lower levels of alexithymia counteracting deficits in empathy and emotion dysregulation. Overall, our findings indicate that psychopathic individuals' limited understanding of their own emotions contributes to their lack of empathy and emotion dysregulation. This underscores the potential benefits of improving emotional awareness in the treatment of individuals with psychopathy.

IntroductionEvidence indicates that sphingolipid accumulation drives complex molecular alterations promoting cardiometabolic diseases. Clinically, it was shown that sphingolipids predict cardiometabolic risk independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, little is known about therapeutic modalities to lower sphingolipid levels. Exercise, a powerful means to prevent and treat cardiometabolic diseases, is a promising modality to mitigate sphingolipid levels in a cost-effective, safe, and patient-empowering manner.MethodsThis randomised controlled trial will explore whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n = 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An 'omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to assess patient fitness changes. Cholesterol, triglycerides, glycated haemoglobin, the homeostatic model assessment for insulin resistance, static retinal vessel analysis, flow-mediated dilatation, and strain analysis of the heart cavities will also be assessed pre- and post-intervention. This study shall inform whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels.Trial registrationThe trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.

Water-borne plant pathogenic fungi and oomycetes are a major threat in greenhouse production systems. Early detection and quantification of these pathogens would enable us to ascertain both economic and biological thresholds required for a timely treatment, thus improving effective disease management. Here, we used Oxford nanopore MinION amplicon sequencing to analyze microbial communities in irrigation water collected from greenhouses used for growing tomato, cucumber and Aeschynanthus sp. Fungal and oomycete communities were characterized using primers that amplify the full internal transcribed spacer (ITS) region. To assess the sensitivity of the MinION sequencing, we spiked serially diluted mock DNA into the DNA isolated from greenhouse water samples prior to library preparation. Relative abundances of fungal and oomycete reads were distinct in the greenhouse irrigation water samples and in water samples from setups with tomato that was inoculated with Fusarium oxysporum. Sequence reads derived from fungal and oomycete mock communities were proportionate in the respective serial dilution samples, thus confirming the suitability of MinION amplicon sequencing for environmental monitoring. By using spike-ins as standards to test the reliability of quantification using the MinION, we found that the detection of spike-ins was highly affected by the background quantities of fungal or oomycete DNA in the sample. We observed that spike-ins having shorter length (538bp) produced reads across most of our dilutions compared to the longer spikes (>790bp). Moreover, the sequence reads were uneven with respect to dilution series and were least retrievable in the background samples having the highest DNA concentration, suggesting a narrow dynamic range of performance. We suggest continuous benchmarking of the MinION sequencing to improve quantitative metabarcoding efforts for rapid plant disease diagnostic and monitoring in the future.

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Arthropods account for a large proportion of animal biomass and diversity in terrestrial systems, making them crucial organisms in our environments. However, still too little is known about the highly abundant and megadiverse groups that often make up the bulk of collected samples, especially in the tropics. With molecular identification techniques ever more evolving, analysis of arthropod communities has accelerated. In our study, which was conducted within the Global Malaise trap Program (GMP) framework, we operated two closely placed Malaise traps in Padang, Sumatra, for three months. We analyzed the samples by DNA barcoding and sequenced a total of more than 70,000 insect specimens. For sequence clustering, we applied three different delimitation techniques, namely RESL, ASAP, and SpeciesIdentifier, which gave similar results. Despite our (very) limited sampling in time and space, our efforts recovered more than 10,000 BINs, of which the majority are associated with "dark taxa". Further analysis indicates a drastic undersampling of both sampling sites, meaning that the true arthropod diversity at our sampling sites is even higher. Regardless of the close proximity of both Malaise traps (< 360 m), we discovered significantly distinct communities.

The human retina contains three classes of cone photoreceptors each sensitive to different portions of the visual spectrum: long (L), medium (M) and short (S) wavelengths. Color information is computed by downstream neurons that compare relative activity across the three cone types. How cone signals are combined at a cellular scale has been more difficult to resolve. This is especially true near the fovea, where spectrally-opponent neurons in the parvocellular pathway draw excitatory input from a single cone and thus even the smallest stimulus projected through natural optics will engage multiple color-signaling neurons. We used an adaptive optics microstimulator to target individual and pairs of cones with light. Consistent with prior work, we found that color percepts elicited from individual cones were predicted by their spectral sensitivity, although there was considerable variability even between cones within the same spectral class. The appearance of spots targeted at two cones were predicted by an average of their individual activations. However, two cones of the same subclass elicited percepts that were systematically more saturated than predicted by an average. Together, these observations suggest both spectral opponency and prior experience influence the appearance of small spots.

Vaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.

Introduction: Coronary heart disease (CHD) is the most common cardiovascular disease in the United States and heart disease is the leading cause of death in North Dakota. Although obesity is a major risk factor for CHD, some studies have reported an inverse relationship between body mass index (BMI) and CHD outcomes. Understanding the epidemiology of CHD among individuals with and without obesity is essential to guide health planning. Therefore, the objectives of this study were to estimate the prevalence and identify predictors of CHD among North Dakota adults with and without obesity. Methods: Behavioral Risk Factor Surveillance System data from 2017 to 2021 were provided by the North Dakota Department of Health and Human Services. Weighted prevalence estimates and 95% confidence intervals (CIs) were computed for CHD and potential risk factors among respondents with and without obesity (BMI ≥30 kg/m2). Multivariable logistic regression was used to identify significant predictors of CHD in both groups. Results: A total of 17,092 respondents were included in the study. Respondents with obesity had a higher prevalence of CHD (4.7%, 95% CI: 4.2–5.4) than those without obesity (3.0%, 95% CI: 2.7–3.4). Predictors of CHD among both groups included age, sex, self-reported general health, high blood pressure, high cholesterol, chronic obstructive pulmonary disease, and diabetes. Having a personal doctor (Odds Ratio [OR] = 1.91, 95% CI: 1.13–3.23) and arthritis (OR = 1.72, 95% CI: 1.34–2.22) were significant predictors of CHD among respondents without obesity, but not among those without obesity. Conclusion: While the prevalence of CHD was significantly higher among adults with obesity compared to those without obesity, the findings of the stratified analysis indicated that predictors of the condition tended to be similar for the two groups. This study provides useful information to guide health planning and control programs that aim to reduce the burden of CHD in North Dakota. [ABSTRACT FROM AUTHOR]

Sleep behavior is present in nearly all animals, and is a vital part of growth, development, and overall health. Infant mammals cycle randomly between short bouts of sleep and wake, and the lengths of these bouts both follow an exponential distribution. As mammals mature into adulthood, the mean sleep and wake bout lengths increase, and we also observe a change in the distribution of wake bout lengths from exponential to power law. Focusing on three regions of the brainstem that are involved in sleep-wake regulation, we develop a novel integrate-and-fire neuronal network model to expand upon previous mathematical models of sleep-wake regulation in mammals, focusing on rats. This model allows fine control over neuronal connectivity while simultaneously increasing the size and complexity of the modeled system to make it more representative of reality. We establish a relationship between neuronal network structure and function that could explain the different sleep-wake behaviors observed in rats as they progress through development. We explore the relationship between three different neuronal populations as well as the overall network behavior of the system. We find that increasing synaptic connectivity strength between the wake-promoting region and the wake-active region accounts for the observed changes in mammalian sleep-wake patterns. This dynamic neuronal connectivity is a possible mechanism that accurately accounts for sleep-wake pattern changes observed during mammalian development. [ABSTRACT FROM AUTHOR]

Conversations encompass continuous exchanges of verbal and nonverbal information. Previous research has demonstrated that gestures dynamically entrain each other and that speakers tend to align their vocal properties. While gesture and speech are known to synchronize at the intrapersonal level, few studies have investigated the multimodal dynamics of gesture/speech between individuals. The present study aims to extend our comprehension of unimodal dynamics of speech and gesture to multimodal speech/gesture dynamics. We used an online dataset of 14 dyads engaged in unstructured conversation. Speech and gesture synchronization was measured with cross-wavelets at different timescales. Results supported previous research on intrapersonal speech/gesture coordination, finding synchronization at all timescales of the conversation. Extending the literature, we also found interpersonal synchronization between speech and gesture. Given that the unimodal and multimodal synchronization occurred at similar timescales, we suggest that synchronization likely depends on the vocal channel, particularly on the turn-taking dynamics of the conversation. [ABSTRACT FROM AUTHOR]

Here we present a new 850-year long coccolithophore record from core SO130-289KL in the northeastern Arabian Sea that spans the Greenland Interstadial 20–Greenland Stadial 20 transition including the timing of the ∼74 ka Youngest Toba Tuff (YTT) supereruption. During the warm interstadial, the coccolithophore assemblage is characterized by Gephyrocapsa oceanica (41%) and Florisphaera profunda (30%) while the succeeding cold stadial is distinguished by the abundance of small placolith species (Emiliania huxleyi + G. ericsonii) (52%). However, the oldest samples of the study interval seem to show a stadial-like coccolithophore assemblage. Spectral analysis revealed an interdecadal cycle imprinted in the coccolithophore record during the interstadial that was also independently reported in other terrestrial and marine proxies. Immediately after the YTT eruption, small placoliths increased by 42% from 5% right below the YTT layer to 47% ∼1 mm above the YTT layer, while G. oceanica and Helicosphaera carteri increased and F. profunda decreased within the ∼1.15 cm layer representing about 8–19 years. Subsequently, the coccolithophore assemblage returned to a composition similar to the warm interstadial period before abruptly changing to a stadial composition characterized by the abundance of small placoliths about 100–130 years after the YTT eruption. Therefore, the YTT eruption had a significant impact on the overall coccolithophore assemblage but appears to have not caused the climate transition from interstadial to stadial conditions, supporting proxy and modeling data. However, the overall mechanism driving the observed changes and cyclicities remains unknown but might be related to rapid atmospheric teleconnections of North Atlantic climate variability to the low latitudes. [ABSTRACT FROM AUTHOR]

Background: The alveolar epithelium is protected by a heparan sulfate-rich, glycosaminoglycan layer called the epithelial glycocalyx. It is cleaved in patients with acute respiratory distress syndrome (ARDS) and in murine models of influenza A (IAV) infection, shedding fragments into the airspace from the cell surface. Glycocalyx shedding results in increased permeability of the alveolar-capillary barrier, amplifying acute lung injury. The mechanisms underlying alveolar epithelial glycocalyx shedding in IAV infection are unknown. We hypothesized that induction of host sheddases such as matrix metalloproteinases (MMPs) during IAV infection results in glycocalyx shedding and increased lung injury. Materials and methods: We measured glycocalyx shedding and lung injury during IAV infection with and without treatment with the pan-MMP inhibitor Ilomastat (ILO) and in an MMP-7 knock out (MMP-7KO) mouse. C57BL/6 or MMP-7KO male and female mice were given IAV A/PR/8/34 (H1N1) at 30,000 PFU/mouse or PBS intratracheally. For some experiments, C56BL/6 mice were infected in the presence of ILO (100mg/kg) or vehicle given daily by IP injection. Bronchoalveolar lavage (BAL) and lung tissue were collected on day 1, 3, and 7 for analysis of glycocalyx shedding (BAL Syndecan-1) and lung injury (histology, BAL protein, BAL cytokines, BAL immune cell infiltrates, BAL RAGE). Expression and localization of the sheddase MMP-7 and its inhibitor TIMP-1 was examined by RNAScope. For in vitro experiments, MLE-12 mouse lung epithelial cells were cultured and treated with active or heat-inactivated heparinase (2.5 U/mL) prior to infection with IAV (MOI 1) and viral load and MMP-7 and TIMP-1 expression analyzed. Results: IAV infection caused shedding of the epithelial glycocalyx into the BAL. Inhibition of MMPs with ILO reduced glycocalyx shedding by 36% (p = 0.0051) and reduced lung epithelial injury by 40% (p = 0.0404). ILO also reduced viral load by 68% (p = 0.027), despite having no significant effect on lung cytokine production. Both MMP-7 and its inhibitor TIMP-1 were upregulated in IAV infected mice: MMP-7 colocalized with IAV, while TIMP-1 was limited to cells adjacent to infection. However, MMP-7KO mice had similar glycocalyx shedding, epithelial injury, and viral load compared to WT littermates, suggesting redundancy in MMP sheddase function in the lung. In vitro, heparinase treatment before infection led to a 52% increase in viral load (p = 0.0038) without altering MMP-7 or TIMP-1 protein levels. Conclusions: Glycocalyx shedding and MMPs play key roles in IAV-induced epithelial injury, with significant impact on IAV viral load. Further studies are needed to understand which specific MMPs regulate lung epithelial glycocalyx shedding. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to compare the efficacy and utility of the McGrath™ videolaryngoscope, using the Macintosh-like McGrath™ MAC blade and the hyperangulated McGrath™ MAC Xblade with a conventional Macintosh blade under simulated resuscitation conditions. Methods: A prospective, randomized study under conditions mimicking ongoing chest compressions was conducted with 90 anesthesiologists. Intubation success rates, time-to-vocal cords, time-to-intubate, and time-to-ventilate were measured. Additionally, the study assessed the subjective ratings and the perceived workload using the 'NASA-task-load-index' during the procedure. Results: The overall intubation success rate was device dependent 99–100%. The McGrath™ MAC and McGrath™ MAC Xblade showed faster visualization times compared to conventional blades. The MAC blade demonstrated superior performance in time-to-intubate and time-to-ventilate compared to both conventional and MAC Xblades. Despite excellent visualization, the MAC Xblade posed challenges in tube placement, reflected in a prolonged intubation time of >120 seconds in one case. Both MAC and MAC Xblade reduced potential dental injuries and interruptions to chest compressions compared to conventional laryngoscopes. User experience significantly impacted intubation times with conventional laryngoscopes, but this effect was mitigated with videolaryngoscopy. Participants reported lower stress and effort when using videolaryngoscopes, with the MAC blade rated superior in perceived time pressure. Conclusion: The study supports the superiority of videolaryngoscopy with a Macintosh-like blade over conventional laryngoscopy during mechanical chest compressions, particularly for less experienced users. The McGrath™ MAC blade, in particular, offers advantages in intubation time, user-friendliness, and reduced stress. However, the MAC Xblade's challenges during tube placement highlight the need for further clinical validation. Continued research is essential to refine guidelines and improve resuscitation outcomes. [ABSTRACT FROM AUTHOR]

BackgroundAirway management can be challenging in neonates and infants. The Pierre Robin sequence (PRS) is a condition characterized by micrognathia, glossoptosis and airway obstruction. The airway management of these patients poses great challenges for anesthesiologists and pediatricians alike. To date, there has been no direct comparison of the hyperangulated GlideScope® Spectrum LoPro (GLP), the straight GlideScope® Spectrum Miller (GSM), a conventional Macintosh (MC) and a conventional Miller blade (ML) in patients with PRS.MethodsFor this purpose, 90 anesthesiologists (43 with limited experience, 47 with extensive experience) performed orotracheal intubation on an Air-Sim® Pierre Robin X manikin using GLP, GSM, MC and ML in randomized order. 'Time-to-vocal-cords', 'time-to-intubate', 'time-to-ventilate', the severity of oral-soft-tissue-trauma and the subjective evaluation of each device were recorded.ResultsA significantly faster and better view of the vocal cords and lower oral-soft-tissue-trauma was achieved using the GLP (p120s) with the GLP. In the sub-group with extensive experience, we found significantly shorter intubation times for the GSM and ML. The GLP was the tool of choice for most participants, while the conventional MC received the lowest rating.ConclusionsVideolaryngoscopy leads to increased safety for the prevention of undetected esophageal intubation in the airway management in a PRS manikin. Hyperangulated blades may ensure a good and fast view of the vocal cords and low oral-soft-tissue-trauma but pose a challenge during the placement of the tube. Specific skills and handling seem to be necessary to ensure a safe tube placement with this sort of blades.

Diabetes mellitus is a multiorgan systemic disease impacting numerous ocular structures that results in significant ocular morbidity and often results in more frequent corneal and glaucoma surgeries for affected individuals. We hypothesize that the systemic metabolic and proteomic derangement observed in the progression of diabetes influences the composition of the aqueous humor (AH), which ultimately impacts the anterior segment health of the eye. To identify changes associated with diabetes progression, we mapped the metabolite profile and proteome of AH samples from patients with varying severities of type II diabetes (T2DM). Patients were classified as nondiabetic (ND or control), non-insulin-dependent diabetic without advanced features of disease (NAD-ni), insulin-dependent diabetic without advanced features (NAD-i), or diabetic with advanced features (AD). AH samples collected from the anterior chamber during elective ophthalmic surgery were evaluated for metabolite and protein expression changes associated with diabetic severity via gas chromatography/mass spectrometry and ultra-high performance liquid chromatography tandem mass spectrometry, respectively. Metabolic and proteomic pathway analyses were conducted utilizing MetaboAnalyst 4.0 and Ingenuity Pathway Analysis. A total of 14 control, 12 NAD-ni, 4 NAD-I, and 14 AD samples were included for analysis. Elevated levels of several branched amino acids (e.g., valine, leucine, isoleucine), and lipid metabolites (e.g., palmitate) were found only with increasing diabetic severity (i.e., the AD group). Similar proteomic trends were noted in amino acid and fatty acid metabolism and the unfolded protein/stress response. These results represent the first report of both metabolomic and proteomic evaluation of aqueous humor. Diabetes results in metabolic and proteomic perturbations detectable in the AH, and unique changes become manifest as T2DM severity worsens. Changes in AH composition may serve as an indicator of disease severity, risk assessment of anterior segment cells and structures, and potential future therapies.

Phytophthora sojae is a soil-borne oomycete and the causal agent of Phytophthora root and stem rot (PRR) in soybean (Glycine max [L.] Merrill). Yield losses attributed to P. sojae are devastating in disease-conducive environments, with global estimates surpassing 1.1 million tonnes annually. Historically, management of PRR has entailed host genetic resistance (both vertical and horizontal) complemented by disease-suppressive cultural practices (e.g., oomicide application). However, the vast expansion of complex and/or diverse P. sojae pathotypes necessitates developing novel technologies to attenuate PRR in field environments. Therefore, the objective of the present study was to couple high-throughput sequencing data and deep learning to elucidate molecular features in soybean following infection by P. sojae. In doing so, we generated transcriptomes to identify differentially expressed genes (DEGs) during compatible and incompatible interactions with P. sojae and a mock inoculation. The expression data were then used to select two defense-related transcription factors (TFs) belonging to WRKY and RAV families. DNA Affinity Purification and sequencing (DAP-seq) data were obtained for each TF, providing putative DNA binding sites in the soybean genome. These bound sites were used to train Deep Neural Networks with convolutional and recurrent layers to predict new target sites of WRKY and RAV family members in the DEG set. Moreover, we leveraged publicly available Arabidopsis (Arabidopsis thaliana) DAP-seq data for five TF families enriched in our transcriptome analysis to train similar models. These Arabidopsis data-based models were used for cross-species TF binding site prediction on soybean. Finally, we created a gene regulatory network depicting TF-target gene interactions that orchestrate an immune response against P. sojae. Information herein provides novel insight into molecular plant-pathogen interaction and may prove useful in developing soybean cultivars with more durable resistance to P. sojae.

Numerous vital signs are reported in association with stress response assessment, but their application varies widely. This work provides an overview over methods for stress induction and strain assessment, and presents a multimodal experimental study to identify the most important vital signs for effective assessment of the response to acute mental stress. We induced acute mental stress in 65 healthy participants with the Mannheim Multicomponent Stress Test and acquired self-assessment measures (Likert scale, Self-Assessment Manikin), salivary α-amylase and cortisol concentrations as well as 60 vital signs from biosignals, such as heart rate variability parameters, QT variability parameters, skin conductance level, and breath rate. By means of statistical testing and a self-optimizing logistic regression, we identified the most important biosignal vital signs. Fifteen biosignal vital signs related to ventricular repolarization variability, blood pressure, skin conductance, and respiration showed significant results. The logistic regression converged with QT variability index, left ventricular work index, earlobe pulse arrival time, skin conductance level, rise time and number of skin conductance responses, breath rate, and breath rate variability (F1 = 0.82). Self-assessment measures indicated successful stress induction. α-amylase and cortisol showed effect sizes of -0.78 and 0.55, respectively. In summary, the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system were successfully activated. Our findings facilitate a coherent and integrative understanding of the assessment of the stress response and help to align applications and future research concerning acute mental stress.

[This corrects the article DOI: 10.1371/journal.pone.0242247.].

BackgroundIn the United States, public health surveillance systems often underestimate the burden of acute gastroenteritis (AGE) because they only identify disease among those who interact with the healthcare system.ObjectiveTo identify factors associated with healthcare-seeking behavior among individuals experiencing community-acquired AGE.MethodsFrom October 2016 -September 2017, we conducted a weekly, age-stratified, random sample of Kaiser Permanente Northwest members located in northwest Oregon and southwest Washington, United States. Individuals who completed the online survey and experienced AGE were included in the analysis. Univariate and multivariable logistic regressions were performed to identify predictors of healthcare-seeking behavior.ResultsOf the 3,894 survey respondents, 395 experienced an AGE episode and were eligible for analysis, of whom, 82 (21%) sought care for their AGE episode. In the final multivariable model, individuals with a concurrent fever (odds ratio [OR]: 4.76, 95% confidence interval [95% CI]: 2.48-9.13), increased diarrhea duration (≥6 days vs 1-4 days, OR: 4.22, 95% CI: 1.78-10.03), or increased vomiting duration (≥3 days vs 1 days, OR: 2.97, 95% CI: 1.22-7.26), were significantly more likely to seek healthcare. In the adjusted model, no sociodemographic or chronic disease variables were associated with healthcare-seeking behavior.ConclusionThese findings suggest that individuals with a short duration of AGE and those without concurrent fever are underrepresented in healthcare facility-based surveillance systems.

Background & aimsBody composition (BC) changes with age and is associated with morbidity and mortality. A physically active lifestyle influences BC and represents an important predictor of successful aging. To emphasize this, the World Health Organization established activity recommendations for all age groups. We describe BC during adulthood using a cross-sectional sample from a German community and investigate the associations between physical activity (PA), physical fitness (PF), and BC.MethodsData from 329 men and women aged 35 to 86 years were analyzed. PA was measured by questionnaire and classified into sport activity and habitual activity. PF was measured through physical performance tests and BC by bioelectrical impedance analysis. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated to represent height-adjusted BC. Associations between PA, PF, and BC were analyzed using linear regression models.ResultsFor both sexes, strength was positively associated with FFMI (♂: ß = 0.313; ♀: ß = 0.213) and phase angle (♂: ß = 0.357; ♀: ß = 0.409). For FMI, a significant negative association with strength was found only in women (ß = -0.189). Cardiorespiratory fitness showed a negative association with FMI (ß = -0.312) and FFMI (ß = -0.201) for men, while in women a positive association was found for FFMI (ß = 0.186). For coordination, a significant association with FMI was observed only in women (ß = -0.190). Regarding PA only one significant relationship between sport activity and FMI among women (ß = -0.170) was found.ConclusionsIn our sample, PF was closer related to BC than PA. Strength and cardiorespiratory fitness were the strongest predictors for BC. This supports the World Health Organization's activity recommendations to include both resistance and endurance training in the weekly sports program to maintain a healthy BC.

We conducted an investigation to explore how neurotypical (NT) listeners perceive the emotional tone of voice in sentences spoken by individuals with high-functioning autism spectrum disorders (ASD) and NT speakers. The investigation included both male and female speakers from both groups. In Study 1, NT listeners were asked to identify the emotional prosody (anger, fear, happiness, surprise or neutral) conveyed by the speakers. Results revealed that emotional expressions produced by male ASD speakers were generally less accurately recognized compared to male NT speakers. In contrast, emotions expressed by female ASD speakers were more accurately categorized compared to female NT speakers, except when expressing fear. This suggests that female ASD speakers may not express emotional prosody in the same way as their male counterparts. In Study 2, a subset of produced materials was rated for valence, voice modulation, and voice control to supplement Study 1 results: Female ASD speakers sounded less negative when expressing fear compared to female NT speakers. Male ASD speakers were perceived as less positive than NT speakers when expressing happiness. Voice modulation also differed between groups, showing a tendency for ASD speakers to follow different display rules for both positive emotions (happiness and surprise) tested. Finally, male ASD speakers were rated to use voice cues less appropriately compared to NT male speakers, an effect less pronounced for female ASD speakers. Together, the results imply that difficulties in social interactions among individuals with high-functioning ASD could be due to non-prototypical voice use of male ASD speakers and emphasize that female individuals do not show the same effects.

Large animal models are frequently used to investigate new medical approaches. In most cases, animals are kept under general anesthesia and mandatory mechanical ventilation during the experiments. However, in some situations assisted spontaneous breathing is essential, e.g. when simulating conditions in a modern intensive care unit. Therefore, we established an anesthesia regime with dexmedetomidine and midazolam/ketamine in porcine models of assisted spontaneous breathing. The total intravenous anesthesia was used in lung healthy pigs, in pigs with oleic acid induced acute respiratory distress syndrome and in pigs with methacholine induced bronchopulmonary obstruction. We were able to maintain stable conditions of assisted spontaneous breathing without impairment of hemodynamic, respiratory or blood gas variables in lung healthy pigs and pigs with induced acute respiratory distress syndrome for a period of five hours and in pigs with induced bronchopulmonary obstruction for three hours. Total intravenous anesthesia containing dexmedetomidine enables stable conditions of assisted spontaneous breathing in healthy pigs, in pigs with induced acute respiratory distress syndrome and in pigs induced bronchopulmonary obstruction as models of intensive care unit conditions.

Background Liver metastases severely reduce the long term survival of colorectal cancer patients. Long non-coding RNAs (lncRNAs) CCAT1 and CCAT2 have previously been found to be associated with impaired patient outcomes in primary colorectal cancer. We aimed to elucidate the role of CCAT1 and CCAT2 in colorectal liver metastases. Methods Total RNA was isolated from 97 human tissue samples of colorectal liver metastases and adjacent normal liver tissue. Gene expression analysis was performed by RT-qPCR and Multiplex ELISA and correlated with patient characteristics and survival. Gene expression, cancer cell migration, invasion, and proliferation were studied after siRNA-mediated knockdown of CCAT1, CCAT2, and MYC in metastatic colorectal cancer cell lines Colo205 and HROC277Met2. Results Elevated expression levels of lncRNAs CCAT1 and CCAT2, and their common target MYC in colorectal liver metastases were associated with prolonged progression-free survival after liver resection. High expression of CCAT1 was likewise associated with prolonged overall survival. Knockdown of CCAT1, CCAT2, and MYC resulted in increased migratory and invasive potential in metastatic colorectal cancer cell lines. Gene expression analysis revealed alterations in constituents of Wnt signaling following knockdown. Conclusion Our findings demonstrate tumor-suppressive functions of lncRNAs CCAT1 and CCAT2 in colorectal liver metastases. They suppress Wnt signaling directly and indirectly through target gene MYC and might prevent further metastatic spread from colorectal liver metastases.

Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.

FAM3C/ILEI is an important factor in epithelial-to-mesenchymal transition (EMT) induction, tumor progression and metastasis. Overexpressed in many cancers, elevated ILEI levels and secretion correlate with poor patient survival. Although ILEI's causative role in invasive tumor growth and metastasis has been demonstrated in several cellular tumor models, there are no available transgenic mice to study these effects in the context of a complex organism. Here, we describe the generation and initial characterization of a Tet-ON inducible Fam3c/ILEI transgenic mouse strain. We find that ubiquitous induction of ILEI overexpression (R26-ILEIind) at weaning age leads to a shortened lifespan, reduced body weight and microcytic hypochromic anemia. The anemia was reversible at a young age within a week upon withdrawal of ILEI induction. Vav1-driven overexpression of the ILEIind transgene in all hematopoietic cells (Vav-ILEIind) did not render mice anemic or lower overall fitness, demonstrating that no intrinsic mechanisms of erythroid development were dysregulated by ILEI and that hematopoietic ILEI hyperfunction did not contribute to death. Reduced serum iron levels of R26-ILEIind mice were indicative for a malfunction in iron uptake or homeostasis. Accordingly, the liver, the main organ of iron metabolism, was severely affected in moribund ILEI overexpressing mice: increased alanine transaminase and aspartate aminotransferase levels indicated liver dysfunction, the liver was reduced in size, showed increased apoptosis, reduced cellular iron content, and had a fibrotic phenotype. These data indicate that high ILEI expression in the liver might reduce hepatoprotection and induce liver fibrosis, which leads to liver dysfunction, disturbed iron metabolism and eventually to death. Overall, we show here that the novel Tet-ON inducible Fam3c/ILEI transgenic mouse strain allows tissue specific timely controlled overexpression of ILEI and thus, will serve as a versatile tool to model the effect of elevated ILEI expression in diverse tissue entities and disease conditions, including cancer.

ObjectiveTo evaluate two user-operated audiometry methods, the AMTASTM PC-based audiometry and a low-cost smartphone audiometry research application (R-App).DesignA repeated-measures within-subject study design was used to compare both user-operated methods to traditional manual audiometry and to evaluate test-retest reliability of each method.Study sample58 subjects were recruited in the study of which 83 ears had normal hearing thresholds and 33 ears had hearing loss (pure-tone average > 25 dB HL). Average age of participants was 44.8 years, with an age range of 11-85.ResultsStandard deviation of absolute differences ranged between 3.9-6.9 dB on AMTASTM and 4.5-6.8 dB on the R-App. The highest variability was found at the 8000 Hz frequency (R-App and AMTASTM test) and 3000 Hz frequency (AMTASTM retest). Evaluation of test-retest reliability of AMTASTM and R-App showed SD of absolute differences ranging between 3.5-5.8 dB and 3.1-5.0 dB, respectively. The mean threshold difference between test and retest was within ±1.5 dB on AMTASTM and ±1 dB on the R-App.ConclusionAccuracy of AMTASTM and the R-App was within acceptable limits for audiometry and comparable to traditional manual audiometry on all tested frequencies (250-8000 Hz). Evaluation of test-retest reliability showed acceptable variation on both AMTASTM and R-App. Both user-operated methods could be reliably performed in a quiet non-soundproofed environment.