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Cognitive motor dissociation (CMD) can improve the accuracy to predict recovery of behaviorally unresponsive patients with acute brain injury, but acquisition and analysis of task-based electroencephalography (EEG) are technically challenging. N2 sleep patterns, such as sleep spindles on EEG, have been associated with good outcomes, rely on similar thalamocortical networks as consciousness and could provide less technically challenging complementary outcome predictors. In this prospective observational cohort study of 226 acutely brain injured patients, well-formed sleep spindles (WFSS) were more likely present in those with CMD than in those without CMD, often preceding the detection of CMD. WFSS were associated with a shorter time to recovery of consciousness, and both CMD and WFSS independently predicted recovery of independence, controlling for age, admission neurological status and injury type. WFSS are seen in approximately every third behaviorally unresponsive patient after acute brain injury, frequently precede detection of CMD and are a promising complementary predictor for recovery of consciousness and functional independence., Competing Interests: Competing interests: The authors declare no competing interests. J. Claassen is a minority shareholder at iCE Neurosystems, but this amounts to less than $10,000 and less than 5% equity in the company. No technology from iCE Neurosystems was used for any of the study procedures, data acquisition or analysis presented here. None of the patients included in this study were managed using any technology from iCE Neurosystems., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Many people are interested in addressing visible signs of aging with non-invasive cosmetic treatments. Development of effective topical products will provide options to delay or support cosmetic procedures., Aims: This study assessed and compared the efficacy and tolerance of a topical product used over the course of 16 weeks to a single ablative laser treatment on women with moderate global photodamage on the face., Methods: Subjects in Cell 1 (Laser Cell) were treated over the entire face with a fractional CO 2 laser system. Subjects in Cell 2 (Topical Serum Cell) were treated with a topical serum containing hydroxypinacolone retinoate and peptides over the entire face, twice per day for 16 weeks. The study was composed of 71 women, with 29 in the Laser Cell (mean age 56.2) and 42 in the Topical Serum Cell (mean age 55.0), between 40 and 65 years old. Expert grading was used to determine efficacy parameters., Results: Participants in the Topical Serum Cell achieved more significant improvement (p < 0.05) in Marionette lines, fine lines (global face), wrinkles (global face), wrinkles (crow's feet), nasolabial folds, texture, smoothness (tactile), global hyperpigmentation, lift, and photodamage compared to participants in the Laser Cell. Participants in the Topical Serum Cell achieved parity in the look of fine lines (crow's feet), forehead lines, glabella, firmness/bounce (tactile), skin tone evenness, radiance., Conclusions: While no statistically significant differences in tolerability were observed, treatment with the topical cosmetic product achieved parity or statistically better improvement in parameters compared to laser treatment at 16 weeks., (© 2024 Estee Lauder Companies. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Nonspecific reactive chemicals often interfere with the interpretation of high-throughput assay results because of their promiscuity and/or cytotoxicity. Using a high-throughput assay to identify such compounds is necessary to efficiently rule out potential assay artifacts. The MSTI, ( E )-2-(4-mercaptostyryl)-1,3,3-trimethyl-3 H -indol-1-ium, assay uses a thiol-containing fluorescent probe to screen for electrophile reactivity and could potentially be used to determine nonspecific reactive compounds. The Tox21 10K compound library was previously screened against a panel of ∼80 cell-based and biochemical assays, including the biochemical MSTI assay. In this study, we compared the MSTI assay activity of the Tox21 10K compounds with their promiscuity and cytotoxicity as reflected by their activities across the Tox21 assay panel to determine: (1) if this assay is predictive of a compound's promiscuity and cytotoxicity and (2) what chemical features create inconsistent results between the MSTI assay activity and promiscuity/cytotoxicity (false negatives and false positives). We found that the MSTI assay can predict a chemical's promiscuity/cytotoxicity with a 0.55 sensitivity and 0.97 specificity. Out of 3,407 unique compounds evaluated, we identified 92 false positive and 227 false negative results. Several structural features such as carboxamides and alkyl halides were found to be apparent in 53% ( p = 2.4 × 10 -07 ) and 19% ( p = 4.3 × 10 -06 ) of the false positives and negatives, respectively. The results of this analysis will help identify the potential challenges of this high-throughput assay and allow researchers to identify if a compound will be cytotoxic or promiscuous in an efficient manner.

Background: Brain activation to motor commands is seen in 15% of clinically unresponsive patients with acute brain injury. This state called cognitive motor dissociation (CMD) is detectable by electroencephalogram (EEG) or functional magnetic resonance imaging, predicts long-term recovery, and is recommended by recent guidelines to support prognostication. However, false negative CMD results are a particular concern, and occult aphasia in clinically unresponsive patients may be a major factor. This study aimed to quantify the impact of aphasia on CMD testing., Methods: We prospectively studied 61 intensive care unit patients admitted with acute primary intracerebral hemorrhage (ICH) who had behavioral evidence of command following or were able to mimic motor commands. All patients underwent an EEG-based motor command paradigm used to detect CMD and comprehensive aphasia assessments. Logistic regression was used to identify predictors of brain activation, including aphasia types and associations with recovery of independence (Glasgow Outcome Scale-Extended score ≥ 4)., Results: Of 61 patients, 50 completed aphasia and the EEG-based motor command paradigm. A total of 72% (n = 36) were diagnosed with aphasia. Patients with impaired comprehension (i.e., receptive or global aphasia) were less likely to show brain activation than those with intact comprehension (odds ratio [OR] 0.23 [95% confidence interval 0.05-0.89], p = 0.04). Brain activation was independently associated with Glasgow Outcome Scale-Extended ≥ 4 by 12 months (OR 2.4 [95% confidence interval 1.2-5.0], p = 0.01) accounting for the Functional Outcome in Patients with Primary ICH score (OR1.3 [95% confidence interval 1.0-1.8], p = 0.01)., Conclusions: Brain activation to motor commands is four times less likely for patients with primary ICH with impaired comprehension. False negative results due to occult receptive aphasia need to be considered when interpreting CMD testing. Early detection of brain activation may help predict long-term recovery in conscious patients with ICH., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

The current small study utilised prospective data collection of patterns of prenatal alcohol and tobacco exposure (PAE and PTE) to examine associations with structural brain outcomes in 6-year-olds and served as a pilot to determine the value of prospective data describing community-level patterns of PAE and PTE in a non-clinical sample of children. Participants from the Safe Passage Study in pregnancy were approached when their child was ∼6 years old and completed structural brain magnetic resonance imaging to examine with archived PAE and PTE data ( n = 51 children-mother dyads). Linear regression was used to conduct whole-brain structural analyses, with false-discovery rate (FDR) correction, to examine: (a) main effects of PAE, PTE and their interaction; and (b) predictive potential of data that reflect patterns of PAE and PTE (e.g. quantity, frequency and timing (QFT)). Associations between PAE, PTE and their interaction with brain structural measures demonstrated unique profiles of cortical and subcortical alterations that were distinct between PAE only, PTE only and their interactive effects. Analyses examining associations between patterns of PAE and PTE (e.g. QFT) were able to significantly detect brain alterations (that survived FDR correction) in this small non-clinical sample of children. These findings support the hypothesis that considering QFT and co-exposures is important for identifying brain alterations following PAE and/or PTE in a small group of young children. Current results demonstrate that teratogenic outcomes on brain structure differ as a function PAE, PTE or their co-exposures, as well as the pattern (QFT) or exposure.

In January 2023, an active surveillance initiative was undertaken in the South Shetland Islands, Antarctica, with the specific objective of ascertaining evidence for the presence of avian influenza, and specifically the highly pathogenic avian influenza virus subtype H5N1 (HPAIV H5N1). The investigation encompassed diverse locations, including Hanna Point (Livingston Island), Lions Rump (King George Island), and Base Escudero (King George Island), with targeted observations on marine mammals (southern elephant seals), flying birds (the kelp gull, snowy sheathbill and brown skua), and penguins (the chinstrap penguin and gentoo penguin). The study encompassed the examination of these sites for signs of mass mortality events possibly attributable to HPAIV H5N1, as well as sampling for influenza detection by means of real-time RT-PCR. Two hundred and seven (207) samples were collected, including 73 fecal samples obtained from the environment from marine mammals (predominantly feces of southern elephant seals), and 77 cloacal samples from penguins of the genus Pygoscelis (predominantly from the gentoo penguin). No evidence of mass mortality attributable to HPAIV H5N1 was observed, and all the collected samples tested negative for the presence of the virus, strongly suggesting the absence of the virus in the Antarctic territory during the specified period. This empirical evidence holds significant implications for both the ecological integrity of the region and the potential zoonotic threats, underscoring the importance of continued surveillance and monitoring in the Antarctic ecosystem.

Animals are faced with a variety of dangers or threats, which are increasing in frequency with ongoing environmental change. While our understanding of fearfulness of such dangers is growing in the context of predation and parasitism risk, the extent to which non-trophic, interspecific dangers elicit fear in animals remains less appreciated. We provide an experimental test for fear responses of savannah ungulates to a dominant and aggressive megaherbivore, the African bush elephant ( Loxodonta africana ), and contrast responses to an apex predator known to elicit fear in this system. Using an automated behavioural response system, we contrast vigilance and run responses of ungulates to elephant, leopard ( Panthera pardus ), and control (red-chested cuckoo Cuculus solitarius ) vocalizations. Overall, we find that ungulates responded to elephant calls, both in terms of an increase in run and vigilance responses relative to controls. The magnitude of most behavioural responses (four of six considered) to elephant vocalizations were not significantly different than responses to leopards. These results suggest that megaherbivores can elicit strong non-trophic fear responses by ungulates and call to broaden frameworks on fear to consider dominant species, such as megaherbivores, as key modifiers of fear-induced interactions.

Background & Aims: Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and the risk of developing IBD using the Prospective Urban Rural Epidemiology cohort., Methods: This was a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed up prospectively at least every 3 years. The main outcome was the development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) were evaluated. Results are presented as adjusted odds ratios (aORs) with 95% CIs., Results: During a median follow-up period of 11.0 years (interquartile range, 9.2-12.2 y), there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; 95% CI, 1.67-4.73; P = .0001) and hormonal medication use (aOR, 4.43; 95% CI, 1.78-11.01; P = .001). Among females, previous or current oral contraceptive use also was associated with IBD development (aOR, 2.17; 95% CI, 1.70-2.77; P < .001). Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80; 95% CI, 1.23-2.64; P = .002), which was driven by long-term use (aOR, 5.58; 95% CI, 2.26-13.80; P < .001). All significant results were consistent in direction for CD and UC with low heterogeneity., Conclusions: Antibiotics, hormonal medications, oral contraceptives, and long-term nonsteroidal anti-inflammatory drug use were associated with increased odds of incident IBD after adjustment for covariates., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The placenta is a fetal organ that performs critical functions to maintain pregnancy and support fetal development, including metabolism and transport of xenobiotics and steroids between the maternal-fetal unit. In vitro placenta models are used to study xenobiotic and steroid disposition, but how well these models recapitulate the human placenta is not well understood. We first characterized the abundance of proteins involved in xenobiotic and steroid disposition in human placental tissue. In pooled human placenta, the following xenobiotic and steroid disposition proteins were detected (highest to lowest), 1) enzymes: glutathione S-transferase P, carbonyl reductase 1, aldo-keto reductase 1B1, hydroxysteroid dehydrogenases (HSD3B1 and HSD11B1), aromatase, epoxide hydrolase 1 (EPHX1) and steryl-sulfatase, and 2) transporters: monocarboxylate transporters (MCT1 and 4), organic anion transporting polypeptide 2B1, organic anion transporter 4, and breast cancer resistance protein (BCRP). Then, the tissue proteomics data were compared with four placental cell lines (BeWo, JEG-3, JAR, and HTR-8/SVneo). The differential global proteomics analysis revealed that the tissue and cell lines shared 1420 cytosolic and 1186 membrane proteins. Although extravillous trophoblast and cytotrophoblast marker proteins were detected in all cell lines, only BeWo and JEG-3 cells expressed the syncytiotrophoblast marker, chorionic somatomammotropin hormone 1. BeWo and JEG-3 cells expressed most target proteins including aromatase, HSDs, EPHX1, MCT1, and BCRP. JEG-3 cells treated with commonly detected phthalates in human biofluids showed dysregulation of steroid pathways. The data presented here show that BeWo and JEG-3 cells are closer to the placental tissue for studying xenobiotic and steroid disposition. SIGNIFICANCE STATEMENT: This is the first study to compare proteomics data of human placental tissue and cell lines (BeWo, JAR, JEG-3, and HTR-8/SVneo). The placental cell line and tissue proteomes are vastly different, but BeWo and JEG-3 cells showed greater resemblance to the tissue in the expression of xenobiotic and steroid disposition proteins. These data will assist researchers to select an optimum cell model for mechanistic investigations on xenobiotic and steroid disposition in the placenta., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

To understand how two dominant African savanna trees will continue to respond to climate changes, we examined their regeneration niche and adult tree distributions. Specifically, we wanted to (1) determine if distributional patterns were shifting, (2) predict future distributions under different climate change scenarios and (3) evaluate the realism of predicted future distributions. We randomly placed 40 grids into 6 strata across a climate gradient in the kingdom of Eswatini. Within these grids, we sampled adult and seedling marula (Scelerocarya birrea) and knobthorn (Senegalia nigrecens) trees and used the data to model their abundance. Next, we quantified shifts in distributional patterns (e.g., expansion or contraction) by measuring the current and projected areas of overlap between seedling and adult trees. Finally, we predicted future distributions of abundance based on predicted climate conditions. We found knobthorn seedlings within a small portion of the adult distribution, suggesting it was unlikely to track climate changes. Alternatively, finding marula seedlings on and beyond one edge of the adult distribution, suggested its range would shift toward cooler climates. Predicted future distributions suggest suitable climate for both species would transition out of savannas and into grasslands. Future projections (2041-2070) appeared consistent with observed distributions of marula, but knobthorn predictions were unrealistic given the lack of evidence for regeneration outside of its current range. The idiosyncratic responses of these species to climate change are likely to decouple these keystone structures in the coming decades and are likely to have considerable cascading effects including the potential rearrangement of faunal communities., (© 2023. The Author(s).)

Importance: Rights and access for transgender individuals, including the participation of transgender athletes in sports, have long been debated. These discussions often center around fairness and mental health impacts on youths associated with identity-based inclusion in sports., Objective: To assess the experiences and perspectives of adolescents and young adults on the inclusion of transgender individuals in competitive sports., Design, Setting, and Participants: In this qualitative study, 5 open-ended survey questions were sent to the MyVoice cohort from December 10 to 17, 2021. MyVoice is a nationwide text-message polling platform of US youths aged 14 to 24 years. All coding and subsequent analysis was completed between January 10 and December 11, 2022., Main Outcomes and Measures: Qualitative perspectives of youths regarding transgender athlete participation in sports as measured by survey responses. Responses were reviewed using an inductive approach to qualitative thematic analysis to develop a codebook. The codes were independently applied to all responses by 2 investigators; discrepancies were resolved with discussion. Summary statistics were calculated for demographic characteristics and code frequencies, and χ2 tests (α = .05, 2-tailed) were used to evaluate differences in opinion based on gender identity and participation in competitive sports., Results: A total of 905 of 1199 youths (75%) responded to the survey. Respondents had a mean (SD) age of 20 (2) years; 482 (53%) identified as male, 29 (3%) identified as transgender, and 306 (34%) reported having participated in high school and/or collegiate athletics. Three themes emerged: (1) youths differed regarding the inclusion of transgender athletes based on gender identity vs sex assigned at birth, (2) many youths did not have personal experience related to the inclusion of transgender athletes, and (3) youths were uncertain about the impacts of gender identity-based participation on cisgender individuals but perceived positive impacts for transgender individuals. Nearly half of respondents (327 of 691 [47%]) thought that transgender athletes should participate based on their gender identity or personal preference, whereas 240 (35%) favored participation based on sex assigned at birth or in a transgender-only category. Respondents mentioned concern about the fairness of identity-based participation, specifically for cisgender women, but many (410 of 697 [59%]) also reported that it would be affirming for transgender athletes to participate based on gender identity., Conclusions and Relevance: The youths in our study differed in their opinions regarding sports participation of transgender youths, but many felt that inclusive policies would affirm and support the mental health of transgender individuals. Negative impacts on fairness were noted by some respondents. These findings suggest that nuanced policies are needed to address the participation of transgender athletes in competitive sports and should consider the impacts on and perspectives of youths most affected.

Introduction: Archived human placental tissue specimens are vital for studying placenta pathophysiology and toxicology. Proteomics analysis of placental tissue provides mechanistic and translational information, but the highly perfused and heterogenous nature of the placenta creates confounding technical variability. In this study, we developed an optimized proteomics-based approach to address the technical variability of proteomics data by normalizing blood contamination and cellular heterogeneity of archived placenta samples., Methods: Placenta samples (n = 99) were homogenized, digested using trypsin, and analyzed by liquid chromatography mass-spectrometry. Label-free quantification (LFQ) intensities of the proteins were analyzed for their correlation with blood (albumin) and placenta (aromatase) markers. Proteins that positively correlated with albumin and negatively correlated with aromatase or vice versa were considered blood and placental proteins, respectively. Next, the cellular heterogeneity of individual placenta samples was evaluated by quantifying specific cellular markers of cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, fibroblasts, Hofbauer cells, and decidual cells., Results: We found that placental proteins were contaminated by 41 to 85% blood proteins. Analysis of cellular markers confirmed syncytiotrophoblasts as the major cell type in placenta (i.e., 41 ± 9% of all cell types). Two samples showed distinct cell compositions with higher levels of the extravillous trophoblasts and decidual cells., Discussion: In summary, the optimized proteomics-based approach to estimate blood contamination and cellular heterogeneity of placental tissues has the potential to address technical variability in placenta proteomics analysis, which can be extended to other highly perfused and heterogenous tissues., Competing Interests: Declaration of competing interest The authors have stated explicitly that no conflicts of interests exist in connection to this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Neuroimaging studies have emphasized the impact of prenatal alcohol exposure (PAE) on brain development, traditionally in heavily exposed participants. However, less is known about how naturally occurring community patterns of PAE (including light to moderate exposure) affect brain development, particularly in consideration of commonly occurring concurrent impacts of prenatal tobacco exposure (PTE)., Methods: Three hundred thirty-two children (ages 8 to 12) living in South Africa's Cape Flats townships underwent structural magnetic resonance imaging. During pregnancy, their mothers reported alcohol and tobacco use, which was used to evaluate PAE and PTE effects on their children's brain structure. Analyses involved the main effects of PAE and PTE (and their interaction) and the effects of PAE and PTE quantity on cortical thickness, surface area, and volume., Results: After false-discovery rate (FDR) correction, PAE was associated with thinner left parahippocampal cortices, while PTE was associated with smaller cortical surface area in the bilateral pericalcarine, left lateral orbitofrontal, right posterior cingulate, right rostral anterior cingulate, left caudal middle frontal, and right caudal anterior cingulate gyri. There were no PAE × PTE interactions nor any associations of PAE and PTE exposure on volumetrics that survived FDR correction., Conclusion: PAE was associated with reduction in the structure of the medial temporal lobe, a brain region critical for learning and memory. PTE had stronger and broader associations, including with regions associated with executive function, reward processing, and emotional regulation, potentially reflecting continued postnatal exposure to tobacco (i.e., second-hand smoke exposure). These differential effects are discussed with respect to reduced PAE quantity in our exposed group versus prior studies within this geographical location, the deep poverty in which participants live, and the consequences of apartheid and racially and economically driven payment practices that contributed to heavy drinking in the region. Longer-term follow-up is needed to determine potential environmental and other moderators of the brain findings here and assess the extent to which they endure over time., (© 2022 Research Society on Alcoholism.)

The placenta is a vital fetal organ that plays an important role in maintaining fetal sex hormone homeostasis. Xenobiotics can alter placental sex-steroidogenic enzymes and transporters, including enzymes such as aromatase (CYP19A1) and the hydroxysteroid dehydrogenases (HSDs) but studying how compounds disrupt in vivo placental metabolism is complex. Utilizing high-throughput in vitro models is critical to predict the disruption of placental sex-steroidogenic enzymes and transporters, particularly by drug candidates in the early stages of drug discovery. JAR and JEG-3 cells are the most common, simple, and cost-effective placental cell models that are capable of high-throughput screening, but how well they express the sex-steroidogenic enzymes and transporters is not well known. Here, we compared the proteomes of JAR and JEG-3 cells in the presence and absence of physiologically relevant concentrations of dehydroepiandrosterone (DHEA, 8 µM) and testosterone (15 nM) to aid the characterization of sex-steroidogenic enzymes and transporters in these cell models. Global proteomics analysis detected 2931 and 3449 proteins in JAR cells and JEG-3 cells, respectively. However, dramatic differences in sex-steroidogenic enzymes and transporters were observed between these cells. In particular, the basal expression of steroid sulfatase (STS), HSD17B1, and HSD17B7 were unique to JEG-3 cells. JEG-3 cells also showed significantly higher protein levels of aldo-keto reductase (AKR) 1A1 and AKR1B1, while JAR cells showed significantly higher levels of HSD17B4 and HSDB12. Aldehyde dehydrogenase (ALDH) 3A2 and HSD17B11 enzymes as well as the transporters sterol O-acyltransferase (SOAT) 1 and ATP binding cassette subfamily G2 (ABCG2) were comparable between the cell lines, whereas sulfotransferases (SULTs) were uniquely present within JAR cells. Androgen treatments significantly lowered HSD17B11, HSD17B4, HSD17B12, and ALDH3A2 levels in JAR cells. DHEA treatment significantly raised the level of HSD17B1 by 51 % in JEG-3 cells, whereas CYP19A1 was increased to significant levels in both JAR and JEG-3 cells after androgen treatments. The proteomics data were supported by a complementary targeted metabolomics analysis of culture media in the DHEA (8 µM) and testosterone (15 nM) treated groups. This study has indicated that untreated JEG-3 cells express more sex-steroidogenic enzymes and transporters. Nevertheless, JEG-3 and JAR cells are unique and their respective proteomics data can be used to select the best model depending on the hypothesis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

The global increase in frequency and intensity of disasters and emergency situations has a major disruptive effect on societies that is especially visible in Africa, where conflict, poverty, diseases and social unrest are some of the biggest factors contributing to societal vulnerability. Developing countries such as South Africa are vulnerable to the impact of disaster situations that strain the society's ability to deal with these emergencies. First responders play an important function responding to disasters but are exposed to work-related stressors that could impact their performance. Several international studies make a link between wellness, performance and resilience and the use of resilience resources in the development and enhancement of wellness, indicating that resilience resources such as a resilient mindset are an indicator of good mental health and performance amongst first responders, despite being exposed to traumatic situations. However, very little research has been carried out on first responders in South Africa, making this study an important stepping stone towards gaining an understanding of the relationship between mindset as a resilience resource and perceived wellness of first responders in a South African context. Data were collected from 52 first responders using a structured questionnaire. The results indicate a statistically significant relationship between mindset and perceived wellness, with all the wellness factors indicating that the mindset of first responders plays a crucial role in their resilience and perception of wellness, necessitating additional research in this specialised field of disaster response., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2022. The Authors.)

Introduction: Increased genomics knowledge and access are advancing precision medicine and care delivery. With the translation of precision medicine across health care, genetics and genomics will play a greater role in primary care services. Health disparities and inadequate representation of racial and ethnically diverse groups threaten equitable access for those historically underserved. Health provider awareness, knowledge, and perceived importance are important determinants of the utilization of genomic applications., Methods: We evaluated the readiness of primary care providers at a Federally Qualified Health Center, the Community Health Center, Inc. (CHCI) for delivering genetic and genomic testing to underserved populations. Online survey questions focused on providers' education and training in basic and clinical genetics, familiarity with current genetic tests, and needs for incorporating genetics and genomics into their current practice., Results: Fifty of 77 (65%) primary care providers responded to the survey. Less than half received any training in basic or clinical genetics (40%), were familiar with specific genetic tests (36%), or felt confident with collecting family health history (44%), and 70% believed patients would benefit from genetic testing., Conclusion: Despite knowledge gaps, respondents recognized the value and need to bring these services to their patients, though would like more education on applying genetics and genomics into their practice, and more training about discussing risk factors associated with race or ethnicity. We provide further evidence of the need for educational resources and standardized guidelines for providers caring for underserved populations to optimize appropriate use and referral of genetic and genomic services and to reduce disparities in care., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population. Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes., Objective: We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development., Methods: The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography-tandem mass spectrometry. Placental transcriptomic data were obtained using paired-end RNA sequencing. Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables. Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) p < 0.05 . Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted p < 0.2 ., Results: We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs. Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites. Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively. Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations., Discussion: To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort. We identified numerous genes and lncRNAs associated with prenatal phthalate exposure. These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure. https://doi.org/10.1289/EHP8973.

Mitochondria and releasable endoplasmic reticulum (ER) calcium modulate neuronal calcium signaling, and both change in Alzheimer's disease (AD). The releasable calcium stores in the ER are exaggerated in fibroblasts from AD patients and in multiple models of AD. The activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key mitochondrial enzyme complex, is diminished in brains from AD patients, and can be plausibly linked to plaques and tangles. Our previous studies in cell lines and mouse neurons demonstrate that reductions in KGDHC increase the ER releasable calcium stores. The goal of these studies was to test whether the relationship was true in human iPSC-derived neurons. Inhibition of KGDHC for one or 24 hr increased the ER releasable calcium store in human neurons by 69% and 144%, respectively. The effect was mitochondrial enzyme specific because inhibiting the pyruvate dehydrogenase complex, another key mitochondrial enzyme complex, diminished the ER releasable calcium stores. The link of KGDHC to ER releasable calcium stores was cell type specific as the interaction was not present in iPSC or neural stem cells. Thus, these studies in human neurons verify a link between KGDHC and releasable ER calcium stores, and support the use of human neurons to examine mechanisms and potential therapies for AD., (© 2020 International Society for Neurochemistry.)

The COVID-19 outbreak has sown clinical and administrative chaos at academic health centers throughout the country. As COVID-19-related burdens on the health care system and medical schools piled up, questions from medical students far outweighed the capacity of medical school administrators to respond in an adequate or timely manner, leaving students feeling confused and without clear guidance. In this article, incoming and outgoing executive leaders of the University of Michigan Medical School Student Council and medical school deans outline the specific ways they were able to bridge the gap between medical students and administrators in a time of crisis. To illustrate the value of student government during uncertain times, the authors identify the most pressing problems faced by students at each phase of the curriculum-preclerkship, clerkship, and postclerkship-and explain how Student Council leadership partnered with administrators to find creative solutions to these problems and provide guidance to learners. They end by reflecting on the role of student government more broadly, identifying 3 guiding principles of student leadership and how these principles enable effective student representation., (Copyright © 2020 by the Association of American Medical Colleges.)

α-Ketoglutaramic acid (KGM, α-ketoglutaramate), also known as 2-oxoglutaramic acid (OGM, 2-oxoglutaramate), is a substrate of ω-amidase, also known as Nitrilase 2 (NIT2), and is essential for studying the canonical role of ω-amidase, as well as its role in multiple diseases. Until now, KGM used for biological studies has been prepared most often by the enzymatic oxidation of l-glutamine using snake venom l-amino acid oxidase, which provides KGM as an aqueous solution, containing by-products including 5-oxoproline and α-ketoglutarate. The enzymatic method for KGM preparation, therefore, cannot provide pure product or an accurate percent yield evaluation. Here, we report a synthetic method for the preparation of this important substrate, KGM, in 3 steps, from l-2-hydroxyglutaramic acid, in pure form, in 53% overall yield., (Published by Elsevier Inc.)

Background: Kerosene, which was until recently considered a relatively clean household fuel, is still widely used in low- and middle-income countries for cooking and lighting. However, there is little data on its health effects. We examined cardiorespiratory effects and mortality in households using kerosene as their primary cooking fuel within the Prospective Urban Rural Epidemiology (PURE) study., Methods: We analyzed baseline and follow-up data on 31,490 individuals from 154 communities in China, India, South Africa, and Tanzania where there was at least 10% kerosene use for cooking at baseline. Baseline comorbidities and health outcomes during follow-up (median 9.4 years) were compared between households with kerosene versus clean (gas or electricity) or solid fuel (biomass and coal) use for cooking. Multi-level marginal regression models adjusted for individual, household, and community level covariates., Results: Higher rates of prevalent respiratory symptoms (e.g. 34% [95% CI:15-57%] more dyspnea with usual activity, 44% [95% CI: 21-72%] more chronic cough or sputum) and lower lung function (differences in FEV 1 : -46.3 ml (95% CI: -80.5; -12.1) and FVC: -54.7 ml (95% CI: -93.6; -15.8)) were observed at baseline for kerosene compared to clean fuel users. The odds of hypertension was slightly elevated but no associations were observed for blood pressure. Prospectively, kerosene was associated with elevated risks of all-cause (HR: 1.32 (95% CI: 1.14-1.53)) and cardiovascular (HR: 1.34 (95% CI: 1.00-1.80)) mortality, as well as major fatal and incident non-fatal cardiovascular (HR: 1.34 (95% CI: 1.08-1.66)) and respiratory (HR: 1.55 (95% CI: 0.98-2.43)) diseases, compared to clean fuel use. Further, compared to solid fuel users, those using kerosene had 20-47% higher risks for the above outcomes., Conclusions: Kerosene use for cooking was associated with higher rates of baseline respiratory morbidity and increased risk of mortality and cardiorespiratory outcomes during follow-up when compared to either clean or solid fuels. Replacing kerosene with cleaner-burning fuels for cooking is recommended., (Copyright © 2020 Elsevier Inc. All rights reserved.)

With any in vivo model, diet plays an important role, even in an organism as simple as the fruit fly - Drosophila melanogaster. Flies serve as good surrogates to study human diseases as approximately 77% of human disease genes are orthologous in the fly. Though breeding and caring for fruit flies is simple, the use of this organism in drug discovery is wide-ranging, especially in the administration of drugs to flies, via their food. We present a standard method for preparing fly food containing drugs for administration to Drosophila melanogaster, from a chemist's perspective., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study qualitatively examined perceptions of the Aerie Real campaign that utilized images that had not been digitally modified, as well as its capacity to contribute to positive body image. A sample of 35 college women, of mean age of 19.48 (range = 18-23 years) participated in individual interviews focused on their perceptions and reactions to the images included in the Aerie Real campaign. They also described the impact of the campaign on their brand perceptions and consumer intentions, as well as their attitudes towards social policy targeting the use of digital airbrushing. Most participants reacted to the images positively and perceived them as representing body diversity across several dimensions. In addition, the majority of participants found the images to be helpful for promoting positive body image and acceptance, through both appearance comparisons, and the modeling of body confidence. In addition, many participants expressed being more likely to purchase products from Aerie and support for the brand. Overwhelmingly, participants called for widespread portrayals of diverse bodies in media, although only partial support emerged for achieving this through policy. These findings support the usefulness of increasing body diversity in media and limiting thin-ideal images as means of promoting positive body image., (Copyright © 2019. Published by Elsevier Ltd.)

Aims: To investigate the association of estimated total daily sleep duration and daytime nap duration with deaths and major cardiovascular events., Methods and Results: We estimated the durations of total daily sleep and daytime naps based on the amount of time in bed and self-reported napping time and examined the associations between them and the composite outcome of deaths and major cardiovascular events in 116 632 participants from seven regions. After a median follow-up of 7.8 years, we recorded 4381 deaths and 4365 major cardiovascular events. It showed both shorter (≤6 h/day) and longer (>8 h/day) estimated total sleep durations were associated with an increased risk of the composite outcome when adjusted for age and sex. After adjustment for demographic characteristics, lifestyle behaviours and health status, a J-shaped association was observed. Compared with sleeping 6-8 h/day, those who slept ≤6 h/day had a non-significant trend for increased risk of the composite outcome [hazard ratio (HR), 1.09; 95% confidence interval, 0.99-1.20]. As estimated sleep duration increased, we also noticed a significant trend for a greater risk of the composite outcome [HR of 1.05 (0.99-1.12), 1.17 (1.09-1.25), and 1.41 (1.30-1.53) for 8-9 h/day, 9-10 h/day, and >10 h/day, Ptrend < 0.0001, respectively]. The results were similar for each of all-cause mortality and major cardiovascular events. Daytime nap duration was associated with an increased risk of the composite events in those with over 6 h of nocturnal sleep duration, but not in shorter nocturnal sleepers (≤6 h)., Conclusion: Estimated total sleep duration of 6-8 h per day is associated with the lowest risk of deaths and major cardiovascular events. Daytime napping is associated with increased risks of major cardiovascular events and deaths in those with >6 h of nighttime sleep but not in those sleeping ≤6 h/night., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

The peritoneal equilibration test (PET) is the most widespread method for assessing water and solute transport across the peritoneal membrane. This study compared three methods: traditional PET (t-PET), mini-PET, and modified PET (mod-PET). Non-diabetic adults (n=21) who had been on peritoneal dialysis (PD) for at least three months underwent t-PET (glucose 2.5%-4 h), mini-PET (glucose 3.86%-1 h), and mod-PET (glucose 3.86%-4 h) to determine dialysate-to-plasma concentration ratio (D/P) for creatinine and dialysate-to-baseline dialysate concentration ratio (D/D0) for glucose. Agreement between methods regarding D/P creatinine and D/D0 glucose was assessed using analysis of variance (ANOVA), Pearson's correlation coefficient, and Bland-Altman analysis. D/P creatinine differed between t-PET and mini-PET (P<0.001) and between mod-PET and mini-PET (P<0.01) but not between t-PET and mod-PET (P=0.746). The correlation of D/P creatinine with t-PET vs mod-PET was significant (r=0.387, P=0.009) but not that of t-PET vs mini-PET (r=0.088, P=0.241). Estimated bias was -0.029 (P=0.201) between t-PET and mod-PET, and 0.206 (P<0.001) between t-PET and mini-PET. D/D0 glucose differed between t-PET and mod-PET (P=0.003) and between mod-PET and mini-PET (P=0.002) but not between t-PET and mini-PET (P=0.885). The correlations of D/D0 glucose in t-PET vs mod-PET (r=-0.017, P=0.421) or t-PET vs mini-PET (r=0.152, P=0.609) were not significant. Estimated bias was 0.122 (P=0.026) between t-PET and mod-PET, and 0.122 (P=0.026) between t-PET and mini-PET. The significant correlation of D/P creatinine between t-PET and mod-PET suggested that the latter is a good alternative to t-PET. There was no such correlation between t-PET and mini-PET.

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

Background: Data are scarce on the availability and affordability of essential medicines for diabetes. Our aim was to examine the availability and affordability of metformin, sulfonylureas, and insulin across multiple regions of the world and explore the effect of these on medicine use., Methods: In the Prospective Urban Rural Epidemiology (PURE) study, participants aged 35-70 years (n=156 625) were recruited from 110 803 households, in 604 communities and 22 countries; availability (presence of any dose of medication in the pharmacy on the day of audit) and medicine cost data were collected from pharmacies with the Environmental Profile of a Community's Health audit tool. Our primary analysis was to describe the availability and affordability of metformin and insulin and also commonly used and prescribed combinations of two medicines for diabetes management (two oral drugs, metformin plus a sulphonylurea [either glibenclamide (also known as glyburide) or gliclazide] and one oral drug plus insulin [metformin plus insulin]). Medicines were defined as affordable if the cost of medicines was less than 20% of capacity-to-pay (the household income minus food expenditure). Our analyses included data collected in pharmacies and data from representative samples of households. Data on availability were ascertained during the pharmacy audit, as were data on cost of medications. These cost data were used to estimate the cost of a month's supply of essential medicines for diabetes. We estimated affordability of medicines using income data from household surveys., Findings: Metformin was available in 113 (100%) of 113 pharmacies from high-income countries, 112 (88·2%) of 127 pharmacies in upper-middle-income countries, 179 (86·1%) of 208 pharmacies in lower-middle-income countries, 44 (64·7%) of 68 pharmacies in low-income countries (excluding India), and 88 (100%) of 88 pharmacies in India. Insulin was available in 106 (93·8%) pharmacies in high-income countries, 51 (40·2%) pharmacies in upper-middle-income countries, 61 (29·3%) pharmacies in lower-middle-income countries, seven (10·3%) pharmacies in lower-income countries, and 67 (76·1%) of 88 pharmacies in India. We estimated 0·7% of households in high-income countries and 26·9% of households in low-income countries could not afford metformin and 2·8% of households in high-income countries and 63·0% of households in low-income countries could not afford insulin. Among the 13 569 (8·6% of PURE participants) that reported a diagnosis of diabetes, 1222 (74·0%) participants reported diabetes medicine use in high-income countries compared with 143 (29·6%) participants in low-income countries. In multilevel models, availability and affordability were significantly associated with use of diabetes medicines., Interpretation: Availability and affordability of essential diabetes medicines are poor in low-income and middle-income countries. Awareness of these global differences might importantly drive change in access for patients with diabetes., Funding: Full funding sources listed at the end of the paper (see Acknowledgments)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: WHO recommends that populations consume less than 2 g/day sodium as a preventive measure against cardiovascular disease, but this target has not been achieved in any country. This recommendation is primarily based on individual-level data from short-term trials of blood pressure (BP) without data relating low sodium intake to reduced cardiovascular events from randomised trials or observational studies. We investigated the associations between community-level mean sodium and potassium intake, cardiovascular disease, and mortality., Methods: The Prospective Urban Rural Epidemiology study is ongoing in 21 countries. Here we report an analysis done in 18 countries with data on clinical outcomes. Eligible participants were adults aged 35-70 years without cardiovascular disease, sampled from the general population. We used morning fasting urine to estimate 24 h sodium and potassium excretion as a surrogate for intake. We assessed community-level associations between sodium and potassium intake and BP in 369 communities (all >50 participants) and cardiovascular disease and mortality in 255 communities (all >100 participants), and used individual-level data to adjust for known confounders., Findings: 95 767 participants in 369 communities were assessed for BP and 82 544 in 255 communities for cardiovascular outcomes with follow-up for a median of 8·1 years. 82 (80%) of 103 communities in China had a mean sodium intake greater than 5 g/day, whereas in other countries 224 (84%) of 266 communities had a mean intake of 3-5 g/day. Overall, mean systolic BP increased by 2·86 mm Hg per 1 g increase in mean sodium intake, but positive associations were only seen among the communities in the highest tertile of sodium intake (p<0·0001 for heterogeneity). The association between mean sodium intake and major cardiovascular events showed significant deviations from linearity (p=0·043) due to a significant inverse association in the lowest tertile of sodium intake (lowest tertile <4·43 g/day, mean intake 4·04 g/day, range 3·42-4·43; change -1·00 events per 1000 years, 95% CI -2·00 to -0·01, p=0·0497), no association in the middle tertile (middle tertile 4·43-5·08 g/day, mean intake 4·70 g/day, 4·44-5.05; change 0·24 events per 1000 years, -2·12 to 2·61, p=0·8391), and a positive but non-significant association in the highest tertile (highest tertile >5·08 g/day, mean intake 5·75 g/day, >5·08-7·49; change 0·37 events per 1000 years, -0·03 to 0·78, p=0·0712). A strong association was seen with stroke in China (mean sodium intake 5·58 g/day, 0·42 events per 1000 years, 95% CI 0·16 to 0·67, p=0·0020) compared with in other countries (4·49 g/day, -0·26 events, -0·46 to -0·06, p=0·0124; p<0·0001 for heterogeneity). All major cardiovascular outcomes decreased with increasing potassium intake in all countries., Interpretation: Sodium intake was associated with cardiovascular disease and strokes only in communities where mean intake was greater than 5 g/day. A strategy of sodium reduction in these communities and countries but not in others might be appropriate., Funding: Population Health Research Institute, Canadian Institutes of Health Research, Canadian Institutes of Health Canada Strategy for Patient-Oriented Research, Ontario Ministry of Health and Long-Term Care, Heart and Stroke Foundation of Ontario, and European Research Council., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Climate change is an environmental phenomenon with the potential to exacerbate existing disaster risks and cause extensive human, financial and environmental losses. The Mooifontein agricultural region in South Africa is considered to be a region vulnerable to climate change-associated risks. These climate risks would pose a substantial threat to the livelihoods of farmers in the Mooifontein area. This article aims to explore climate-smart agriculture (CSA) as a resilience-building tool to ensure sustainable agricultural practices. A qualitative research approach was utilised to gain insights into climate change and the lived experiences of farmers and agricultural experts in Mooifontein. The findings revealed that agricultural communities should focus on the identification and application of adaptation strategies like CSA. The adoption of appropriate CSA practices will play a vital role in ensuring sustainable livelihoods and improved community resilience for farming communities in the Mooifontein region., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

Background: Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development., Methods: We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level., Findings: The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle-income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2·23, 95% CI 1·59-3·12); p<0·0001), combination therapy (1·53, 1·13-2·07; p=0·054), and have their blood pressure controlled (2·06, 1·69-2·50; p<0·0001) than were those in communities where blood pressure-lowering medicines were not available. Participants with known hypertension from households able to afford four blood pressure-lowering drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted OR 1·42, 95% CI 1·25-1·62; p<0·0001), combination therapy (1·26, 1·08-1·47; p=0·0038), and have their blood pressure controlled (1·13, 1·00-1·28; p=0·0562) than were those unable to afford the medicines., Interpretation: A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure-lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries., Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Although cells comprising esophageal submucosal glands (ESMGs) represent a potential progenitor cell niche, new models are needed to understand their capacity to proliferate and differentiate. By histologic appearance, ESMGs have been associated with both overlying normal squamous epithelium and columnar epithelium. Our aim was to assess ESMG proliferation and differentiation in a 3-dimensional culture model., Methods: We evaluated proliferation in human ESMGs from normal and diseased tissue by proliferating cell nuclear antigen immunohistochemistry. Next, we compared 5-ethynyl-2'-deoxyuridine labeling in porcine ESMGs in vivo before and after esophageal injury with a novel in vitro porcine organoid ESMG model. Microarray analysis of ESMGs in culture was compared with squamous epithelium and fresh ESMGs., Results: Marked proliferation was observed in human ESMGs of diseased tissue. This activated ESMG state was recapitulated after esophageal injury in an in vivo porcine model, ESMGs assumed a ductal appearance with increased proliferation compared with control. Isolated and cultured porcine ESMGs produced buds with actively cycling cells and passaged to form epidermal growth factor-dependent spheroids. These spheroids were highly proliferative and were passaged multiple times. Two phenotypes of spheroids were identified: solid squamous (P63+) and hollow/ductal (cytokeratin 7+). Microarray analysis showed spheroids to be distinct from parent ESMGs and enriched for columnar transcripts., Conclusions: Our results suggest that the activated ESMG state, seen in both human disease and our porcine model, may provide a source of cells to repopulate damaged epithelium in a normal manner (squamous) or abnormally (columnar epithelium). This culture model will allow the evaluation of factors that drive ESMGs in the regeneration of injured epithelium. The raw microarray data have been uploaded to the National Center for Biotechnology Information Gene Expression Omnibus (accession number: GSE100543).

Introduction: Scoliosis and other spinal deformities involve 3-4% of the population during growth. Their so-called conservative treatment is in the field of competence of physical and rehabilitation medicine (PRM) physicians. This evidence based position paper represents the official position of the European Union through the European Union of Medical Specialists (UEMS) - PRM Section. The aim of the paper was to improve PRM specialists' professional practice for patients with spinal deformities during growth., Evidence Acquisition: A systematic review of the literature and a Consensus procedure with 26 recommendations by means of a Delphi method process has been performed involving the delegates of all European countries represented in the UEMS-PRM Section., Evidence Synthesis: the systematic literature review is reported together with 26 recommendations coming from the Consensus Delphi procedure., Conclusions: The professional role of PRM physicians in spinal deformities during growth is to propose a complete PRM treatment for the patients considering all the concurring diseases and pathologies, impairments, activity limitations and participation restrictions. The PRM physician's role is to coordinate the individual PRM project developed in team with other health professionals and medical specialists, in agreement with the patient and his family, according to the specific medical diagnoses.

Objective: Cigarette smoking in South Africa decreased sharply since the early 1990s. Waterpipe smoking increased, especially among students. We estimate the prevalence of waterpipe and cigarette smoking and associated characteristics among university students in the Western Cape., Methods: An anonymous self-administered online questionnaire was sent to all registered students at 4 public Western Cape universities. The 4578 valid responses were weighted to represent the Western Cape's university student population. We present descriptive statistics and logistic regressions., Results: We found that 63% of Western Cape university students ever smoked waterpipe, 9.9% of students smoked waterpipe in the past 30 days and 17.7% of students smoked cigarettes in the past 30 days. Waterpipe smoking has a strong socialization aspect. Controlling for confounders, current waterpipe smoking is associated with alcohol consumption (positively), age (negatively), population group (mixed-race and Indian students smoke more), religion (Muslims smoke more), faculty (medical students smoke less), and spending money (positively). Current cigarette smoking is associated with similar covariates, but not with age., Conclusion: Waterpipe smoking in the Western Cape is widespread, but less than cigarette smoking. Because all tobacco products are harmful, the government has an obligation to impose appropriate regulatory measures to reduce waterpipe consumption.

Objective: The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling., Design: PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated., Results: Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in healthy liver. BDL induced PTN in MF-HSC and increased PTPRZ1 in MF-HSC and RDC. In WT mice, BDL triggered a DR characterised by periportal accumulation of collagen, RDC and MF-HSC. All aspects of this DR were increased in PTN-KO mice and suppressed in PTPRZ1-KO mice. In vitro studies revealed PTN-dependent accumulation of phosphoproteins that control cell-cell adhesion and migration, with resultant inhibition of cell migration. PTPRZ1-positive cells were prominent in the DRs of patients with ductal plate defects and adult cholestatic diseases., Conclusions: PTN, and its receptor, PTPRZ1, regulate the DR to liver injury by controlling the migration of resident cells in adult liver progenitor niches., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53-80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development., (Copyright © 2016 the American Physiological Society.)

Scaffold design incorporating multiscale cues for clinically relevant, aligned tissue regeneration has potential to improve structural and functional integrity of multitissue interfaces. The objective of this preclinical study is to develop poly(ε-caprolactone) (PCL) scaffolds with mesoscale and microscale architectural cues specific to human ligament progenitor cells and assess their ability to form aligned bone-ligament-cementum complexes in vivo. PCL scaffolds are designed to integrate a 3D printed bone region with a micropatterned PCL thin film consisting of grooved pillars. The patterned film region is seeded with human ligament cells, fibroblasts transduced with bone morphogenetic protein-7 genes seeded within the bone region, and a tooth dentin segment positioned on the ligament region prior to subcutaneous implantation into a murine model. Results indicate increased tissue alignment in vivo using micropatterned PCL films, compared to random-porous PCL. At week 6, 30 μm groove depth significantly enhances oriented collagen fiber thickness, overall cell alignment, and nuclear elongation relative to 10 μm groove depth. This study demonstrates for the first time that scaffolds with combined hierarchical mesoscale and microscale features can align cells in vivo for oral tissue repair with potential for improving the regenerative response of other bone-ligament complexes., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hazard-prone areas in southern Africa experience many natural hazards, which include cyclones, floods and droughts. The severe climatic conditions of southern Africa have an especially large impact on the agricultural practices of small-scale farmers. These hazards should be mitigated to ensure more resilient communities and food security. This study mainly focuses on the timing of agricultural production in hazard-prone areas to prevent losses at peak-risk periods by adapting the agricultural cycle. This study focuses on the agricultural activities of small-scale farmers in Malawi, Madagascar and Mozambique. A literature review is presented, and a mixed-method research design were followed to determine the timing of production followed by these small-scale farmers and its impact on production and food security. Although this study found that the small-scale farmers generally plant with the first rains, it is recommended by literature that early planting should be practised to ensure optimal production. It is also recommended that small-scale farmers should implement water-management techniques for dry periods, and when farmers practice late planting, the use of residual-moisture retention should be utilised as a mitigation measure. This will in effect ensure that the communities are less vulnerable during peak-risk periods by improving or ensuring food security. Therefore, adapting the planting and production time in these hazard-prone areas at peak-risk periods could limit losses and increase communities' resilience., Competing Interests: The author declares that she has no financial or personal relationships which may have inappropriately influenced her in writing this article.

Background: Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation., Objectives: We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH., Methods: CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH., Results: Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity and correlated with worse liver cell apoptosis, inflammation, and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice., Conclusion: In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.

Aims: Recent studies have suggested that oesophageal submucosal gland (ESMG) ducts harbour progenitor cells that may contribute to oesophageal metaplasia. Our objective was to determine whether histological differences exist between the ESMGs of individuals with and without oesophageal adenocarcinoma (EAC)., Methods and Results: We performed histological assessment of 343 unique ESMGs from 30 control patients, 24 patients with treatment-naïve high-grade columnar dysplasia (HGD) or EAC, and 23 non-EAC oesophagectomy cases. A gastrointestinal pathologist assessed haematoxylin and eosin-stained ESMG images by using a scoring system that assigns individual ESMG acini to five histological types (mucous, serous, oncocytic, dilated, or ductal metaplastic). In our model, ductal metaplastic acini were more common in patients with HGD/EAC (12.7%) than in controls (3.5%) (P = 0.006). We also identified greater proportions of acini with dilation (21.9%, P < 0.001) and, to a lesser extent, ductal metaplasia (4.3%, P = 0.001) in non-EAC oesophagectomy cases than in controls. Ductal metaplasia tended to occur in areas of mucosal ulceration or tumour., Conclusions: We found a clear association between ductal metaplastic ESMG acini and HGD/EAC. Non-EAC cases had dilated acini and some ductal dilation. Because ESMGs and ducts harbour putative progenitor cells, these associations could have significance for understanding the pathogenesis of EAC., (© 2015 John Wiley & Sons Ltd.)

Objective: Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis., Design: Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled in vitro using hepatocytes derived from WT and caspase-2-deficient mice., Results: We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes., Conclusions: These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Biodegradable collagen scaffolds are used clinically for oral soft tissue augmentation to support wound healing. This study sought to provide a novel ex vivo model for analyzing healing kinetics and gene expression of primary human gingival fibroblasts (hGF) within collagen scaffolds. Sponge type and gel type scaffolds with and without platelet-derived growth factor-BB (PDGF) were assessed in an hGF containing matrix. Morphology was evaluated with scanning electron microscopy, and hGF metabolic activity using MTT. We quantitated the population kinetics within the scaffolds based on cell density and distance from the scaffold border of DiI-labled hGFs over a two-week observation period. Gene expression was evaluated with gene array and qPCR. The sponge type scaffolds showed a porous morphology. Absolute cell number and distance was higher in sponge type scaffolds when compared to gel type scaffolds, in particular during the first week of observation. PDGF incorporated scaffolds increased cell numbers, distance, and formazan formation in the MTT assay. Gene expression dynamics revealed the induction of key genes associated with the generation of oral tissue. DKK1, CYR61, CTGF, TGFBR1 levels were increased and integrin ITGA2 levels were decreased in the sponge type scaffolds compared to the gel type scaffold. The results suggest that this novel model of oral wound healing provides insights into population kinetics and gene expression dynamics of biodegradable scaffolds.

Thyroid hormone (TH) is important for tissue repair because it regulates cellular differentiation. Intrahepatic TH activity is controlled by both serum TH levels and hepatic deiodinases. TH substrate (T4) is converted into active hormone (T3) by deiodinase 1 (D1) but into inactive hormone (rT3) by deiodinase 3 (D3). Although the relative expressions of D1 and D3 are known to change during liver injury, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repair-related activation of the Hedgehog pathway in stromal cells. We localized deiodinase expression, assessed changes during injury, and determined how targeted manipulation of Hedgehog signaling in stromal cells impacted hepatic deiodinase expression, TH content, and TH action in rodents. Humans with chronic liver disease were also studied. In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, whereas stromal expression of D3 increased, particularly in myofibroblasts. Conditionally disrupting Hedgehog signaling in myofibroblasts normalized deiodinase expression. Repair-related changes in deiodinases were accompanied by reduced hepatic TH content and TH-regulated gene expression. In patients, this was reflected by increased serum rT3. Moreover, the decreases in the free T3 to rT3 and free T4 to rT3 ratios distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and free T4. In conclusion, the Hedgehog-dependent changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T3, an important factor for cellular differentiation.

Background: The optimal range of sodium intake for cardiovascular health is controversial., Methods: We obtained morning fasting urine samples from 101,945 persons in 17 countries and estimated 24-hour sodium and potassium excretion (used as a surrogate for intake). We examined the association between estimated urinary sodium and potassium excretion and the composite outcome of death and major cardiovascular events., Results: The mean estimated sodium and potassium excretion was 4.93 g per day and 2.12 g per day, respectively. With a mean follow-up of 3.7 years, the composite outcome occurred in 3317 participants (3.3%). As compared with an estimated sodium excretion of 4.00 to 5.99 g per day (reference range), a higher estimated sodium excretion (≥ 7.00 g per day) was associated with an increased risk of the composite outcome (odds ratio, 1.15; 95% confidence interval [CI], 1.02 to 1.30), as well as increased risks of death and major cardiovascular events considered separately. The association between a high estimated sodium excretion and the composite outcome was strongest among participants with hypertension (P=0.02 for interaction), with an increased risk at an estimated sodium excretion of 6.00 g or more per day. As compared with the reference range, an estimated sodium excretion that was below 3.00 g per day was also associated with an increased risk of the composite outcome (odds ratio, 1.27; 95% CI, 1.12 to 1.44). As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a reduced risk of the composite outcome., Conclusions: In this study in which sodium intake was estimated on the basis of measured urinary excretion, an estimated sodium intake between 3 g per day and 6 g per day was associated with a lower risk of death and cardiovascular events than was either a higher or lower estimated level of intake. As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a lower risk of death and cardiovascular events. (Funded by the Population Health Research Institute and others.).

Background and Objectives: Although 24-h urinary measure to estimate sodium and potassium excretion is the gold standard, it is not practical for large studies. We compared estimates of 24-h sodium and potassium excretion from a single morning fasting urine (MFU) using three different formulae in healthy individuals., Methods: We studied 1083 individuals aged 35-70 years from the general population in 11 countries. A 24-h urine and MFU specimen were obtained from each individual. A subset of 448 individuals repeated the measures after 30-90 days. The Kawasaki, Tanaka, and INTERSALT formulae were used to estimate urinary excretion from a MFU specimen., Results: The intraclass correlation coefficient (ICC) between estimated and measured sodium excretion was higher with Kawasaki (0.71; 95% confidence interval, CI: 0.65-0.76) compared with INTERSALT (0.49; 95% CI: 0.29-0.62) and Tanaka (0.54; 95% CI: 0.42-0.62) formulae (P <0.001). For potassium, the ICC was higher with the Kawasaki (0.55; 95% CI: 0.31-0.69) than the Tanaka (0.36; 95% CI: -0.07 to 0.60; P <0.05) formula (no INTERSALT formula exists for potassium). The degree of bias (vs. the 24-h urine) for sodium was smaller with Kawasaki (+313 mg/day; 95% CI: +182 to +444) compared with INTERSALT (-872 mg/day; 95% CI: -728 to -1016) and Tanaka (-548 mg/day; 95% CI: -408 to -688) formulae (P <0.001 and P = 0.02, respectively). Similarly for potassium, the Kawasaki formula provided the best agreement and least bias. Blood pressure correlated most closely and similarly with the 24-h and Kawasaki estimates for sodium compared with the other two formulae., Conclusion: In a diverse population, the Kawasaki formula is the most valid and least biased method of estimating 24-h sodium excretion from a single MFU and is suitable for population studies.

Peter Mark Roget (1779-1869) is best known for his Thesaurus, a project completed late in his long life. He trained as a physician, practiced medicine, and was interested in many branches of science. Much of his life was dedicated to the systematization of knowledge and identifying relationships. Although not an experimentalist in the modern sense of the word, he contributed to "neuroscience" in journal and encyclopaedia articles, as well as in books and lectures. He wrote extensively on comparative physiology, sensory systems, phrenology, optics, and various disorders affecting the nervous system. He viewed his two-volume Bridgewater Treatise of 1834 as his most significant achievement, turning to physiology and comparative anatomy to argue that God's existence can be seen in how living forms and their components are designed. Roget was active in many scholarly organizations, most notably the Royal Society of London, where he served for more than two decades as its secretary before "retiring" to pursue his Thesaurus., (© 2013 Elsevier B.V. All rights reserved.)

The concepts underlying the connectivity of neurons and the dynamics of interaction required to explain information processing have undergone significant change over the past century. A re-examination of the evolution of the modern view in historical context reveals that rules for connectivity have changed in a manner that might be expected from critical analysis enabled by technical advance. A retrospective examination of some germane issues that moved Camillo Golgi to question the widely held dogma of his era reveals network principles that could not have been recognized a century ago. The currently evolving rules of cellular discontinuity and interaction have proven sufficiently complex to justify the arguments of critical skepticism that sustain scientific progress., (Copyright © 2010 Elsevier B.V. All rights reserved.)

While Golgi's concept of the sensory neuron provided sound reasons for his rejection of the polarity principles underlying the 'neuron doctrine', it is now apparent that his concern about recovery of function after injury and the vast modern findings of ephemerality of connexin-clustered connections in the cerebral cortex and elsewhere in the central nervous system, and credibly termed 'reticularist', has somewhat eclipsed the polarized neuron doctrine of reflex physiology with the "fixed and immutable" connections championed by Cajal. Although Golgi's view was not the result of incisive reasoning based on subsequently confirmed observation, both principles espoused by these combatant Nobel laureate partners have proven robustly operative in different spheres and time frames of neural activity that have vastly enhanced contemporary understanding of neural connectivity.

The 100th anniversary of the shared first Nobel prize in neuroscience by Camillo Golgi and Ramon y Cajal invites reappraisal of the merits of the arguments adduced by these two combative scientists in the light of contemporary knowledge. Guided by cogent reasons for reluctance in accepting the inviolable polarity principle of the neuron doctrine and concern for explaining cerebral recovery of function, Golgi joined the 'reticularists' of his generation. Modern observations of axo-axonic and dendro-dendritic synapses, gap-junction interconnections, rules for the direction and mode of analog or impulse conduction, the myriad diversity of ion channels and gating principles and the complexities of synaptic plasticity have eclipsed the polarized neuron doctrine explanations of reflex physiology and the 'fixed and immutable' connections successfully championed by Cajal. Without violating the cell theory, expanded modes of neuronal and glial communication have encompassed reticularist notions and provided insight into the long-term changes underlying synaptic and extra-synaptic neural patterns. Both laureates espoused operative principles that have survived in different modes and distinctive temporal domains. Together, they reflect the roots of our contemporary understanding of neural interaction.

Background and Purpose: Although sleep apnea (SA) is a risk factor for ischemic stroke and an important prognosticator in affected patients, the exact pathophysiological link between SA and stroke remains to be established. We investigated whether levels of C-reactive protein (CRP) and fibrinogen are increased in patients with acute stroke and SA compared with stroke patients without SA., Patients and Methods: 117 consecutive patients with ischemic stroke admitted to our stroke unit within 12 h after stroke onset were included in this study. On admission, CRP and fibrinogen levels were determined. All patients received cardiorespiratory polygraphy during the first 72 h of their hospital stay. In all patients, demographic data, National Institutes of Health Stroke Scale score and cerebrovascular risk factors were assessed., Results: SA defined by an apnea-hypopnea index (AHI) of > or =10/h was found in 64 (55%) patients. Elevated CRP and fibrinogen levels were seen twice as often in patients with SA than in patients without (CRP: 52 vs. 26%; fibrinogen: 72 vs. 37%). After multivariate logistic regression analysis, an AHI of > or =10/h was independently correlated with raised levels of both of these parameters., Conclusion: SA is independently associated with raised levels of CRP and fibrinogen in patients with acute ischemic stroke. We assume that both proteins are part of the pathophysiological pathway linking SA to stroke., ((c) 2007 S. Karger AG, Basel)