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Pericardial edema - fluid accumulation within the pericardium - is a frequently observed malformation in zebrafish embryo-based chemical toxicity screens. We recently discovered that the severity of triphenyl phosphate (TPHP)-induced pericardial edema was dependent on the ionic strength of exposure media. TPHP is an aryl phosphate ester (APE) widely used as a plasticizer and flame retardant. APEs are characterized by having one or more aryl groups bound to a phosphate center, with TPHP containing only unsubstituted aryl groups. Therefore, the objective of this study was to begin investigating whether, similar to TPHP, pericardial edema induced by other structurally related APEs is dependent on the ionic composition of exposure media. We first mined the peer-reviewed literature to identify other APEs that 1) induced pericardial edema in zebrafish embryos within a minimum of three peer-reviewed publications, and 2) demonstrated a statistically significant induction of pericardial edema in at least 70 % of the studies evaluated. Based on this meta-analysis, we identified four other APEs that caused pericardial edema in zebrafish embryos: isopropylated triphenyl phosphate (IPTPP), cresyl diphenyl phosphate (CDP), tricresyl phosphate (TMPP), and 2-ethylhexyl diphenyl phosphate (EDHPHP). Using TPHP as a positive control and pericardial edema as a readout, we developed concentration-response curves for all four APEs based on static exposure from 24 to 72 h post-fertilization (hpf). We then conducted co-exposures with D-Mannitol (an osmotic diuretic) and exposures within reverse osmosis (RO) water determine whether the ionic composition of exposure media mitigated APE-induced pericardial edema at 72 hpf. Using pericardial edema as an endpoint, the approximate EC50s for TPHP (positive control), IPTPP, CDP, TMPP, and EDHPHP were 6.25, 3.125, 3.125, 25, and 100 µM, respectively, based on exposure from 24 to 72 hpf. Interestingly, similar to our findings with TPHP, co-exposure with D-Mannitol and exposure within ion-deficient water significantly mitigated IPTPP- CDP-, TMPP-, and EDHPHP-induced pericardial edema in zebrafish embryos, suggesting that chemically-induced pericardial edema may be 1) dependent on the ionic composition of exposure media and 2) driven by a disruption in osmoregulation across the embryonic epidermis. Therefore, similar to other assay parameters, our findings underscore the need to standardize the osmolarity of exposure media in order to minimize the potential for false positive/negative hits in zebrafish embryo-based chemical toxicity screens conducted around the world.

Parents may experience a range of emotions when hearing that their child may be on the autism spectrum, including shock or denial (Martins et al., 2021). While hearing the word "autism" can be challenging for families, early identification of autism (also referred to as autism spectrum disorder [ASD]) allows families more time to process the diagnosis and find the best supports for their unique child. The purpose of this manuscript is to give providers an evidence-informed process that will guide them toward early conversations about autism with families using family-centered and culturally responsive best practices.

BackgroundRepairing instead of replacing partially defective dental restorations represents a minimally invasive treatment concept, and repairs are associated with advantages over complete restoration replacement. To participate in the shared decision-making process when facing partially defective restorations, patients need to be aware of the indications, limitations, and advantages or disadvantages of repairs. Patients are increasingly using the internet to gain health information like this online. ObjectiveWe aimed to assess the quality of German-speaking dentist websites on repairs of partially defective restorations. MethodsThree electronic search engines were used to identify German-speaking websites of dental practices mentioning repairs. Regarding information on repairs, websites were assessed for (1) technical and functional aspects, (2) comprehensiveness of information, and (3) generic quality and risk of bias. Domains 1 and 3 were scored using validated tools (LIDA and DISCERN). Comprehensiveness was assessed using a criterion checklist related to evidence, advantages and disadvantages, restorations and defects suitable for repairs, and information regarding technical implementation. Generalized linear modeling was used to assess the impact of practice-specific parameters (practice location, practice setting, dental society membership, and year of examination or license to practice dentistry) on the quality of information. An overall quality score was calculated by averaging the quality scores of all three domains and used as primary outcome parameter. Quality scores of all three domains were also assessed individually and used as secondary outcomes. ResultsFifty websites were included. The median score of quality of information was 23.2% (interquartile range [IQR] 21.7%-26.2%). Technical and functional aspects (55.2% [IQR 51.7%-58.6%]) showed significantly higher quality than comprehensiveness of information (8.3% [IQR 8.3%-16.7%]) and generic quality and risk of bias (3.6% [IQR 0.0%-7.1%]; P.05/generalized linear modeling). ConclusionsThe quality of German-speaking dentist websites on repairs was limited. Despite sufficient technical and functional quality, the provided information was neither comprehensive nor trustworthy. There is great need to improve the quality of information to fully and reliably inform patients, thereby allowing shared decision making.

Abstract Test-negative designs (TNDs) are used to assess vaccine effectiveness (VE). Protection from infection-induced immunity may confound the association between case and vaccination status, but collecting reliable infection history can be challenging. If vaccinated individuals have less infection-induced protection than unvaccinated individuals, failure to account for infection history could underestimate VE, though the bias is not well understood. We simulated individual-level SARS-CoV-2 infection and COVID-19 vaccination histories and a TND. VE against symptomatic infection and VE against severe disease estimates unadjusted for infection history underestimated VE compared to estimates adjusted for infection history, and unadjusted estimates were more likely to be below 0%, which could lead to an incorrect interpretation that COVID-19 vaccines are harmful. TNDs assessing VE immediately following vaccine rollout introduced the largest bias and potential for negative VE against symptomatic infection. Despite the potential for bias, VE estimates from TNDs without prior infection information are useful because underestimation is rarely more than 8 percentage points.

Abstract Psoriasis is a prevalent, inflammatory skin disease without cure. Further research is required to unravel dysregulated processes and develop new therapeutic interventions. The lack of suitable in vivo and in vitro preclinical models is an impediment in the psoriasis research. Recently, the development of 3D skin models has progressed including replicas with disease-like features. To investigate the use of in vitro models as preclinical test tools, the study focused on treatment responses of 3D skin replicas. Cytokine-priming of skin organoids induced psoriatic features like inflammation, antimicrobial peptides (AMP), hyperproliferation and impaired differentiation. Topical application of dexamethasone (DEX) or celastrol (CEL), a natural anti-inflammatory compound reduced the secretion of pro-inflammatory cytokines. DEX and CEL decreased the gene expression of inflammatory mediators. DEX barely affected the psoriatic AMP transcription but CEL downregulated psoriasis-driven AMP genes. Subcutaneous application of adalimumab (ADM) or bimekizumab (BMM) showed anti-psoriatic effects via protein induction of the differentiation marker keratin-10. Dual blockage of TNF-α and IL-17A repressed the inflammatory psoriasis phenotype. BMM inhibited the psoriatic expression of AMP genes and induced KRT10 and cell-cell contact genes. The present in vitro model provides a 3D environment with in vivo-like cutaneous responses and represents a promising tool for preclinical investigations.

Abstract Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with pancreatic islet MPS (PANIS) enabling MASLD progression and islet dysfunction to be assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF) conditions, under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic-factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient-specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying disease mechanisms, and advancing precision medicine.

Triphenyl phosphate (TPHP) - a widely used organophosphate-based flame retardant - blocks cardiac looping during zebrafish development in a concentration-dependent manner, a phenotype that is dependent on disruption of embryonic osmoregulation and pericardial edema formation. However, its currently unclear whether (1) TPHP-induced effects on osmoregulation are driven by direct TPHP-induced injury to the embryonic epidermis and (2) whether TPHP-induced pericardial edema is reversible or irreversible following cessation of exposure. Therefore, the objectives of this study were to determine whether TPHP-induced pericardial edema is reversible and whether TPHP causes injury to the embryonic epidermis by quantifying the number of DAPI-positive epidermal cells and analyzing the morphology of the yolk sac epithelium using scanning electron microscopy. First, we found that exposure to 5 μM TPHP from 24-72 h post-fertilization (hpf) did not increase prolactin - a hormone that regulates ions and water levels - in embryonic zebrafish, whereas high ionic strength exposure media was associated with elevated levels of prolactin. Second, we found that exposure to 5 μM TPHP from 24-72 hpf did not decrease DAPI-positive epidermal cells within the embryonic epithelium, and that co-exposure with 2.14 μM fenretinide - a synthetic retinoid that promotes epithelial wound repair - from 24-72 hpf did not mitigate the prevalence of TPHP-induced epidermal folds within the yolk sac epithelium when embryos were exposed within high ionic strength exposure media. Finally, we found that the pericardial area and body length of embryos exposed to 5 μM TPHP from 24-72 hpf were similar to vehicle-treated embryos at 120 hpf following transfer to clean water and depuration of TPHP from 72-120 hpf. Overall, our findings suggest that (1) the ionic strength of exposure media may influence the baseline physiology of zebrafish embryos; (2) TPHP does not cause direct injury to the embryonic epidermis; and (3) TPHP-induced effects on pericardial area and body length are reversible 48 h after transferring embryos to clean water.

BACKGROUND: Protection against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]) can limit transmission and the risk of post-COVID conditions, and is particularly important among healthcare personnel. However, lower vaccine effectiveness (VE) has been reported since predominance of the Omicron SARS-CoV-2 variant. METHODS: We evaluated the VE of a monovalent messenger RNA (mRNA) booster dose against COVID-19 from October 2021 to June 2022 among US healthcare personnel. After matching case-participants with COVID-19 to control-participants by 2-week period and site, we used conditional logistic regression to estimate the VE of a booster dose compared with completing only 2 mRNA doses >150 days previously, adjusted for multiple covariates. RESULTS: Among 3279 case-participants and 3998 control-participants who had completed 2 mRNA doses, we estimated that the VE of a booster dose against COVID-19 declined from 86% (95% confidence interval, 81%-90%) during Delta predominance to 65% (58%-70%) during Omicron predominance. During Omicron predominance, VE declined from 73% (95% confidence interval, 67%-79%) 14-60 days after the booster dose, to 32% (4%-52%) ≥120 days after a booster dose. We found that VE was similar by age group, presence of underlying health conditions, and pregnancy status on the test date, as well as among immunocompromised participants. CONCLUSIONS: A booster dose conferred substantial protection against COVID-19 among healthcare personnel. However, VE was lower during Omicron predominance, and waning effectiveness was observed 4 months after booster dose receipt during this period. Our findings support recommendations to stay up to date on recommended doses of COVID-19 vaccines for all those eligible.

Objective To determine if the prevalence of schistosomiasis in children aged 9- 12 years is associated with the prevalence in 5-8-year-olds and adults after preventive chemotherapy in schools or the community. Methods We combined data from four community-randomized, preventive chemotherapy trials in treatment-naive populations in Cote d'Ivoire, Kenya and the United Republic of Tanzania during 2010-2016 according to the number of praziquantel treatments and the delivery method. Schistosoma mansoni infection was sought on two slides prepared from each participant's first stool using the Kato-Katz technique. We assessed associations between S. mansoni prevalence in 9-12-year-olds and 5- 8-year-olds and adults in the community before and after treatment using Bayesian regression models. Findings Stool samples from 47 985 5-8-year-olds, 81 077 9-12-year-olds and 20 492 adults were analysed. We found associations between the prevalence in 9-12-year-olds and that in 5-8-year-olds and adults after preventive treatment, even when only school-age children were treated. When the prevalence in 9-12-year-olds was under 10%, the prevalence in 5-8-year-olds was consistently under 10%. When the prevalence in 9-12-year-olds was under 50%, the prevalence in adults after two or four rounds of preventive chemotherapy was 10%-15% lower than before chemotherapy. Post-chemotherapy age-group associations were consistent with pre-chemotherapy associations in this analysis and previous studies. Conclusion The prevalence of S. mansoni infection in 9-12-year-olds was associated with the prevalence in other age groups and could be used to guide community treatment decisions. Abstracts in [phrase omitted], Francais, [phrase omitted] and Espanol at the end of each article. [phrase omitted] Objectif Determiner si la prevalence de la schistosomiase chez les enfants de 9 a 12 ans est associee a celle observee chez les 5-8 ans et les adultes apres une chimiotherapie preventive au sein des ecoles ou de la communaute. Methodes Nous avons regroupe les donnees provenant de quatre essais randomises de chimiotherapie preventive menes en milieu communautaire aupres de populations n'ayant jamais ete traitees en Cote d'Ivoire, au Kenya et en Republique-Unie de Tanzanie entre 2010 et 2016, en fonction du nombre de traitements au praziquantel et du mode d'administration. Une infection a Schistosoma mansoni a ete recherchee sur deux lames preparees a partir des premieres selles de chaque participant, a l'aide de la technique de Kato-Katz. Nous avons employe des modeles de regression bayesienne qui nous ont permis d'identifier un rapport entre la prevalence de S. mansoni au sein de la communaute chez les 9-12 ans d'une part, et chez les 5-8 ans et les adultes de l'autre, avant et apres traitement. Resultats Les echantillons de selles de 47 985 enfants ages de 5 a 8 ans, 81 077 enfants de 9 a 12 ans et 20 492 adultes ont ete analyses. Nous avons constate qu'apres un traitement preventif, la prevalence chez les 9-12 ans ainsi que chez les 5-8 ans et les adultes etait liee, meme quand seuls les enfants d'age scolaire etaient traites. Lorsque la prevalence chez les 9-12 ans etait inferieure a 10%, celle chez les 5-8 ans etait systematiquement sous les 10%. Lorsque la prevalence chez les 9-12 ans etait inferieure a 50%, celle chez les adultes apres deux ou quatre traitements par chimiotherapie preventive etait 10 a 15% plus faible qu'avant toute chimiotherapie. Les liens par categorie d'age en post-chimiotherapie etaient coherents avec ceux en pre-chimiotherapie, tant dans la presente analyse que dans de precedentes etudes. Conclusion La prevalence de l'infection a S. mansoni chez les 9-12 ans etait associee a la prevalence dans d'autres categories d'age, ce qui pourrait servir a orienter les decisions de prise en charge au sein de la communaute. [phrase omitted] Objetivo Determinar si la prevalencia de la esquistosomiasis en ninos de 9 a 12 anos esta asociada con la prevalencia en ninos de 5 a 8 anos y adultos tras la quimioterapia preventiva en escuelas o en la comunidad. Metodos Se combinaron datos de cuatro ensayos aleatorizados a nivel comunitario de quimioterapia preventiva en poblaciones sin tratamiento en Costa de Marfil, Kenia y la Republica Unida de Tanzania entre 2010 y 2016 segun el numero de tratamientos con praziquantel y el metodo de administracion. La infeccion por Schistosoma mansoni se busco en dos laminillas preparadas a partir de las primeras heces de cada participante mediante la tecnica de Kato-Katz. Se evaluaron las asociaciones entre la prevalencia de S. mansoni en ninos de 9 a 12 anos y de 5 a 8 anos y adultos en la comunidad antes y despues del tratamiento mediante modelos de regresion bayesiana. Resultados Se analizaron muestras de heces de 47 985 ninos de 5 a 8 anos, 81 077 ninos de 9 a 12 anos y 20 492 adultos. Se encontraron asociaciones entre la prevalencia en ninos de 9 a 12 anos y la de ninos de 5 a 8 anos y adultos tras el tratamiento preventivo, incluso cuando solo se trato a ninos en edad escolar. Cuando la prevalencia en ninos de 9 a 12 anos era inferior al 10%, la prevalencia en ninos de 5 a 8 anos era siempre inferior al 10%. Cuando la prevalencia en ninos de 9 a 12 anos era inferior al 50%, la prevalencia en adultos despues de dos o cuatro ciclos de quimioterapia preventiva era entre un 10% y un 15% inferior que antes de la quimioterapia. Las asociaciones entre grupos de edad tras la quimioterapia fueron coherentes con las asociaciones previas a la quimioterapia en este analisis y en estudios anteriores. Conclusion La prevalencia de la infeccion por S. mansoni en ninos de 9 a 12 anos se asocio con la prevalencia en otros grupos de edad. Ademas, podria utilizarse para orientar las decisiones de tratamiento en la comunidad., Introduction Control programmes for schistosomiasis, the human disease caused by worms of the genus Schistosoma, focus on collecting and evaluating data from school-age children. (1) The use of school-age children [...]

Background: Youths with extreme obesity (Body mass index (BMI)>40) are at increased risk for physical and mental health impairments but this patient group has received little attention in research. This study aimed to analyze the pain experience and mental health impairments of youths with extreme obesity compared to those with mild and moderate obesity (BMI=30–39.9) by considering gender differences. Methods: Cross-sectional data of 431 youths (M=16.6; SD=2.3; 53.1% female) were analyzed. Of these, 159 (36.8%) youths were characterized by extreme obesity. Self-reported sociodemographic data, pain-related variables, depression, and health-related quality of life (HRQoL) were assessed with standardized questionnaires. Data were analyzed with univariate tests and logistic regression models. Results: Youths with extreme obesity reported more pain in the last 4 weeks (p=.018), increased pain-related impairments in daily life (p=.009), more pain-related days of absence (p=.030), higher depression scores (p = .030), and reduced HRQoL (p=.005) compared to youths with mild and moderate obesity. In regression models, extreme obesity and pain in the last 4 weeks were associated when additionally including sex and age in the model (odds ratio 1.88; 95 % confidence interval 1.16 - 30.40, p=.010). In the subgroup of extreme obesity (n=159), women (n=83) reported more pain in the last 4 weeks (p=.001), higher depression scores (p

Abstract Background Surgical aortic valve replacement (SAVR) is an established therapy for severe calcific aortic stenosis. Enhanced recovery after cardiac surgery (ERACS) protocols have been shown to improve outcomes for elective cardiac procedures. The COVID-19 pandemic prompted early extubation post-elective surgeries to preserve critical care resources. Aim of this study To investigate the effects of extubating patients within 6 h post-elective SAVR on hospital and ICU length of stay, mortality rates, ICU readmissions, and postoperative pneumonia. Study Design and methods The retrospective analysis at the University Hospital Aachen, Germany, includes data from 2017 to 2022 and compares a total of 73 elective SAVR patients. Among these, 23 patients were extubated within 6 h (EXT group), while 50 patients remained intubated for over 6 h (INT group). Results The INT group experienced longer postoperative ventilation, needed more vasopressor support, had a higher incidence of postoperative pneumonia, and longer ICU length of stay. No significant differences were noted in overall hospital length of stay, mortality, or ICU readmission rates between the groups. Conclusion This study demonstrates that early extubation in high-risk, multimorbid surgical aortic valve replacement patients is safe, and is associated with a reduction of pneumonia rates, and with shorter ICU and hospital length of stays, reinforcing the benefits of ERACS protocols, especially critical during the COVID-19 pandemic to optimize intensive care use.

Abstract Background Marginal zone lymphomas of mucosa-associated lymphatic tissues (MZL of MALT) are a group of indolent B-cell neoplasms, which are thought to arise from chronic antigenic stimulation of B-cells either due to underlying chronic infection or autoimmune disease. Little is known about potential causative pathogens in pulmonary MZL (PMZL), although some data suggests a potential role of Achromobacter (A.) xylosoxidans. Methods An index case of chronic pulmonary colonisation with Tropheryma (T.) whipplei and subsequent development of PMZL was identified by T. whipplei specific PCR and metagenomic next genome sequencing (mNGS). This case prompted a retrospectively conducted analysis of T. whipplei-specific PCRs in lung tissue from PMZL patients (n = 22), other pulmonary lymphomas, and normal controls. Positive results were confirmed by mNGS. A systematic search for T. whipplei and A. xylosoxidans in our in-house mNGS dataset comprising autopsy lungs, lung biopsies and lung resection specimens (n = 181) was subsequently performed. Results A 69-year-old patient presented with weight loss and persistent pulmonary consolidation. Subsequent mNGS analysis detected T. whipplei in the resected lung specimen. An antibiotic regimen eventually eliminated the bacterium. However, the consolidation persisted, and the diagnosis of PMZL was made in a second lung resection specimen. A second case of T. whipplei-associated PMZL was subsequently detected in the retrospectively analysed PMZL cohort. Both cases showed comparatively few mutations and no mutations in genes encoding for NF-κB pathway components, suggesting that T. whipplei infection may substitute for mutations in these PMZL. None of the samples in our in-house dataset tested positive for T. whipplei. In contrast, A. xylosoxidans was frequently found in both autopsy lungs and lung biopsy / resection specimens that were not affected by PMZL (> 50%). Conclusions Our data suggests that T. whipplei colonisation of lungs may trigger PMZL as a potential driver. Systematic analyses with larger cohorts should be conducted to further support this hypothesis. The frequent detection of A. xylosoxidans in lung tissue suggests that it is a common component of the pulmonary microbiome and therefore less likely to trigger lymphomas.