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This publication is the second part of the German-language S3 guideline on urticaria. It covers the management of urticaria and should be used together with Part 1 of the guideline on classification and diagnosis. This publication was prepared according to the criteria of the AWMF on the basis of the international English-language S3 guideline with special consideration of health system conditions in German-speaking countries. Chronic urticaria has a high impact on the quality of life and daily activities of patients. Therefore, if causal factors cannot be eliminated, effective symptomatic treatment is necessary. The recommended first-line treatment is to administer new generation, non-sedating H1 antihistamines. If the standard dose is not sufficiently effective, the dose should be increased up to fourfold. For patients who do not respond to this treatment, the second-line treatment in addition to antihistamines in the treatment algorithm is omalizumab and, if this treatment fails, ciclosporin. Other low-evidence therapeutic agents should only be used if all treatments in the treatment algorithm agreed upon by the guideline group fail. Both the benefit-risk profile and cost should be considered. Corticosteroids are not recommended for long-term treatment due to their inevitable severe side effects.

Die vorliegende Publikation ist der zweite Abschnitt der deutschsprachigen S3-Leitlinie Urtikaria. Sie umfasst das Management der Urtikaria und sollte gemeinsam mit Teil 1 der Leitlinie zur Klassifikation und Diagnostik genutzt werden. Diese Publikation wurde auf der Basis der internationalen englischsprachigen S3-Leitlinie unter besonderer Berücksichtigung der medizinischen Gegebenheiten im deutschsprachigen Raum entsprechend den Kriterien der AWMF erstellt. Eine chronische Urtikaria hat einen hohen Einfluss auf Lebensqualität und Leistungsfähigkeit der Patienten. Sofern kausale Faktoren nicht beseitigt werden können, ist daher eine effektive symptomatische Behandlung notwendig. Die empfohlene Therapie der ersten Wahl ist die Gabe von nicht sedierenden H1-Antihistaminika der neuen Generation. Wenn die Standarddosierung nicht ausreichend wirksam ist, sollte die Dosis bis auf das Vierfache erhöht werden. Bei Patienten, die auch auf eine solche Behandlung nicht ansprechen, sind Therapeutika der zweiten Wahl zusätzlich zu Antihistaminika im Rahmen des Therapiealgorithmus zunächst Omalizumab und, bei Versagen dieser Therapie, Ciclosporin. Weitere Therapeutika mit geringer Evidenz sollten nur bei Versagen aller Therapien des konsentierten Algorithmus verwendet werden. Dabei sollten sowohl das Nutzen-Risiko-Profil als auch die Kosten berücksichtigt werden. Kortikosteroide werden für die Langzeitbehandlung aufgrund ihrer unvermeidbaren schweren Nebenwirkungen nicht empfohlen.

Die Lebenszeitprävalenz für Urtikaria, die zu den schweren allergischen Erkrankungen zählt, liegt bei nahezu 20%. Sie schränkt nicht nur die Lebensqualität der Betroffenen ein, sondern die generelle Leistungsfähigkeit in Beruf und Alltag. Die vorliegende Publikation ist der erste Abschnitt der Leitlinie Urtikaria. Dieser Teil der Leitlinie umfasst deren Klassifikation und Diagnostik unter Einbeziehung der wesentlichen Fortschritte in der Erforschung ihrer Ursachen, auslösenden Faktoren und Pathomechanismen. Zudem befasst sie sich mit Strategien zur ökonomischen Diagnostik der verschiedenen Unterformen der Urtikaria. Dies ist entscheidend für eine individuelle, patientenorientierte Therapie, die im zweiten Teil behandelt wird. Diese deutschsprachige Leitlinie wurde auf der Basis der internationalen englischsprachigen S3-Leitlinie unter besonderer Berücksichtigung der medizinischen Gegebenheiten im deutschsprachigen Raum entsprechend den Kriterien der AWMF erstellt. Die Leitlinie beschreibt in diesem Abschnitt die Klassifikation der Urtikaria, wobei spontan auftretende Quaddeln und Schwellungen von Urtikariaformen mit induzierbaren Symptomen abgegrenzt werden. Urtikaria wird als plötzlich auftretende Quaddeln, Schwellungen oder beides definiert, ist dabei aber abzugrenzen von Zuständen bei denen Quaddeln als kurzfristiges Symptom auftreten, wie zum Beispiel bei der Anaphylaxie. Die Diagnostik stützt sich auf (eingeschränkte) Laboruntersuchungen, aber insbesondere auch die Anamnese. Darüber hinaus stehen validierte Instrumente zur Verfügung, die den Schweregrad, die Aktivität und den Verlauf erfassen.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

This paper reviews algorithmic or artificial intelligence (AI) bias in education technology, especially through the lenses of speculative fiction, speculative and liberatory design. It discusses the causes of the bias and reviews literature on various ways that algorithmic/AI bias manifests in education and in communities that are underrepresented in EdTech software development. While other recent work has responded to mainstream or private sector technology development, this review looks elsewhere where practitioners, artists, and activists engage underrepresented communities in brainstorming processes to identify and solve tough challenges. Their creative work includes films, toolkits, applications, prototypes and other physical artifacts, and other future-facing ideas that can provide guideposts for private sector development. Acknowledging the gaps in what has been studied, this paper proposes a different approach that includes speculative and liberatory design thinking, which can help developers better understand the educational and personal contexts of underrepresented groups. Early efforts to advocate for fairness and equity in AI and EdTech by groups such as the Algorithmic Justice League, the EdTech Equity Project, and EdSAFE AI Alliance is also explored.

We prepared a collection of complex cycloheptatriene-containing azetidine lactones by applying two key photochemical reactions: "aza-Yang" cyclization and Buchner carbene insertion into aromatic rings. While photolysis of phenacyl amines leads to a rapid charge transfer and elimination, we found that a simple protonation of the amine enables the formation of azetidinols as single diastereomers. We provide evidence, through ultrafast spectroscopy, for the electron transfer from free amines in the excited state. Further, we characterize the aza-Yang reaction by establishing the dependence of the initial reaction rates on the rates of photon absorption. An unanticipated change in reactivity in morpholine analogues is explained through interactions with the tosylate anion. The Buchner reaction proceeds with a slight preference for one diastereomer over the other, and successful reaction requires electron-donating carbene-stabilizing substituents. Overall, 16 compounds were prepared over seven steps. Guided by an increase in structural complexity, efforts such as this one extend the reach of chemists into unexplored chemical space and provide useful quantities of new compounds for studies focused on their properties.

Mycotoxin contamination is a leading cause of food spoilage and waste on a global scale. Patulin, a mycotoxin produced by Penicillium spp. during postharvest pome fruit decay, causes acute and chronic effects in humans, withstands pasteurization, and is not eliminated by fermentation. While much is known about the impact of patulin on human health, there are significant knowledge gaps concerning the effect of patulin during postharvest fruit–pathogen interactions. Application of patulin on six apple cultivars reproduced some blue mold symptoms that were cultivar-independent and dose-dependent. Identical symptoms were also observed in pear and mandarin orange. Six Penicillium isolates exposed to exogenous patulin exhibited delayed germination after 24 h, yet all produced viable colonies in 7 days. However, four common postharvest phytopathogenic fungi were completely inhibited by patulin during conidial germination and growth, suggesting the toxin is important for Penicillium to dominate the postharvest niche. Using clorgyline, a broad-spectrum efflux pump inhibitor, we demonstrated that efflux plays a role in Penicillium auto-resistance to patulin during conidial germination. The work presented here contributes new knowledge of patulin auto-resistance, its mode of action, and inhibitory role in fungal–fungal interactions. Our findings provide a solid foundation to develop toxin and decay mitigation approaches.

The Prosperity Gospel (PG) has gotten an increasing amount of attention recently as a major theological force driving Americans' political attitudes and identity. A number of studies have also examined how the PG affects racial minorities, especially Black Protestants, for whom it works counter to Social Gospel theology that is commonly associated with Black religious leaders and believers. This paper employs a unique data set that shows the prevalence of PG identity and beliefs across racial and religious categories, comparing the political outputs of the confluence of race, theology, and religious identity.

Aims: This study provides a multimodal conversation analytic account of directive sequences used in the presence of a child aged 1;8-2;4 growing up in an English-dominant environment and acquiring Polish as a heritage language. Design: The video recorded data are drawn from naturally occurring interactions, in which the child is present when one caregiver produces a directive turn (request, proposal, or suggestion) and another one carries it out in an embodied fashion. Analysis: The analysis focuses on the sequential unfolding of the triadic interactions, the two adults’ and child’s verbal turns, gaze direction, manual actions, and handling of objects. Findings: Although the child is not always verbally active in the directive sequences, she observes them and sometimes takes part, either through bodily actions or verbal utterances. The multimodal analysis also shows that even if the child’s verbal activity might indicate understanding a prior turn and responding to it, the child may not actually be orienting to the conversation. Observing adults carrying out heritage language directive sequences is only possible when the child is interacting with two speakers of her heritage language, or a speaker of that language and a person who has some passive knowledge of it. Seeing adults’ mutual social actions offers the child a social environment, in which she can get a rich linguistic model and also observe the benefits of using the heritage language in everyday interactional situations. Originality: This is the first study to offer a multimodal conversation analysis of directive sequences in which one adult produces the directive and another adult responds to it in the presence of a child acquiring a heritage language.

Background Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005–2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO2) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO2 or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate Results There were no associations between NO2 or supplemental folic acid intake and epigenetic age acceleration of GC. NO2 and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO2 exposure was associated with 1.7% higher DNAm. There was no association between NO2 and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO2-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies. Conclusions We found no associations between NO2, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.

Adolescent girls, independent of their migration background, and adolescent boys, specifically with a migration background, experience more depressive symptoms than boys without a migration background. Adolescent girls also benefit more from depression prevention programs than boys. However, no studies have examined the role of migration background on depression prevention. This cluster-randomized trial included 439 eighth-grade students (43.5% girls, 42.4% with a migration background) in Germany. Adolescents were randomized into either a 10-week universal prevention program or school-as-usual. Following our secondary analyses and as predicted, depressive symptoms decreased in girls in the prevention but not in the control group. Consistent with our hypotheses, boys did not benefit from the prevention program, nor was there a significant interaction between gender and migration background. Independent of condition, depressive symptoms increased in adolescents with a migration background. More research is needed to improve depression prevention for adolescent boys and in adolescents with a migration background.

OBJECTIVE: To examine the association between dietary folate intake and antral follicle count (AFC) among women seeing treatment for infertility. DESIGN: Cohort study SETTING: Academic fertility center PATIENTS: 552 women attending the Massachusetts General Hospital Fertility Center (2007-2019) who participated in the Environment and Reproductive Health Study. INTERVENTION(S): None. Folate intake was measured using a validated food frequency questionnaire at study entry. Multivariable Poisson regression models with robust standard errors were used to estimate the association of folate intake with AFC adjusting for calorie intake, age, BMI, physical activity, education, smoking status, year of AFC, and intakes of vitamin B12, iron, and vitamin D. Non-linearity was assessed with restricted cubic splines. MAIN OUTCOME MEASURES: AFC as measured with transvaginal ultrasonography as part of routine care. RESULTS: Among the 552 women (median age 35.0 years, median folate intake 1,005 μg/day), total and supplemental folate intake had a significant non-linear relationship with AFC (P for non-linearity 0.05 and 0.02, respectively). There was a positive linear association with AFC up to approximately 1200 μg/day for total folate intake and up to 800 μg/day for supplemental folate intake; however, there was no additional benefit of higher folate intakes. The magnitude of association was modest – for example, the predicted adjusted difference in AFC between a woman consuming 400 versus 800 μg/day of supplemental folate was approximately 1.5 follicles. CONCLUSIONS: Higher intake of folate, particularly from supplements, was associated with modestly higher ovarian reserve as measured by AFC among women attending a fertility center. TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT00011713

Purpose:Most aggressive thyroid cancers are commonly associated with a BRAFV600E mutation. Preclinical and clinical data in BRAFV600E cancers suggest that combined BRAF and MEK inhibitor treatment results in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAFV600E thyroid cancer than in single-agent or BRAF and MEK inhibitors.Experimental Design:The combined drug activity was analyzed to predict any synergistic effect using high-throughput screening (HTS) of active drugs. We performed follow-up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs.Results:The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion, and migration in BRAFV600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720-resistant BRAFV600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In an orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (P < 0.05), decreased the number of metastases (P < 0.05), and increased survival (P < 0.05) compared with monotherapy and vehicle control.Conclusions:Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAFV600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

Supplementary figures and tables

IMPACT II

TCGA normal vs tumor raw data

Purpose: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer–related deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDAC) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response.Experimental Design: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its antiproliferative effect in vitro and in vivo.Results: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2–M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase-3/7 activity and decreased survivin levels and decreased cellular migration and invasion. CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Finally, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.Conclusions: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer. Clin Cancer Res; 23(17); 5044–54. ©2017 AACR.

Table S1. Summary of mutations present in the thyroid cancer cell lines and expression levels of differentiation markers. The table depicts known mutations in the six thyroid cancer cell lines we have utilized in our study. It also indicates the presence or absence (based on Ct values > 28) of thyroid differentiation markers in normal thyroid tissue, such as sodium-iodide symporter (NIS), thyroglobulin (Tg), and thyroid peroxidase (TPO) based on mRNA expression in these cell lines.

Supplementary method and data

Purpose: Mitochondrial glycerophosphate dehydrogenase (MGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin in the liver. There are no data on the expression and role of MGPDH as a metformin target in cancer. In this study, we evaluated MGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism.Experimental Design: We analyzed MGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer–derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on MGPDH expression were determined by qRT-PCR and Western blot analysis. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and MGPDH expression in metastatic thyroid cancer mouse models.Results: We show for the first time that MGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that MGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of MGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high MGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth-inhibitory effects of metformin in vitro and in vivo.Conclusions: Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin. Clin Cancer Res; 24(16); 4030–43. ©2018 AACR.

STR PROFILE

Background Certain symptoms associated with infertility are associated with cardiovascular disease, including menstrual cycle irregularity, early menopause, and obesity; however, few studies have investigated the association between infertility and cardiovascular disease risk. Methods and Results Participants in the NHSII (Nurses' Health Study II) who reported infertility (12 months of trying to conceive without success, including women who subsequently conceived) or who were gravid, with no infertility were followed from 1989 until 2017 for development of incident, physician‐diagnosed coronary heart disease (CHD) (myocardial infarction, coronary artery bypass grafting, angioplasty, stent) and stroke. Time‐varying Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs and were adjusted a priori for potential confounding variables. Among 103 729 participants, 27.6% reported having ever experienced infertility. Compared with gravid women who had not reported infertility, women with a history of infertility had greater risk of CHD (HR, 1.13 [95% CI, 1.01–1.26]) but not stroke (HR, 0.91 [95% CI, 0.77–1.07]). The association between history of infertility and CHD was strongest among women who reported infertility at an earlier age (HR for infertility first reported at ≤25 years, 1.26 [95% CI, 1.09–1.46]; HR at 26–30 years, 1.08 [95% CI, 0.93–1.25]; HR at >30 years, 0.91 [95% CI, 0.70–1.19]). When we investigated specific infertility diagnoses, elevated risk of CHD was observed among women whose infertility was attributed to an ovulatory disorder (HR, 1.28 [95% CI, 1.05–1.55]) or endometriosis (HR, 1.42 [95% CI, 1.09–1.85]). Conclusions Women with infertility may be at an increased risk of CHD. Risk differed by age at first infertility diagnosis and was restricted to ovulatory‐ and endometriosis‐related infertility.

Background Among all racial/ethnic groups, people who identify as African American/Blacks have the second highest colorectal cancer (CRC) incidence in the USA. This disparity may exist because African American/Blacks, compared to other racial/ethnic groups, have a higher prevalence of risk factors for CRC, including obesity, low fiber consumption, and higher intakes of fat and animal protein. One unexplored, underlying mechanism of this relationship is the bile acid-gut microbiome axis. High saturated fat, low fiber diets, and obesity lead to increases in tumor promoting secondary bile acids. Diets high in fiber, such as a Mediterranean diet, and intentional weight loss may reduce CRC risk by modulating the bile acid-gut microbiome axis. The purpose of this study is to test the impact of a Mediterranean diet alone, weight loss alone, or both, compared to typical diet controls on the bile acid-gut microbiome axis and CRC risk factors among African American/Blacks with obesity. Because weight loss or a Mediterranean diet alone can reduce CRC risk, we hypothesize that weight loss plus a Mediterranean diet will reduce CRC risk the most. Methods This randomized controlled lifestyle intervention will randomize 192 African American/Blacks with obesity, aged 45–75 years to one of four arms: Mediterranean diet, weight loss, weight loss plus Mediterranean diet, or typical diet controls, for 6 months (48 per arm). Data will be collected at baseline, mid-study, and study end. Primary outcomes include total circulating and fecal bile acids, taurine-conjugated bile acids, and deoxycholic acid. Secondary outcomes include body weight, body composition, dietary change, physical activity, metabolic risk, circulating cytokines, gut microbial community structure and composition, fecal short-chain fatty acids, and expression levels of genes from exfoliated intestinal cells linked to carcinogenesis. Discussion This study will be the first randomized controlled trial to examine the effects of a Mediterranean diet, weight loss, or both on bile acid metabolism, the gut microbiome, and intestinal epithelial genes associated with carcinogenesis. This approach to CRC risk reduction may be especially important among African American/Blacks given their higher risk factor profile and increased CRC incidence. Trial registration ClinicalTrials.gov NCT04753359. Registered on 15 February 2021.