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The unconventional superconductor Sr2RuO4 has long served as a benchmark for theories of correlated-electron materials. The determination of the superconducting pairing mechanism requires detailed experimental information on collective bosonic excitations as potential mediators of Cooper pairing. We have used Ru L3-edge resonant inelastic x-ray scattering to obtain comprehensive maps of the electronic excitations of Sr2RuO4 over the entire Brillouin zone. We observe multiple branches of dispersive spin and orbital excitations associated with distinctly different energy scales. The spin and orbital dynamical response functions calculated within the dynamical mean-field theory are in excellent agreement with the experimental data. Our results highlight the Hund metal nature of Sr2RuO4 and provide key information for the understanding of its unconventional superconductivity. The authors present resonant inelastic x-ray scattering measurements of Sr2RuO4 in the normal Fermi-liquid state. They find that spin excitations are confined below 200 meV, while orbital fluctuations appear only at higher energies. This separation of energy scales is a hallmark of Hund's-rule-induced electron correlations. [ABSTRACT FROM AUTHOR]

Background: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero., Methods and Findings: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin., Conclusions: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany., Competing Interests: The authors have declared that no competing interests exist. JR, NW, KP, BK, and UH are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. These are post-authorization safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry. The study presented was not funded by the pharmaceutical industry., (Copyright: © 2024 Reinold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objective: Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero., Methods: Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations., Results: The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation)., Conclusions: We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug., (© 2023. The Author(s).)

Background and Objective: Methotrexate should be withdrawn before pregnancy because of its teratogenic potential. We aimed to describe the use of methotrexate in women of childbearing age in Germany and the occurrence and outcomes of pregnancies exposed to methotrexate., Methods: Using the German Pharmacoepidemiological Research Database (GePaRD, covering ~ 20% of the German population), we determined the age-specific and age-standardized prevalence of methotrexate use for each year between 2004 and 2019 among women aged 13-49 years (cross-sectional analyses). In a cohort analysis, we assessed the number and outcomes of pregnancies exposed to methotrexate in the critical time window. Exposure was defined as a dispensation overlapping with the onset of pregnancy or a dispensation in the first 8 weeks of pregnancy. For children born from exposed pregnancies, the mother's and children's data were linked and the occurrence of malformations was assessed by reviewing all available data of these children., Results: The age-standardized prevalence of methotrexate use per 1000 females increased from 1.5 in 2004 to 2.3 in 2019, i.e., by 52%. Overall, we identified 184 pregnancies exposed to methotrexate. Of these, 53% ended in a live birth (21% preterm) and 11% in an induced abortion. Among 81 live-born children linked to their mothers, five children (6%) had relevant malformations including congenital heart defects and musculoskeletal malformations., Conclusions: In Germany, the use of methotrexate in women of childbearing age has substantially increased since 2004. Despite the known teratogenic effect, there was a considerable number of exposed pregnancies.  Also, malformations likely associated with methotrexate and thus avoidable were observed., (© 2022. The Author(s).)

Background: Authorizations of fingolimod, teriflunomide and cladribine were accompanied by risk minimization measures concerning their teratogenic potential. Real-world data on their use are scarce. We aimed to assess trends in the use of fingolimod, teriflunomide and cladribine among women of childbearing age, estimate the number of pregnancies occurring under treatment and explore the occurrence of malformations in newborns exposed during early pregnancy in Germany., Methods: Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from ∼20% of the German population), we determined annual age-standardized prevalences of fingolimod, teriflunomide and cladribine use from their authorization until 2019 among women aged 13-49 years (cross-sectional analyses). In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether there was an overlap between the exposure windows assigned to dispensations and the onset of pregnancy or a dispensation in the first eight weeks of pregnancy. For live births, a mother-baby linkage was performed. All available data of children with in-utero exposure and malformation codes in the first year of life were reviewed to verify the occurrence of congenital malformations., Results: For fingolimod, the age-standardized prevalence of use per 1,000 females increased from 0.14 in 2011 to 0.46 in 2019; for teriflunomide, from 0.06 in 2013 to 0.28 in 2019; for cladribine, from 0.01 in 2017 to 0.07 in 2019. The proportion of users aged ≤40 years was 60% for fingolimod, 45% for teriflunomide and 65% for cladribine. We identified 136 pregnancies exposed to fingolimod, 50 to teriflunomide and one to cladribine. For fingolimod and teriflunomide, respectively, 72% and 62% of exposed pregnancies ended in a live birth. Mother-newborn linkage was successful in 64 (fingolimod) and 20 (teriflunomide) live-born children. Among these, there were six with relevant malformations (mainly heart defects) for fingolimod and two for teriflunomide., Conclusion: Use of fingolimod, teriflunomide and cladribine among women of childbearing age has substantially increased in Germany. A high proportion of users was in age groups in which pregnancies typically occur. Despite risk minimization measures, early pregnancy exposure to these drugs was observed., Competing Interests: Declaration of Competing Interest The authors are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are post-authorization safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry. The study presented was not funded by the pharmaceutical industry and was performed in line with the ENCePP Code of Conduct., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: To characterize pregnancies among women with epilepsy who have filled a prescription for valproate at any time before or during pregnancy and to assess other antiepileptic drug (AED) prescriptions., Methods: Based on health claims data (German Pharmacoepidemiological Research Database - GePaRD; covering ~20% of the population), we selected pregnancies beginning between 2014 and 2016 in women with at least three years of observation period before pregnancy and with at least one epilepsy diagnosis code in the year before pregnancy. Among those, we selected pregnancies with at least one valproate dispensation any time before or during pregnancy. We further described these pregnancies regarding patterns in the dispensation of valproate and other AED among the women from their first day in the database until the end of the pregnancy., Results: Among 2068 pregnancies fulfilling the inclusion criteria, we identified 454 pregnancies (89% ending in live births and 8% in induced abortions) in 430 women with at least one valproate dispensation before or during pregnancy. In 357 of these pregnancies (79%), valproate was only dispensed before pregnancy, while 97 pregnancies (21%) had a valproate dispensation during pregnancy and of these, 77% (N = 75) during the first trimester. The proportion with a valproate dispensation during pregnancy declined from 2014 (25%) to 2016 (19%), also concerning exposure during the first trimester (2014: 20%, 2015: 17%, 2016: 12%), while the proportion ending in an induced abortion was increasing (2014: 5%, 2015: 8%, 2016: 13%). In 48% of exposed pregnancies (N = 36), there was no other AED dispensed during the entire observation time before pregnancy. This proportion was lower for pregnancies beginning in 2016 (33%) than for those beginning in 2014 and 2015 (53% and 50%, respectively)., Conclusion: In most women with epilepsy using valproate before or during pregnancy, valproate was dispensed only well before pregnancy beginning. The proportion exposed to valproate during the first trimester declined between 2014 and 2016, but the low proportion treated with alternative AED before valproate treatment suggests there is still room for improvement., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Little is known about the utilization of St. John's wort (Hypericum perforatum L.) during pregnancy. In Germany, certain preparations of St. John's wort can be reimbursed by statutory health insurances, facilitating to investigate exposure to St. John's wort based on claims data. We therefore aimed to characterize pregnancies exposed to St. John's wort and to explore potential malformations in the babies. Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), pregnancies exposed to St. John's wort during at least one trimester between 2006 and 2016 and the corresponding babies were identified. Exposure was identified via outpatient dispensations. Pregnancies were characterized regarding timing of exposure, use of other antidepressants, pregnancy outcomes and the occurrence of major malformations in the babies (not considering codes for musculoskeletal and other malformations due to low data quality in this regard). Out of 496 pregnancies with a dispensation of St. John's wort during pregnancy, 420 (85 %) had a dispensation during the first trimester. There was a dispensation of other antidepressants before pregnancy in 21 % (during pregnancy: 12 %). Eleven percent of pregnancies ended in non-live births. In 312 babies linked to 305 pregnancies, major malformations were coded in 18 babies (5.8 %), of which 17 were exposed in the first trimester. The crude relative risk of major malformations for babies exposed during the first vs. the second or third trimester only was 3.56 (0.48-26.17). Our results suggest that only in a minority of pregnancies, St. John's wort is used as an alternative to other antidepressants. Even though the relatively high rates of non-live births and major malformations after exposure to St. John's wort during the first trimester need to be interpreted with caution, the findings are striking and generate hypotheses that merit further investigation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Estimating the beginning of pregnancy is crucial when studying drug safety in pregnancy, but important information in this regard, such as the last menstrual period (LMP), is generally not recorded in claims databases. The beginning of pregnancy is therefore usually estimated by subtracting a median length of pregnancy from the date of birth. Due to the variability in pregnancy lengths, this might result in non-negligible errors. German claims data may offer the possibility to estimate the beginning of pregnancy more precisely based on the expected delivery date (EDD) which can be coded once or more often during a pregnancy. Purpose: To estimate the beginning of pregnancy in German claims data focusing on the potential of the expected delivery date (EDD). Methods: We included data of all pregnancies in women aged 12-50 years ending in a live birth between 2006 and 2015 identified in the German Pharmacoepidemiological Research Database (GePaRD). We assessed the number of coded EDDs per pregnancy and the concordance if ≥ 2 EDDs were coded. We estimated the beginning of pregnancy by subtracting 280 days from the EDD or the most frequent EDD (in case of discordant EDDs). To examine plausibility, we determined the distribution of pregnancy lengths and assessed whether the gestational age at which prenatal examinations were coded was plausible. For pregnancies without EDD, the beginning was estimated by subtracting the respective observed median lengths of pregnancy for preterm births, term births, and births after due date from the actual dates of birth. Results: In 82.4% of pregnancies, at least one EDD was available (thereof 6.1% with only one EDD and 80.9% with ≥ 2 EDDs that were all concordant). The maximal difference between discordant EDDs was in median 5 days (interquartile range: 3-7 days). Based on the EDD, the median length of pregnancy was 276 days for term births and in 84.7% of pregnancies the second antibody screening test was performed in the recommended interval ± 2 weeks. In pregnancies without EDD the respective proportion was 84.9%. Conclusions: By using the EDD, the beginning of pregnancy can plausibly be estimated in German claims data., (Copyright © 2020 Schink, Wentzell, Dathe, Onken and Haug.)

"Strange metals" with resistivity depending linearly on temperature T down to low T have been a long-standing puzzle in condensed matter physics. Here, we consider a lattice model of itinerant spin-[Formula: see text] fermions interacting via onsite Hubbard interaction and random infinite-ranged spin-spin interaction. We show that the quantum critical point associated with the melting of the spin-glass phase by charge fluctuations displays non-Fermi liquid behavior, with local spin dynamics identical to that of the Sachdev-Ye-Kitaev family of models. This extends the quantum spin liquid dynamics previously established in the large-M limit of [Formula: see text] symmetric models to models with physical [Formula: see text] spin-[Formula: see text] electrons. Remarkably, the quantum critical regime also features a Planckian linear-T resistivity associated with a T-linear scattering rate and a frequency dependence of the electronic self-energy consistent with the marginal Fermi liquid phenomenology., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Purpose: For studying drug utilization and safety in pregnancy based on administrative health care data, the reliable identification and classification of pregnancy outcomes in the data is essential. We aimed to optimize an existing algorithm for the identification and classification of pregnancy outcomes in the German Pharmacoepidemiological Research Database (GePaRD) with a particular focus on births., Methods: We reconsidered all codes used by the original algorithm and applied it to data of GePaRD from 2006 to 2014. Longitudinal records of pregnancies were used to identify targets for enhancing the algorithm's specificity. We checked the plausibility of the results, eg, regarding the age distribution of persons with pregnancy outcomes. Based on 20 longitudinal records of pregnancies, we compared the outcome classification by clinical experts with the results of the modified algorithm., Results: Our algorithm identified 1 235 261 pregnancy outcomes in the database, with the majority (94%) being live births, classified as preterm (10%), term (78%), and (12%) births after the expected delivery date. The median age of pregnant women was 32 years (Q1 28; Q3 35). Implausible sequence of outcomes (for example, an induced abortion within a pregnancy categorized as ending in a live birth) were rare (0.03%). The case profile review by clinical experts resulted in the same outcome type and date as the algorithm in 95%., Conclusions: Our algorithm led to plausible results regarding the identification and classification of pregnancy outcomes. It will be an important foundation for studies on drug utilization and drug safety during pregnancy based on GePaRD., (© 2018 John Wiley & Sons, Ltd.)

Background: Measures to raise awareness of the teratogenic potential of valproate and restrict its use in girls/women of childbearing age have been intensified. For Germany, the impact of these measures on valproate prescription rates remains unknown., Objectives: Trends in prescribing valproate, the underlying treatment indication, and the specialty of the prescribing physician are analyzed., Materials and Methods: With claims data from several statutory health insurance providers from 2004 to 2016 (approximately 3.5 million insured persons per year) considering treatment indication and medical specialties of prescribing physicians, we assessed the rate of girls/women (12 to 50 years) with at least one valproate dispensation per year., Results: The age-standardized rate of girls/women with at least one valproate dispensation declined by 28% between 2004 and 2016 (2.91/1000 vs. 2.09/1000). For 2015, the indications were epilepsy (66.9%), bipolar disorder (13.6%), migraine/headache (5.6%), schizoaffective disorder (4.3%), and other mental disorders (8.9%). Among epilepsy patients, the proportion treated with valproate declined from 26.2 to 16.8%, but changed little in patients with bipolar disorder (9.3% vs. 8.0%). A total of 46.3% of valproate dispensations were issued by neurologists or psychiatrists and 29.6% by general practitioners, internal medicine specialists, or family doctors., Conclusions: Based on German claims data, a decline of valproate dispensations was shown for epilepsy patients of childbearing age, while the proportion in other indications has hardly changed since 2004.

Scanning tunneling spectroscopy (STS) and scanning tunneling microscopy (STM) are perhaps the most promising ways to detect the superconducting gap size and structure in the canonical unconventional superconductor Sr2RuO4 directly. However, in many cases, researchers have reported being unable to detect the gap at all in STM conductance measurements. Recently, an investigation of this issue on various local topographic structures on a Sr-terminated surface found that superconducting spectra appeared only in the region of small nanoscale canyons, corresponding to the removal of one RuO surface layer. Here, we analyze the electronic structure of various possible surface structures using first principles methods, and argue that bulk conditions favorable for superconductivity can be achieved when removal of the RuO layer suppresses the RuO4 octahedral rotation locally. We further propose alternative terminations to the most frequently reported Sr termination where superconductivity surfaces should be observed. [ABSTRACT FROM AUTHOR]

The Patient Safety Culture Improvement Tool (PSCIT) was developed to assist healthcare organizations in identifying practical actions to improve their culture. This article describes the development process of the PSCIT and provides a guide to using the PSCIT. The tool is based on a safety culture maturity model, which describes five stages of cultural evolution, from pathological to generative. The PSCIT consists of nine elements that cover five patient safety culture dimensions, namely, leadership, risk analysis, workload management, sharing and learning and resource management. Each element describes the systems in place at each level of maturity, enabling organizations to identify their current level of maturity and actions to move to the next level. The PSCIT should be used with caution as there is currently a lack of reliability and validity data.

The pairing symmetry of Sr2RuO4 is a long-standing fundamental question in the physics of superconducting materials with strong electronic correlations. We use the functional renormalization group to investigate the behavior of superconductivity under uniaxial strain in a two-dimensional realistic model of Sr2RuO4 obtained with density functional theory and incorporating the effect of spin-orbit coupling. We find a dominant d x 2 − y 2 superconductor mostly hosted by the dxy-orbital, with no other closely competing superconducting state. Within this framework, we reproduce the experimentally observed enhancement of the critical temperature under strain and propose a simple mechanism driven by the density of states to explain our findings. We also investigate the competition between superconductivity and spin-density wave ordering as a function of interaction strength. By comparing theory and experiment, we discuss constraints on a possible degenerate partner of the d x 2 − y 2 superconducting state. [ABSTRACT FROM AUTHOR]

Purpose: Large health-care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof-of-concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child., Methods: We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA-exposed ones to all pregnancies., Results: Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA-exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7-88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA-exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9-76.0)., Conclusions: Our proof-of-concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

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The treatment of dermatological diseases during pregnancy and breastfeeding poses particular challenges for the therapist for medical and legal reasons. Maternal and fetal influencing factors must be taken into account and the special need for protection of the fetus, infant, and mother must be considered in the treatment decision, usually outside of the approval process. Due to the lack of or insufficient evidence for most therapies during pregnancy and breastfeeding, an individual risk-benefit assessment should always be carried out, which also takes into account the risk of nontreatment. In the case of difficult or potentially momentous decisions, information from relevant databases, intercollegiate consultation and, if possible, advice from a clinical ethics committee should be obtained. In any case, the parents, and in particular the mother, should be carefully informed and their consent should be obtained and documented. Recommendations can be made for common chronic inflammatory and infectious dermatoses, but these should be reviewed on a case-by-case basis. For other therapy situations, an individual analysis and decision-making process is necessary. Overall, however, it can be stated that digital data processing and availability, combined with careful analysis, empathetic consideration and information for those affected, enables a successful treatment decision to be made in the vast majority of cases., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Psoriasis, a common chronic inflammatory skin disorder, encompasses various subtypes, including guttate, pustular, erythrodermic, and the most common type, plaque psoriasis. Irrespective of the subtype, psoriasis can manifest with multisystemic presentations, including psoriatic arthritis, metabolic disorders, cardiovascular disease, malignancies, chronic kidney disease (CKD), psychiatric illness, and inflammatory bowel disease (IBD). Many comorbidities and concomitant conditions must be considered when selecting the most appropriate therapy for a patient (Kaushik et al., 2019 and Monks et al., 2021) . Ongoing clinical trials and the development of new therapeutic targets contribute to the continuous improvement of available treatment options. Given the dynamic landscape of therapies, particularly when managing complex patients with multiple comorbidities, dermatologists are constantly challenged with the task of adeptly tailoring treatments to each psoriasis patient. This article systematically reviews the current evidence, presenting it as an updated Psoriasis Decision Tree to assist physicians in selecting tailored treatment options., (© 2024 the International Society of Dermatology.)

Effects of valproate (VPA) dose and treatment discontinuation during the first trimester of pregnancy on the risks of spontaneous abortions (SAB) and major birth defects were analyzed. Pregnancies with first trimester VPA exposure (n = 484) prospectively recorded by the German Embryotox center in 1997–2016 were compared with a randomly selected, non-exposed cohort (n = 1446). The SAB risk was not significantly increased in the VPA cohort [HRadj 1.31 (95% CI 0.85–2.02)] but major birth defects were significantly more frequent [8.7% vs. 3.4%; ORadj 2.61 (95% CI 1.51–4.50)]. Risk was even higher in pregnancies with no VPA discontinuation in first trimester [ORadj 3.66 (95% CI 2.04–6.54)]. Significant ORs were found for nervous system defects in general [ORadj 5.69 (95% CI 1.73–18.78)], severe microcephaly [ORadj 6.65 (95% CI 1.17–37.68)], hypospadias [ORadj 19.49 (95% CI 1.80–211)] and urinary system defects [ORadj 6.51 (95% CI 1.48–28.67)]. VPA dose had a stronger effect than antiepileptic poly- versus monotherapy; for VPA dose ≥ 1500 mg/day the ORadj was 5.41 (95% CI 2.32–12.66)]. A daily dose increase of 100 mg was calculated to raise the risk for major birth defects by 15% [OR 1.15 (95% CI 1.08–1.23)]. Overall, maternal first trimester treatment regimen had a relevant impact on birth defect risk. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs., Competing Interests: Declarations Conflict of Interest RM received funding for Travel, Meeting attendance or Advisory Board participation from Alexion, Argenx, Biomarin, Catalyst, SANOFI, Regeneron and UCB.FS received public speaking honoraria from Alexion, argenx, Biogen, Genpharm, Medpharma, Medison Pharma, Mylan, Neopharm Israel, Novartis, Roche, Sanofi, Zai Lab; compensation for advisory boards from Alexion, Almirall, argenx, Astrazeneca, Avexis, Biogen, Forward Pharma, Dianthus, Lexeo Therapeutics, Merk, Novartis GmBh, Reata, Roche, Sandoz, Sanofi, Takeda; consultation fees from Alexion, Dianthus, EPG Comunication Holding ltd, Forward Pharma, Medscape, Novatek,PeerView, Vitaccess; he has been clinical trial principal investigator for Alexion, argenx, Dianthus, Immunovant, Lediant, Novartis, Prilenia, Sanofi.GA declares conference honoraria, advisory board and travel grants from Kedrion, Jannsen, Alnylam, Alexion, Argenx, Takeda.DMB declares advisory board honoraria from Argenx, Alexion, Roche; research support as PI for Roche and Alexion; speaker's Honoraria from Argenx, Alexion, UCB.AE has no competing interests to declare.FH has no competing interests to declare.RL declares lecture fees, advisory board, videointerview, fees for meeting chairing and scientific organization from Summeet, Alexion Pharma Italy, UCB Pharma, Med Stage, Amicus Therapeutics, Alfasigma, ECM network, Healthware group, PTS, Aim Education, Sanofi Genzyme Corporation.EP reports personal fees from Biogen, Roche, Novartis, Alexion and UCB Biopharma outside the submitted work. EP is part of the advisory boards for Biogen, Roche, Alexion, UCB Pharma.CR received honoraria for speaking, advisory boards and compensation for congress participations from Alexion, Argenx, and UCB, outside the submitted work.AS, MS and GP have no competing interests to declare., (© 2024. Fondazione Società Italiana di Neurologia.)

The universality of the strange metal phase in many quantum materials is often attributed to the presence of a quantum critical point (QCP), a zero-temperature phase transition ruled by quantum fluctuations. In cuprates, where superconductivity hinders direct QCP observation, indirect evidence comes from the identification of fluctuations compatible with the strange metal phase. Here we show that the recently discovered charge density fluctuations (CDF) possess the right properties to be associated to a quantum phase transition. Using resonant x-ray scattering, we studied the CDF in two families of cuprate superconductors across a wide doping range (up to p = 0.22). At p* ≈ 0.19, the putative QCP, the CDF intensity peaks, and the characteristic energy Δ is minimum, marking a wedge-shaped region in the phase diagram indicative of a quantum critical behavior, albeit with anomalies. These findings strengthen the role of charge order in explaining strange metal phenomenology and provide insights into high-temperature superconductivity. It has been suggested that the strange metal phase in cuprates stems from a quantum critical point slightly above optimal doping. By resonant x-ray scattering in two cuprate families in a wide doping range, Arpaia et al. show that charge density fluctuations could be associated with this quantum critical point. [ABSTRACT FROM AUTHOR]

Purpose: To examine prescriptions of valproate and oral antiepileptic drugs (OAED) in Germany irrespective of the indication in women in general and particularly in women of childbearing age (13–49 years) and during pregnancy between 2010 and 2020, that is, before, during and after the implementation of the EU risk minimization measures (RMMs). Methods: Analysis of claims data. Study population: all women continuously insured with the AOK health insurance fund in the respective observation year (2010–2020) and the previous year. OAED were identified by ATC code N03. Period of pregnancy was calculated based on birth information in claims data. Main outcomes measures: (i) prevalent use of valproate/OAED: number of women with at least one prescription of valproate/OAED per year divided by all women of the study population (rate per 1000 women); (ii) percentage of OAED recipients with at least one valproate prescription during pregnancy (13–49 years) in the respective observation year. Results: Prevalence rate/1000 women for valproate use decreased by −31.33% across all age groups (2010–2014: −7.48%; 2014–2018: −16.47%; 2018–2020: −11,17%) with a strong reduction in women 13–49 years between 2014 and 2018 (−28.74%). The rate for OAED across all age groups rose from 33.43/1000 women in 2010 to 41.03/1000 (+22,73%). Valproate use during pregnancy of women with OAED declined from 1.29% in 2010 to 0.59% in 2020 (−54,26%) (2010–2014: −5.14%; 2014–2018: −42.31%; 2018–2020: −16.69%). Conclusion: Even if, due to the descriptive nature of the study, no causal relationship can be postulated between the RMMs and the strong decrease in valproate prescriptions, our results are compatible with the hypothesis that the measures have improved drug therapy safety. [ABSTRACT FROM AUTHOR]

Semiconductor nanowires coupled to superconductors can host Andreev bound states with distinct spin and parity, including a spin-zero state with an even number of electrons and a spin-1/2 state with odd-parity. Considering the difference in spin of the even and odd states, spin-filtered measurements can reveal the underlying ground state. To directly measure the spin of single-electron excitations, we probe an Andreev bound state using a spin-polarized quantum dot that acts as a bipolar spin filter, in combination with a non-polarized tunnel junction in a three-terminal circuit. We observe a spin-polarized excitation spectrum of the Andreev bound state, which can be fully spin-polarized, despite strong spin-orbit interaction in the InSb nanowires. Decoupling the hybrid from the normal lead causes a current blockade, by trapping the Andreev bound state in an excited state. Spin-polarized spectroscopy of hybrid nanowire devices, as demonstrated here, is proposed as an experimental tool to support the observation of topological superconductivity. Andreev bound states can form in hybrid semiconducting-superconducting devices and can mirror the experimental signatures of the much sought topologically non-trivial Majorana bound states. Here, van Driel, Wang and coauthors present a method of directly measuring the spin-polarized excitation spectrum of Andreev bound states. [ABSTRACT FROM AUTHOR]

Realizing the promises of molecular electronic devices requires an understanding of transport on the nanoscale. Here, we consider a Su-Schrieffer-Heeger model for semi-conducting trans-polyacetylene molecular wires in which we endow charge carriers with a finite lifetime. The aim of this exercise is two-fold: (i) the simplicity of the model allows an insightful numerical and analytical comparison of the Landauer and Kubo linear-response formalism; (ii) we distill the prototypical characteristics of charge transport through gapped mesoscopic systems and compare these to bulk semiconductors. We find that both techniques yield a residual differential conductance at low temperatures for contacted polyacetylene chains of arbitrary length—in line with the resistivity saturation in some correlated narrow-gap semiconductors. Quantitative agreement, however, is limited to not too long molecules. Indeed, while the Landauer transmission is suppressed exponentially with the system size, the Kubo response only decays hyperbolically. Our findings inform the choice of transport methodologies for the ab initio modelling of molecular devices. [ABSTRACT FROM AUTHOR]

Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3–4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS. [ABSTRACT FROM AUTHOR]

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines fromSt. John'swort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John's wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin - but not to valerenic acid-is likely to be minimal. [ABSTRACT FROM AUTHOR]

Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification. [ABSTRACT FROM AUTHOR]

The strange metal behavior, usually characterized by a linear-in-temperature (T) resistivity, is a still unsolved mystery in solid-state physics. It is often associated with the proximity to a quantum critical point (a second order transition at temperature T = 0 , leading to a broken symmetry phase) focusing on the related divergent order parameter correlation length. Here, we propose a paradigmatic shift, focusing on a divergent characteristic time scale due to a divergent dissipation acting on the fluctuating critical modes while their correlation length stays finite. To achieve a divergent dissipation, we propose a mechanism based on the coupling between a local order parameter fluctuation and electron density diffusive modes that accounts both for the linear-in-T resistivity and for the logarithmic specific heat versus temperature ratio C V / T ∼ log (1 / T) , down to low temperatures. [ABSTRACT FROM AUTHOR]

The superconducting order parameter (SOP) of a triplet superconductor UTe 2 was constructed using the topological space group approach, in which, in contrast to phenomenological and topological approaches, the single pair function and phase winding in condensate are different quantities. The connection between them is investigated for the D 2 h point group and the m ′ m ′ m magnetic group. It is shown how a non-unitary pair function of UTe 2 can be constructed using one-dimensional real irreducible representations and Ginzburg–Landau phase winding. It is also shown that the total phase winding is non-zero in magnetic symmetry only. Experimental data on the superconducting order parameter of topological superconductors UPt 3 , Sr 2 RuO 4 , LaPt 3 P, and UTe 2 are considered and peculiarities of their nodal structures are connected with the theoretical results of the topological space group approach. [ABSTRACT FROM AUTHOR]

Purpose: Health care insurance claims databases are becoming a more common data source for studies of medication safety during pregnancy. While pregnancies have historically been identified in such databases by pregnancy outcomes, International Classification of Diseases, 10th revision Clinical Modification (ICD‐10‐CM) Z3A codes denoting weeks of gestation provide more granular information on pregnancies and pregnancy periods (i.e., start and end dates). The purpose of this study was to develop a process that uses Z3A codes to identify pregnancies, pregnancy periods, and links infants within a commercial health insurance claims database. Methods: We identified pregnancies, gestation periods, pregnancy outcomes, and linked infants within the US‐based Optum Research Database between 2015 and 2020 via a series of algorithms utilizing diagnosis and procedure codes on claims. The diagnosis and procedure codes included ICD‐10‐CM codes, Current Procedural Terminology (CPT) codes, and Healthcare Common Procedure Coding System (HCPCS) codes. Results: We identified 1 030 874 pregnancies among 841 196 women of reproductive age. Of pregnancies with livebirth outcomes, 84% were successfully linked to infants. The prevalence of pregnancy outcomes (livebirth, stillbirth, ectopic, molar, and abortion) was similar to national estimates. Conclusions: This process provides an opportunity to study drug safety and care patterns during pregnancy and may be replicated in other claims databases containing ICD‐10‐CM, CPT, and HCPCS codes. Work is underway to validate and refine the various algorithms. [ABSTRACT FROM AUTHOR]

When confronted with non-psychotic mental disorders, pregnant women often refrain from using synthetic drugs and resort to herbal medicines such as St. John's wort, California poppy, valerian, lavender, and hops. Nevertheless, these herbal medicines have not yet been officially approved in pregnancy due to lack of safety data. Using a variety of in vitro methods (determination of cytotoxicity, apoptosis induction, genotoxicity, effects on metabolic properties, and inhibition/induction of differentiation) in a commonly used placental cell line (BeWo b30), we were previously able to show that extracts from these plants are likely to be safe at the usual clinical doses. In the present work, we wanted to extend our safety assessment of these herbal medicines by 1) looking for possible effects on gene expression and 2) using the same in vitro methods to characterize effects of selected phytochemicals that might conceivably lead to safety issues. Proteomics results were promising, as none of the five extracts significantly affected protein expression by up- or down-regulation. Protopine (contained in California poppy), valerenic acid (in valerian), and linalool (in lavender) were inconspicuous in all experiments and showed no adverse effects. Hyperforin and hypericin (two constituents of St. John's wort) and valtrate (typical for valerian) were the most obvious phytochemicals with respect to cytotoxic and apoptotic effects. A decrease in cell viability was evident with hypericin (≥1 µM) and valtrate (≥10 µM), whereas hyperforin (≥3 µM), hypericin (30 µM) and valtrate (≥10 µM) induced cell apoptosis. None of the tested phytochemicals resulted in genotoxic effects at concentrations of 0.1 and 1 µM and thus are not DNA damaging. No decrease in glucose consumption or lactate production was observed under the influence of the phytochemicals, except for valtrate (at all concentrations). No compound affected cell differentiation, except for hyperforin (≥1 µM), which had an inhibitory effect. This study suggests that extracts from St. John's wort, California poppy, valerian, lavender, and hops are likely to be safe during pregnancy. High plasma concentrations of some relevant compounds—hyperforin and hypericin from St. John's wort and valtrate from valerian—deserve special attention, however. [ABSTRACT FROM AUTHOR]

Recently fabricated InSe monolayers exhibit remarkable characteristics that indicate the potential of this material to host a number of many-body phenomena. In this work, we systematically describe collective electronic effects in hole-doped InSe monolayers using advanced many-body techniques. To this end, we derive a realistic electronic-structure model from first principles that takes into account the most important characteristics of this material, including a flat band with prominent van Hove singularities in the electronic spectrum, strong electron–phonon coupling, and weakly screened long-ranged Coulomb interactions. We calculate the temperature-dependent phase diagram as a function of band filling and observe that this system is in a regime with coexisting charge density wave and ferromagnetic instabilities that are driven by strong electronic Coulomb correlations. This regime can be achieved at realistic doping levels and high enough temperatures, and can be verified experimentally. We find that the electron–phonon interaction does not play a crucial role in these effects, effectively suppressing the local Coulomb interaction without changing the qualitative physical picture. [ABSTRACT FROM AUTHOR]

By precisely writing down the matrix element of the local Boltzmann operator ( e - τ h , where h is the Hermitian conjugate pairs of off-diagonal operators), we have proposed a new path integral formulation for quantum field theory and developed a corresponding Monte Carlo algorithm. With the current formula, the Hubbard–Stratonovich transformation is not necessary, accordingly the determinant calculation is not needed, which can improve the computational efficiency. The results show that, the simulation time has the square-law scaling with system sizes, which is comparable with the usual first-principles calculations. The current formula also improves the accuracy of the Suzuki–Trotter decomposition. As an example, we have studied the one-dimensional half-filled Hubbard model at finite temperature. The obtained results are in excellent agreement with the known solutions. The new formula and Monte Carlo algorithm could be applied to various studies in future. [ABSTRACT FROM AUTHOR]

An accurate estimated date of delivery (EDD) helps pregnant women make adequate preparations before delivery and avoid the panic of parturition. EDD is normally derived from some formulates or estimated by doctors based on last menstruation period and ultrasound examinations. This study attempted to combine antenatal examinations and electronic medical records to develop a hybrid model based on Gradient Boosting Decision Tree and Gated Recurrent Unit (GBDT-GRU). Besides exploring the features that affect the EDD, GBDT-GRU model obtained the results by dynamic prediction of different stages. The mean square error (MSE) and coefficient of determination (R2) were used to compare the performance among the different prediction methods. In addition, we evaluated predictive performances of different prediction models by comparing the proportion of pregnant women under the error of different days. Experimental results showed that the performance indexes of hybrid GBDT-GRU model outperformed other prediction methods because it focuses on analyzing the time-series predictors of pregnancy. The results of this study are helpful for the development of guidelines for clinical delivery treatments, as it can assist clinicians in making correct decisions during obstetric examinations. [ABSTRACT FROM AUTHOR]