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Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Urinary incontinence (UI) is a widespread condition affecting about 200 million people worldwide, with women affected more often than men and prevalence increasing with age. UI is a significant health problem that negatively impacts affected women’s well-being, sociality, and productivity. Therefore, seeking medical advice is highly recommended since valid treatment options exist. However, a definitive solution to the problem is not always possible. In these cases, absorbent containment products can help women deal with the persistent symptoms of incontinence, minimising the effects on the quality of life. High-quality products are paramount to avoid or reduce the onset of irritating skin phenomena, which can sometimes lead to more serious consequences, such as skin infections. Cotton is a natural fibre characterised by softness and hypoallergenic properties that has already shown its ability to improve skin health when used as a component of pads and other absorbent containment products. The aim of this work was to assess the safety and efficacy of a new organic cotton pull-on absorbent product in reducing skin erythema and oedema in women suffering from moderate to heavy urinary incontinence. In-vitro and clinical studies were performed. Results showed that the tested product effectively reduces skin erythema and oedema caused by the conventional use of synthetic pull-on absorbent products. Moreover, good compliance with the use was demonstrated compared to a non-cotton competitor device available on the market. In conclusion, the organic cotton absorbent device tested has improved the quality of life of women suffering from moderate to heavy urinary incontinence.

As neurons age, protein homeostasis becomes less efficient, resulting in misfolding and aggregation. Chaperone proteins perform vital functions in the maintenance of cellular proteostasis, and chaperone-based therapies that promote sequestration of toxic aggregates may prove useful in blocking the development of neurodegenerative disease. We previously demonstrated that proSAAS, a small secreted neuronal protein, exhibits potent chaperone activity against protein aggregation in vitro, and blocks the cytotoxic effects of amyloid and synuclein oligomers in cell culture systems. We now examine whether cytoplasmic expression of proSAAS results in interaction with protein aggregates in this cellular compartment. We report that expression of proSAAS within the cytoplasm generates dense, membraneless 2 μm proSAAS spheres which progressively fuse to form larger spheres, suggesting liquid droplet-like properties. ProSAAS spheres selectively accumulate a C-terminally truncated fluorescently-tagged form of TDP-43, initiating its cellular redistribution; these TDP-43 -containing spheres also exhibit dynamic fusion. Efficient encapsulation of TDP-43 into proSAAS spheres is driven by its C-terminal prion-like domain; spheres must be formed for sequestration to occur. Three proSAAS sequences, a predicted coiled-coil; a conserved region (residues 158–169); and the positively charged sequence 181–185 are all required for proSAAS to form spheres able to encapsulate TDP-43 aggregates. Substitution of lysines for arginines in the 181–185 sequence results in nuclear translocation of proSAAS and encapsulation of nuclear-localized TDP-43(216–414). As a functional output, we demonstrate that proSAAS expression results in cytoprotection against full-length TDP-43 toxicity in yeast. We conclude that proSAAS can act as a functional holdase for TDP-43 via this phase-separation property, representing a cytoprotectant whose unusual biochemical properties can potentially be exploited in the design of therapeutic molecules.

Supplementary Figures 1-6, Table 1 from G-Quadruplexes Induce Apoptosis in Tumor Cells

Several G-rich oligodeoxynucleotides (ODNs), which are capable of forming G-quadruplexes, have been shown to exhibit antiproliferative activity against tumor cell lines and antitumor activity in nude mice carrying prostate and breast tumor xenografts. However, the molecular basis for their antitumor activity remains unclear. In the current study, we showed that a variety of telomeric G-tail oligodeoxynucleotides (TG-ODNs) exhibited antiproliferative activity against many tumor cells in culture. Systematic mutational analysis of the TG-ODNs suggests that the antiproliferative activity depends on the G-quadruplex conformation of these TG-ODNs. TG-ODNs were also shown to induce poly(ADP-ribose) polymerase-1 cleavage, phosphatidylserine flipping, and caspase activation, indicative of induction of apoptosis. TG-ODN–induced apoptosis was largely ataxia telangiectasia mutated (ATM) dependent. Furthermore, TG-ODN–induced apoptosis was inhibited by the c-Jun NH2-terminal kinase (JNK) inhibitor SP600125. Indeed, TG-ODNs were shown to activate the JNK pathway in an ATM-dependent manner as evidenced by elevated phosphorylation of JNK and c-Jun. Interestingly, a number of G-quadruplex ODNs (GQ-ODN) derived from nontelomeric sequences also induced ATM/JNK-dependent apoptosis, suggesting a possible common mechanism of tumor cell killing by GQ-ODNs. (Cancer Res 2006; 66(24): 11808-16)

Our study aimed to evaluate the acceptability, adverse effects and continuation rates among adolescents who accepted the etonogestrel (ENG) subdermal implant and compared to adolescents who chose other methods during the immediate postpartum period before hospital discharge, with one year follow-up up.We conducted a cohort non-randomised study at the Women's Hospital, University of Campinas. All women up to 19 years of age, who gave birth at the hospital between July 2019 and April 2020, were invited to participate and were offered the ENG-implant or the routine contraceptive methods. They were followed for one year postpartum.We included 100 teenagers and 72 accepted the ENG-implant. Students are more likely to accept the ENG-implant than non-students (PR: 1.25 [95%CI 0.99-1.59]). Up to one year of follow-up, survival analysis showed that the time of adherence to the method was longer for the ENG-implant users (Provision ENG-implant for adolescents in the immediate postpartum demonstrated high acceptance and ensured effective contraception. After one year, most of them were satisfied, with a high continuation rate and without unplanned pregnancies.

Overweight and obesity are public health problems worldwide despite being modifiable conditions. The association between birth defects and pregestational maternal body mass index is not entirely clear. We aimed to assess the prevalence and estimate the risk of birth defects related to pregestational body mass index and other maternal factors. We explored a 30-year time series database in a cross-section study. We analysed 40,217 cases, among them 2.8% had birth defects. Bivariate analysis showed a higher prevalence of birth defects with increased pre-pregnancy body mass index and in extremes of maternal age, white skin colour, and primiparity. Multivariable logistic regression showed a higher chance of birth defects in women with pre-pregnancy overweight/obesity (OR:1.19 [CI95%:1.01-1.41]), maternal age ≥ 40 years (OR:1.68 [CI95%:1.11-2.54]), and white skin colour (OR:1.44 [CI95%:1.19-1.75]). Maternal weight is a modifiable risk factor that must be considered and addressed in preconception counselling to minimise possible deleterious effects on embryogenesis.IMPACT STATEMENT

Background Doxorubicin–mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Purpose: We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO–DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100), pAMPK, NF–kB, and 13 chemokines (IL–1α, IL–1β, IL–2, IL–4, IL–6, IL–10, IL–12, IL17–α, IL–18, IFN–γ, TNF–α, G–CSF, and GM–CSF) were quantified through ELISA and western blot methods. Results DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF–kB in cardiac tissues was seen in DOXO–DAPA group compared to DOXO mice (p Conclusion In this preclinical study, DAPA is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.

Background Anthracyclines are essential adjuvant therapies for a variety of cancers, particularly breast, and gastric and esophageal cancers. Whilst prolonging cancer–related survival, these agents can in–duce drug–related cardiotoxicity. Spirulina, Reishi (Ganoderma Lucidum) and Moringa are three nutaceuticals with anti–inflammatory effects that are currently used in cancer patients to improve quality of life and fatigue. Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with short–term doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), Singo at 12 mg/kg (Singo, n=6) or doxorubicin combined to Singo (DOXO–Singo, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100, Fujifilm). Myocardial expression of NLRP3, DAMPs (galectine 3 and calgranulin S100) and 13 cytokines (IL–1α, IL–1β, IL–2, IL–4, IL–6, IL–10, IL–12, IL17–α, IL–18, IFN–γ, TNF–α, G–CSF, and GM–CSF) were quantified through selective mouse ELISA methods. Myocadial fibrosis, necrosis and hypertrophy were analyzed through Immunohistochemistry (IHC). Human cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (200 nM) alone or in combination to Singo ( at 10, 25 and 50 µg/ml) for 24 and 48h. Cell viability studies were performed through MTS assay. Expression of NLRP3 and p65/NF–kB) were made through selective ELISA methods. Results In preclinical models of short–term DOXO cardiotoxicity, Singo improved significantly EF and FS and prevented the reduction of radial and longitudinal strain after 10 days of treatment with DOXO. A reduced expression of myocardial NLRP3 and NF–kB levels in cardiac tissues were seen in DOXO–Singo group compared to DOXO mice (p Conclusion Singo is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. Cardioprotective properties of Singo are mediated by the reduction of lipid peroxidation products and expression of NLRP3–NF–kB –cytokine pathways.

Unusual and discrepant ABO phenotypes are often due to genetic variants that lead to altered levels or activity of ABO transferases and consequently to altered expression of ABO antigens. This report describes eight genetic alterations found in 15 cases with reduced or undetectable expression of ABO antigens. Forward and reverse ABO grouping was performed by standard gel or tube methods. Adsorption-heat elution and saliva testing for H and A substances followed the AABB technical manual procedures. Genomic DNA extracted from whole blood was PCR-amplified to cover the entire ABO coding sequence, splice junctions, proximal promoter, and intron 1 enhancer. Amplification products were sequenced by next-generation or Sanger dideoxy methods, either directly or after cloning into a bacterial plasmid vector. Eight unreported alleles were found in the 15 cases analyzed. Alleles ABO*A(28+1C) and ABO*A(29–5G) harbor variants that alter the consensus sequence at the intron 1 donor and acceptor splice sites, respectively. The other alleles harbor variants that alter the consensus sequence at transcription factor–binding sites in the intron 1 enhancer: specifically, ABO*A(28+5792T), ABO*A(28+5859A), and ABO*A(28+5860G) at GATA-1 sites; ABO*B(28+5877T) and ABO*B(28+5878G) at a RUNX1 site; and ABO*A(28+5843A) at or near a C/EBP site. Molecular and serologic characterization of ABO alleles can help in their future identification and in the resolution of discrepancies.

Objective: To describe the incidence, clinical features and perinatal outcome of late onset growth restriction (FGR) associated with genetic syndromes or aneuploidy, structural malformation, or congenital infection. Methods: Retrospective multicenter cohort study conducted at four tertiary maternity hospitals in Italy. We included singleton pregnancies between 32+0 and 36+6 weeks of gestation with either abdominal circumference or estimated fetal weight

Kinase inhibition continues to be a major focus of pharmaceutical research and discovery due to the central role of these proteins in the regulation of cellular processes. One family of kinases of pharmacological interest, due to its role in activation of immunostimulatory pathways, is the Janus kinase family. Small molecule inhibitors targeting the individual kinase proteins within this family have long been sought-after therapies. High sequence and structural similarity of the family members makes selective inhibitors difficult to identify but critical because of their inter-related multiple cellular regulatory pathways. Herein, we describe the identification of inhibitors of the important Janus kinase, TYK2, a regulator of type I interferon response. In addition, the biochemical and structural confirmation of the direct interaction of these small molecules with the TYK2 pseudokinase domain is described and a potential mechanism of allosteric regulation of TYK2 activity through stabilization of the pseudokinase domain is proposed.

When the SEGH international board released a short editorial paper back in 2019, we described an aim to increase the membership offering, whilst improving the diversity of input regionally, by scientific discipline and to ensure greater and more regular contact across the regions from 2020 onwards. Wider aspirations described in 2019 (Watts et al. 2019) are discussed within this short communication at the end of 2021 to evaluate progress made. In particular, how the SEGH community adapted to the unprecedented circumstances that have challenged each and every one of us throughout the COVID-19 pandemic since early 2020 and are likely to influence our activities for the foreseeable future.

Background: Abnormal umbilical, cerebral and uterine artery Doppler findings and fetal biometry below the 3rd percentile have been proposed as risk factors for perinatal complications in late-onset fetal growth restriction (FGR). Recent evidence has allowed to reach a consensus on the clinical use of Doppler ultrasound for the monitoring and timing of delivery in early-onset FGR, however there is limited data on the relationship between abnormal Doppler and severity of the growth restriction and adverse outcome when a diagnosis of late-onset FGR is made. Objective: To evaluate the relationship between the ultrasound parameters measured at diagnosis and perinatal adverse outcome within a cohort of late-onset FGR fetuses. Methods: This is a multicentre retrospective study between 2014 and 2019 including non-anomalous singleton pregnancies complicated by late-onset FGR, which was defined either by abdominal circumference (AC), estimated fetal weight (EFW) 95th percentile at diagnosis proved to be independently associated with obstetric intervention due to intrapartum distress (p95th percentile at diagnosis is independently associated with intrapartum distress leading to obstetric intervention.

Unusual and discrepant ABO phenotypes are often due to genetic variants that lead to altered levels or activity of ABO transferases and consequently to altered expression of ABO antigens. This report describes eight genetic alterations found in 15 cases with reduced or undetectable expression of ABO antigens. Forward and reverse ABO grouping was performed by standard gel or tube methods. Adsorption-heat elution and saliva testing for H and A substances followed the AABB technical manual procedures. Genomic DNA extracted from whole blood was PCR-amplified to cover the entireUnusual and discrepant ABO phenotypes are often due to genetic variants that lead to altered levels or activity of ABO transferases and consequently to altered expression of ABO antigens. This report describes eight genetic alterations found in 15 cases with reduced or undetectable expression of ABO antigens. Forward and reverse ABO grouping was performed by standard gel or tube methods. Adsorption-heat elution and saliva testing for H and A substances followed the AABB technical manual procedures. Genomic DNA extracted from whole blood was PCR-amplified to cover the entire

Integrative medicine is a holistic approach to health care that acknowledges multiple dimensions of health, including its physical, emotional, and spiritual aspects. It approaches health not just as absence of disease but as a state of optimal vitality, and utilizes all appropriate evidence-based modalities, including lifestyle interventions, complementary treatments, and conventional allopathic methods, in one paradigm. Utilization of non-conventional therapies by women and interest in integrative care is very high. Much disinformation exists and many women engage in non-conventional therapies without medical advice, sometimes benefiting from them, but also possibly delaying needed care or placing themselves at risk. Research and clinical interest in non-conventional methods also is rising within the medical community, with increased recognition of the value of an integrative health model for individuals and communities. Obstetrician-gynecologists are in a unique position to support their patients in holistic health optimization by choosing beneficial integrative strategies while identifying potentially harmful practices.

Mobile devices are an integral part of modern medical education, as convenient platforms for access to online interactive learning resources; students’ use of textbooks has correspondingly declined. We designed an interactive iBook(©) for pre-clinical students encompassing the content of the pulmonary segment in an organ-based multidisciplinary course. We found, via a survey-based study, that students preferred the iBook to other faculty-supplied materials (PowerPoints and PDFs), mainly due to its interactive images, animations, and study questions. Students’ test performance did not change significantly after introducing the iBook. This study suggests that expanded use of interactive learning resources may enhance students’ engagement with pre-clinical courses.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. We establish that p38α MAPK phosphorylates TDP-43 at pathological serine 409/410 (S409/S410) and serine 292 (S292), which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we show that protein arginine methyltransferase 1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.

We analyse the high-quality Hertzsprung-Russell diagram (HRD) derived from Gaia data release 2 for the Solar Neighbourhood. We start building an almost-complete sample within 200 pc and for |b|>25 deg, so as to limit the impact of known errors and artefacts in the Gaia catalog. Particular effort is then put into improving the modelling of population of binaries, which produce two marked features in the HRD: the sequence of near-equal mass binaries along the lower main sequence, and the isolated group of hot subdwarfs. We describe a new tool, BinaPSE, to follow the evolution of interacting binaries in a way that improves the consistency with PARSEC evolutionary tracks for single stars. BinaPSE is implemented into the TRILEGAL code for the generation of "partial models" for both single and binary stellar populations, taking into account the presence of resolved and unresolved binaries. We then fit the Gaia HRD via MCMC methods that search for the star formation history (SFH) and initial binary fraction (by mass) that maximise the likelihood. The main results are (i) the binary fraction derived from the lower main sequence is close to 0.4, while twice larger values are favoured when the upper part of the HRD is fitted; (ii) present models predict the observed numbers of hot subdwarfs to within a factor of 2; (iii) irrespective of the prescription for the binaries, the star formation rate peaks at values 1.5e-4 Msun/yr at ages slightly above 2 Gyr, and then decreases to 0.8e-4 Msun/yr at very old ages., resubmitted to MNRAS after final minor changes requested by referee

We implemented a didactic experiment to study the angular correlation between the two gamma rays emitted in typical $^{60}$Co radioactive decays. We used two NaI(Tl) scintillators, already available in our laboratory, and a low-activity $^{60}$Co source. The detectors were mounted on two rails, with the source at their center. The first rail was fixed, while the second could be rotated around the source. We performed several measurements by changing the angle between the two scintillators in the range from $90^\circ$ to $180^\circ$. Dedicated background runs were also performed, removing the source from the experimental setup. We found that the signal rate increases with the angular separation between the two scintillators, with small discrepancies from the theoretical expectations., 15 pages, 12 figures

TOI-216 hosts a pair of warm, large exoplanets discovered by the TESS Mission. These planets were found to be in or near the 2:1 resonance, and both of them exhibit transit timing variations (TTVs). Precise characterization of the planets' masses and radii, orbital properties, and resonant behavior can test theories for the origins of planets orbiting close to their stars. Previous characterization of the system using the first six sectors of TESS data suffered from a degeneracy between planet mass and orbital eccentricity. Radial velocity measurements using HARPS, FEROS, and PFS break that degeneracy, and an expanded TTV baseline from TESS and an ongoing ground-based transit observing campaign increase the precision of the mass and eccentricity measurements. We determine that TOI-216c is a warm Jupiter, TOI-216b is an eccentric warm Neptune, and that they librate in the 2:1 resonance with a moderate libration amplitude of 60 +/- 2 degrees; small but significant free eccentricity of 0.0222 +0.0005/-0.0003 for TOI-216b; and small but significant mutual inclination of 1.2-3.9 degrees (95% confidence interval). The libration amplitude, free eccentricity, and mutual inclination imply a disturbance of TOI-216b before or after resonance capture, perhaps by an undetected third planet., Comment: AJ accepted

En este trabajo, que es parte de una investigación más extensa, sobre mejoramiento de la enseñanza de química universitaria, se presentan algunos resultados obtenidos luego de aplicar una nueva propuesta de enseñanza, destinada a la comprensión y resolución de problemas sobre el tema «Soluciones». Con el objeto de facilitar el aprendizaje significativo, la propuesta de trabajo incluye el uso de las denominadas herramientas metacognitivas que permitan aplicar metodologías conducentes al logro de dichos aprendizajes por parte de los estudiantes. Luego de aplicar las mencionadas herramientas, se procedió a realizar la evaluación de los estudiantes participantes para obtener datos sobre los logros alcanzados y sus aprendizajes. El análisis de los resultados muestra que el uso del nuevo enfoque instruccional ayuda a los estudiantes en sus procesos de aprendizaje, en la medida que se vayan haciendo conscientes de los mecanismos que se utilizan para obtener aprendizaje significativo. This work, which is part of a more extensive research project on the improvement of Chemistry teaching at university level, presents the results obtained by applying an innovative teaching methodology. This methodology was designed with the objective of helping students to better understand and solve problems regarding the topic "Solutions". In order to facilitate learning, the proposed methodology includes the use of metacognitive tools (concept maps, Gowin's Vee and clinical interviews), which allows the students to apply significant learning methodologies. After applying these tools, we evaluated the students in order to measure their achievements and their learning. The analysis of the results shows that the use of this new instructional approach helps the students in their learning process because they become aware of the mechanism they use to achieve significant learning.