Focus on today's evidence while keeping an eye on the future: lessons derived from hypertension in women

Bipolar disorder (BD) is a common mental disorder characterized by recurrent mood episodes, which causes major socioeconomic burdens globally. Though its disease pathogenesis is largely unknown, the high heritability of BD indicates strong contributions from genetic factors. In this review, we summarize the recent achievements in the genetics of BD, particularly those from genome-wide association study (GWAS) of common variants and next-generation sequencing analysis of rare variants. These include the identification of dozens of robust disease-associated loci, deepening of our understanding of the biology of BD, objective description of correlations with other psychiatric disorders and behavioral traits, formulation of methods for predicting disease risk and drug response, and the discovery of a single gene associated with bipolar disorder and schizophrenia spectrum with a large effect size. On the other hand, the findings to date have not yet made a clear contribution to the improvement of clinical psychiatry of BD. We overview the remaining challenges as well as possible paths to resolve them, referring to studies of other major neuropsychiatric disorders.

Evidence from epidemiological studies on the role of tea drinking in gastric cancer risk remains inconsistent. We aimed to investigate and quantify the relationship between tea consumption and gastric cancer in the Stomach cancer Pooling (StoP) Project consortium. Methods. A total of 9438 cases and 20,451 controls from 22 studies...

Due to the prolonged inflammatory process induced by infection of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indices of autonomic nervous system dysfunction may persist long after viral shedding. Previous studies showed significant changes in HRV parameters in severe (including fatal) infection of SARS-CoV-2. However, few studies have comprehensively examined HRV in individuals who previously presented as asymptomatic or mildly symptomatic cases of COVID-19. In this study, we examined HRV in asymptomatic or mildly symptomatic individuals 5"“7 weeks following positive confirmation of SARS-CoV-2 infection. Sixty-five ECG Holter recordings from young (mean age 22.6"‰Â±"‰3.4 years), physically fit male subjects 4"“6 weeks after the second negative test (considered to be the start of recovery) and twenty-six control male subjects (mean age 23.2"‰Â±"‰2.9 years) were considered in the study. Night-time RR time series were extracted from ECG signals. Selected linear as well as nonlinear HRV parameters were calculated. We found significant differences in Porta's symbolic analysis parameters V0 and V2 (p"‰<"‰0.001), α2 (p"‰<"‰0.001), very low-frequency component (VLF; p"‰="‰0.022) and respiratory peak (from the PRSA method; p"‰="‰0.012). These differences may be caused by the changes of activity of the parasympathetic autonomic nervous system as well as by the coupling of respiratory rhythm with heart rate due to an increase in pulmonary arterial vascular resistance. The results suggest that the differences with the control group in the HRV parameters, that reflect the functional state of the autonomic nervous system, are measurable after a few weeks from the beginning of the recovery even in the post-COVID group-a young and physically active population. We indicate HRV sensitive markers which may be used in long-term monitoring of patients after recovery.

Automated driving systems (ADS) have undergone a significant improvement in the last years. ADS and more precisely self-driving cars technologies will change the way we perceive and know the world of transportation systems in terms of user experience, mode choices and business models. The emerging field of Deep Learning (DL) has been successfully applied for the development of innovative ADS solutions. However, the attempt to single out the best deep neural network architecture and tuning its hyperparameters are all expensive processes, both in terms of time and computational resources. In this work, Bayesian optimization (BO) is used to optimize the hyperparameters of a Spatiotemporal-Long Short Term Memory (ST-LSTM) network with the aim to obtain an accurate model for the prediction of the steering angle in a ADS. BO was able to identify, within a limited number of trials, a model-namely BO_ST-LSTM-which resulted, on a public dataset, the most accurate when compared to classical end-to-end driving models.

Microbial communities and their associated bioactive compounds1,2,3 are often disrupted in conditions such as the inflammatory bowel diseases (IBD)4. However, even in well-characterized environments (for example, the human gastrointestinal tract), more than one-third of microbial proteins are uncharacterized and often expected to be bioactive5,6,7. Here we systematically identified more than 340,000 protein families as potentially bioactive with respect to gut inflammation during IBD, about half of which have not to our knowledge been functionally characterized previously on the basis of homology or experiment. To validate prioritized microbial proteins, we used a combination of metagenomics, metatranscriptomics and metaproteomics to provide evidence of bioactivity for a subset of proteins that are involved in host and microbial cell"“cell communication in the microbiome; for example, proteins associated with adherence or invasion processes, and extracellular von Willebrand-like factors. Predictions from high-throughput data were validated using targeted experiments that revealed the differential immunogenicity of prioritized Enterobacteriaceae pilins and the contribution of homologues of von Willebrand factors to the formation of Bacteroides biofilms in a manner dependent on mucin levels. This methodology, which we term MetaWIBELE (workflow to identify novel bioactive elements in the microbiome), is generalizable to other environmental communities and human phenotypes. The prioritized results provide thousands of candidate microbial proteins that are likely to interact with the host immune system in IBD, thus expanding our understanding of potentially bioactive gene products in chronic disease states and offering a rational compendium of possible therapeutic compounds and targets.

Silver-Russel syndrome (SRS) is a representative imprinting disorder (ID) characterized by growth failure and diagnosed by clinical features. Recently, international consensus has recommended using the Netchine-Harbison clinical scoring system (NH-CSS) as clinical diagnostic criteria. Loss of methylation of H19/IGF2:intergenic differentially methylated region (H19LOM) and maternal uniparental disomy chromosome 7 (UPD(7)mat) are common etiologies of SRS; however, other IDs, pathogenic variants (PVs) of genes, and pathogenic copy number variants (PCNVs) have been reported in patients meeting NH-CSS. To clarify the frequency and clinical characteristics of each etiology, we conducted (epi)genetic analysis in 173 patients satisfying NH-CSS. H19LOM and UPD(7)mat were identified in 34.1%. PCNVs, other IDs, and PVs were in 15.0%. Patients with all six NH-CSS items were most frequently observed with H19LOM and UPD(7)mat. This study confirmed the suitability of NH-CSS as clinical diagnostic criteria, the (epi)genetic heterogeneity of SRS, and showed the necessity of further discussion regarding the "SRS spectrum".

European Journal of Clinical Nutrition (2022)Cite this article. This study aimed to investigate the association of breakfast consumption frequency (BCF) with glycemic control indices in a cross-sectional sample of adults from families at high risk for type 2 diabetes mellitus (T2DM), exploring the role of sex and socioeconomic status (SES).

Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by variants in MECP2. Emerging evidence of ethnic specificity of genetic variations has allowed precise diagnostic approaches with tailored therapies. In this study, we reviewed the variation spectrum of MECP2 in Korean RTT(-like)Â patients and compared it with previous reports in multiple ethnic groups. We reevaluated variants found in Korean RTTÂ patients according to the new Clinical Genome Resource guideline to reinterpret and reclassify variants of uncertain significance in MECP2. Among 377 cases, 56 (14.9%) showed pathogenic variants, and three novel variants, p.(Ala277Argfs*7), p.(Ala378Glyfs*8), and p.(Arg270_Ser332del), were identified. Comprehensive data from Korea revealed an overall consistent variation spectrum with those from other ethnicities. Through the reevaluation of variants, nine that previously had insufficient evidence for pathogenicity were reclassified into pathogenic variants. Our study provided insight on the genetic contribution of MECP2 in RTT and a useful background for genetic counseling in the Korean population.

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2"“3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.

Loss or deletion of survival motor neuron 1 gene (SMN1) is causative for a severe and devastating neuromuscular disease, Spinal Muscular Atrophy (SMA). SMN1 produces SMN, a ubiquitously expressed protein, that is essential for the development and survival of motor neurons. Major advances and developments in SMA therapeutics are shifting the natural history of the disease. With three relatively new available therapies, nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi), patients survive longer and have improved outcomes. However, patients and families continue to face many challenges associated with use of these therapies, including poor treatment response and a variability in the benefits to those that do respond, suggesting that the quest for the SMA cure is not over. In this review, we discuss the current therapies, their limitations, and highlight necessary gaps that need to be addressed to guarantee the best outcomes for SMA patients.

A novel vinyl polymer bearing an extended conjugated disodium dicarboxylate structure, specifically, the terphenyl side chain structure, which has a favorable electrochemical performance, has been synthesized and evaluated as an anode for sodium-ion batteries. The electrochemical performance was significantly improved over that of the vinyl polymer with disodium terephthalate. In particular, the discharge potential shifted by ~0.1"‰V to a lower potential at 0.28"‰V (vs. Na/Na+). Additionally, a specific capacity of 121"‰mAh"‰g"“1 at 10"‰mA"‰g"“1, which corresponds to an 88% theoretical capacity, was observed. Moreover, better rate performance was also achieved through the extended Ï€-conjugated system.

Aging is associated with a reduced magnitude of primary immune responses to vaccination. mRNA-based SARS-CoV-2 vaccines have shown efficacy in older adults but virus variant escape is still unclear. Here we analyze humoral and cellular immunity against an early-pandemic viral isolate and compare that to the P.1 (Gamma) and B.1.617.2 (Delta) variants in two cohorts (<50 and >55 age) of mRNA vaccine recipients. We further measure neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595, with the latter SARS-CoV-2 isolate bearing the spike mutation E484Q. Robust humoral immunity is measured following second vaccination, and older vaccinees manifest cellular immunity comparable to the adult group against early-pandemic SARS-CoV-2 and more recent variants. More specifically, the older cohort has lower neutralizing capacity at 7-14 days following the second dose but equilibrates with the younger cohort after 2-3 months. While long-term vaccination responses remain to be determined, our results implicate vaccine-induced protection in older adults against SARS-CoV-2 variants and inform thinking about boost vaccination.

I definitely had a 'yikes' moment when Sean Ekins presented the work at the Spiez conference, even though the exact details of the model remained opaque (and there are good reasons why these details were obscured in the Comment article4). The model generated some very toxic known nerve agents among the resulting dataset comprising 40,000 compounds. It is also safe to assume that among those that diverged from the known chemical space, there will be some that are extremely toxic. So yes, there is clearly a misuse potential, and raising awareness of this potential is a merit of the article.

Governing food-system transitions requires innovation in the study of impacts and futures. Current approaches to impact assessment require greater complexity in systems modelling and complementation with alternative mechanisms to overcome limitations in scoping, conceptual assumptions and methodologies. Global food systems are under pressure for reform owing to their detrimental impacts...

Children’s Cancer Hospital 57357 and Cairo University, Cairo, Egypt. Kathmandu Institute of Applied Sciences, Kathmandu, Nepal. Institute of Tropical Medicine Pedro Kouri, Havana, Cuba. Huan Jiang. BGI, Shenzhen, China. Firdausi Qadri. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. National Institute of Biomedical Genomics, Kalyani, India. On behalf of...

In the version of this article initially published, the second paragraph of the Discussion had several incorrect reference citations (62"“65 in the original). They have been removed and the remaining references renumbered throughout. The changes have been made to the HTML and PDF versions of the article. Public Health...

For most cancers, spread to the lymph nodes (LNs) is a marker of poor prognosis and typically precedes dissemination to distant sites. Despite this well-known association, it was unclear whether LN seeding is necessary for further spread and what role LNs have in shaping distant metastasis. A new study in Cell shows that LN colonization by tumour cells is crucial for distant metastasis, not as a source of metastatic precursors, but by generating tumour-specific immune tolerance, involving tumour-intrinsic epigenetic reprogramming, evasion of immune-mediated cytotoxicity and induction of regulatory T (Treg) cells.

Aim of the study was to assess: (a) the prevalence and type of strabismus, ptosis and eyelid dynamic disorders features, (b) the prevalence of refractive errors, amblyopia and, (c) their association with ocular/systemic syndromes in a cohort of patients. This is a retrospective observational multicenter cohort study. Patients with coexisting ocular motility disorders, comitant and incomitant strabismus, ptosis and dynamic eyelid disorders who have never undergone surgery were enrolled throughout a 3-years a study period. 137 out of 19,089 patients were enrolled, of which 97 with uniocular and 40 with binocular disease. Isolated congenital ptosis was observed in 84 patients. A polymalformative syndrome was present in almost one third of cases, whilst among strabismus type, esotropia was slightly more prevalent. Most patients were hypermetropic. In monocular disease, myopia mainly affected older patients, who were characterized by a worse ptosis margin reflex distance and levator function, and significantly higher astigmatism. Amblyopia occurred in 67.4% of the study sub-population. Of note, in monocular disease this was mild in 25.8%, moderate in 24.2% and severe in 11.3% of cases, whilst in binocular disease it was mild in 25%, moderate in 41.7% and severe in 16.7%. All patients with coexisting eyelid and ocular motility dysfunctions in pediatric age need ophthalmologic and systemic evaluation to accurately assess amblyopia, refractive errors and systemic/ocular disorders.

Retraction of: Scientific Reports https://doi.org/10.1038/srep12770, published online 31 July 2015. An investigation by Universiteit Leiden has concluded1 that that data from 16 participants were excluded from the results of the trial reported in this article. The exclusion of these data is not disclosed in the article. The Editors therefore no longer have confidence in the results and conclusions presented.

You have full access to this article via your institution. By October last year, Meg Brydon could see the terrible toll the pandemic had taken on children at her school. Brydon was a teacher at Ashwood High School, in the suburbs of Melbourne, Australia — the city that has spent more time in COVID-19 lockdowns than any other in the world. The school had been closed, on and off, for about seven months.