Search

Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The reproductive tract microbiota plays a crucial role in maintenance of normal pregnancy and influences reproductive outcomes. Microbe-host interactions in pregnancy remain poorly understood and their role in shaping immune modulation is still being uncovered. In this review, we describe the composition of vaginal microbial communities in the reproductive tract and their association with reproductive outcomes. We also consider strategies for manipulating microbiota composition by using live biotherapeutics, selective eradication of pathogenic bacteria with antibiotics and vaginal microbiota transplantation. Finally, future developments in this field and the need for mechanistic studies to explore the functional significance of reproductive tract microbial communities are highlighted., (© 2021 The Author(s).)

Background: Sleep difficulties are highly prevalent among adolescents, and are associated with significant impairments. The effectiveness and acceptability of Cognitive Behavioural Therapy-based (CBT-based) treatment for insomnia in adolescents is established for High Income Countries, but unknown for African settings. Thus, the aim of this study was to assess the effect of CBT-based intervention among in-school adolescents with sleep difficulties in Southern Nigeria., Methods: This was a pilot controlled trial involving 50 adolescents with highest ranked scores on the Insomnia Severity Index (ISI) recruited from four schools (two government and two privately owned). Balloting was used to assign two schools (public and private) with 25 participants to the intervention group, and the other two schools (public and private) with 25 participants as waiting-list controls. The two groups were dyad-matched for baseline ISI scores, gender, and type of school to reduce baseline differences. The treatment group received weekly group-based manualised CBT-based intervention over 5 weeks. Primary outcome was ISI score at 6th week. Secondary outcomes were sleep onset latency (SOL), Total sleep duration (TSD), depressive symptoms, sleep hygiene, and knowledge about sleep., Results: Participants were aged 13-17 years (M = 14.9, SD = 1.16) and consisted of 18 males and 32 females. Controlling for baseline scores, the intervention group showed significantly lower post-intervention insomnia scores compared with the control group {F (1, 34) = 1.10, p = 0.0001, (ηp 2  = 0.59}, shorter SOL {F (1, 33) = 1.41, p = 0.0001, ηp 2  = 0.39}, longer TSD {F (1, 33) = 1.03, p = 0.0001, ηp 2  = 0.47}, lower depressive symptoms {F (1, 31) = 1.32, p = 0.002 (ηp 2  = 0.34}, higher knowledge of sleep {F (1, 34) = 1.02, p = 0.001, ηp 2  = 0.36}, but no significant change in sleep hygiene {F (1, 32) = 1.08, p = 0.08, ηp 2  = 0.15}. All participants in the intervention group rated the programme as good or excellent., Conclusion: This pilot CBT-based intervention for adolescents with insomnia was feasible, well received and showed promising efficacy in this setting. Larger controlled trials are recommended to establish the generalisability of these findings in this region. Trial registration Pan African Clinical Trial Registry (Registration Number PACTR202001710494962)., (© 2021. The Author(s).)

In vitro differentiation of embryonic stem cells (ESCs) provides a convenient basis for the study of microRNA-based gene regulation that is relevant for early cardiogenic processes. However, to which degree insights gained from in vitro differentiation models can be readily transferred to the in vivo system remains unclear. In this study, we profiled simultaneous genome-wide measurements of mRNAs and microRNAs (miRNAs) of differentiating murine ESCs (mESCs) and integrated putative miRNA-gene interactions to assess miRNA-driven gene regulation. To identify interactions conserved between in vivo and in vitro, we combined our analysis with a recent transcriptomic study of early murine heart development in vivo. We detected over 200 putative miRNA-mRNA interactions with conserved expression patterns that were indicative of gene regulation across the in vitro and in vivo studies. A substantial proportion of candidate interactions have been already linked to cardiogenesis, supporting the validity of our approach. Notably, we also detected miRNAs with expression patterns that closely resembled those of key developmental transcription factors. The approach taken in this study enabled the identification of miRNA interactions in in vitro models with potential relevance for early cardiogenic development. Such comparative approaches will be important for the faithful application of stem cells in cardiovascular research.

Redox reactions are intrinsically linked to energy metabolism. Therefore, redox processes are indispensable for organismal physiology and life itself. The term reactive oxygen species (ROS) describes a set of distinct molecular oxygen derivatives produced during normal aerobic metabolism. Multiple ROS-generating and ROS-eliminating systems actively maintain the intracellular redox state, which serves to mediate redox signaling and regulate cellular functions. ROS, in particular hydrogen peroxide (H 2 O 2 ), are able to reversibly oxidize critical, redox-sensitive cysteine residues on target proteins. These oxidative post-translational modifications (PTMs) can control the biological activity of numerous enzymes and transcription factors (TFs), as well as their cellular localization or interactions with binding partners. In this review, we describe the diverse roles of redox regulation in the context of physiological cellular metabolism and provide insights into the pathophysiology of diseases when redox homeostasis is dysregulated., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immune transcripts are essential for depicting onco-immunologic interactions. However, whether cancer cells mimic immune transcripts to reprogram onco-immunologic interaction remains unclear. Here, single-cell transcriptomic analyses of 7,737 normal and 37,476 cancer cells reveal increased immune transcripts in cancer cells. Cells gradually acquire immune transcripts in malignant transformation. Notably, cancer cell-derived immune transcripts contribute to distinct prognoses of immune gene signatures. Optimized immune response signature (oIRS), obtained by excluding cancer-related immune genes from immune gene signatures, and offers a more reliable prognostic value. oIRS reveals that antigen presentation, NK cell killing and T cell signaling are associated with favorable prognosis. Patients with higher oIRS expression are associated with favorable responses to immunotherapy. Indeed, CD83 + cell infiltration, which indicates antigen presentation activity, predicts favorable prognosis in breast cancer. These findings unveil that immune mimicry is a distinct cancer hallmark, providing an example of cancer cell plasticity and a refined view of tumor microenvironment., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population., Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults., Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status., Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001)., Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease., Competing Interests: Funding Support and Author Disclosures This study was supported by the Medical Research Council, UK (MC-A658-5QEB0); the National Institute for Health Research Imperial College Biomedical Research Centre; the National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit; the British Heart Foundation (NH/17/1/32725, RG/19/6/34387, RE/18/4/34215); Fondation Leducq (16 CVD 03); Wellcome Trust (107469/Z/15/Z, 200990/A/16/Z); the National Heart and Lung Institute Foundation; the Royston Centre for Cardiomyopathy Research; Rosetrees and CORDA (Dr Prasad); Academy of Medical Sciences (SGL015/1006; Dr de Marvao); Mason Medical Research Trust grant (Dr de Marvao); SmartHeart EPSRC Programme Grant (EP/P001009/1; Dr Bai and Dr Rueckert); and a Rosetrees and Stoneygate Imperial College Research Fellowship (Dr Whiffin). Dr Ware has consulted for MyoKardia, Inc. and Foresite Labs. Dr Cook holds shares in Enleofen Bio Pte. Ltd. Dr O’Regan has consulted for Bayer AG. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their "loser" phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([ 11 C]PBR28), amyloid-β (Aβ) ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [ 11 C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Recently, Amyloid IQ was introduced as a new canonical image-based algorithm to quantify amyloid PET scans and demonstrated increased power over traditional SUV ratio (SUVR) approaches when assessed in cross-sectional and longitudinal analyses. We build further on this mathematical framework to develop a Tau IQ algorithm for the quantitative analysis of the more complex spatial distribution displayed by tau PET radiotracers. Methods: Cross-sectional ( n = 615) and longitudinal ( n = 149) 18 F-flortaucipir data were obtained from the Alzheimer's Disease Neuroimaging Initiative along with necessary adjunct amyloid PET and T1-weighted structural MRI data. A subset of these data were used to derive a chronological tau dataset, using Amyloid IQ analysis of associated amyloid PET data to calculate the subject's temporal position in the canonical AD disease process, from which canonical images for the nonspecific and specific binding components of 18 F-flortaucipir in AD were calculated. These 2 canonical images were incorporated into the Tau IQ algorithm that enables the quantification of both global and local tau outcome measures using an image-based regression and statistical parametric analysis of the initial residual image. Performance of the Tau IQ algorithm was compared with SUVR approaches for cross-sectional analyses, longitudinal analyses, and correlation with clinical measures (Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], Clinical Dementia Rating scale-sum of boxes [CDR-SB], and Mini-Mental State Examination [MMSE]). Results: Tau IQ successfully calculated global tau load (Tau L ) in all 791 scans analyzed (range, -3.5% to 185.2%; mean ± SD, 23% ± 20.5%) with a nonzero additional local tau component being required in 31% of all scans (cognitively normal [CN], 22%; mild cognitive impairment [MCI], 35%; dementia, 72%). Tau IQ was compared with the best SUVR approach in the cross-sectional analysis (Tau L increase in effect size: CN- vs. CN+, +45%; CN- vs. MCI+, -5.6%; CN- vs. dementia+, +2.3%) (+/- indicates amyloid-positive or -negative) and correlation with clinical scores (Tau L increase in r 2 : CDR-SB+, 7%; MMSE+, 38%; ADAS-Cog+, 0%). Tau IQ substantially outperformed SUVR approaches in the longitudinal analysis (Tau IQ increase in power: CN+, >3.2-fold; MCI+, >2.2-fold; dementia+, >2.9-fold). Conclusion: Tau L as calculated by Tau IQ provides a superior approach for the quantification of tau PET data. In particular, it provides a substantial improvement in power for longitudinal analyses and the early detection of tau deposition and thus should have significant value for clinical imaging trials in AD that are investigating the attenuation of tau deposition with novel therapies., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on β cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on β cell function in vivo by imaging Ca 2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented β cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the β cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in β cell function and intra-islet connectivity which are likely to contribute to diabetes remission., (© 2021. The Author(s).)

Background: In pre-implantation genetic testing (PGT), fertile couples undergo IVF with genetic testing of embryos to avoid conceptions with a genetic condition. There is an exponentially increasing uptake with over 600 applications listed by the Human Fertilisation and Embryology Authority in the UK. The psychological aspects of the decision-making process and the experience of PGT, however, are relatively underevaluated, with the potential to leave patients unsupported in their journeys., Objective and Rationale: In this review, we aim to comprehensively report on every aspect of couples' experiences of PGT. We consider what motivates users, the practical and ethical decisions involved and how couples navigate the decision-making process. Additionally, we report on the social and psychological impact on couples who are actively undergoing or have completed the PGT process., Search Methods: A systematic search of English peer-reviewed journals of three computerized databases was undertaken following PRISMA guidelines. Studies that examined the motivations, attitudes, decision-making factors and experiences of patients who have been actively engaged in the PGT process were included. No restrictions were placed on study design or date of publication. Studies examining patients using PGT in a hypothetical context or solely using PGT for aneuploidy were excluded. Qualitative data were extracted using thematic analysis., Outcomes: The main outcomes were patient motivations, deciding factors and attitudes, as well as the patient experience of coming to a decision and going through PGT.Patients were primarily motivated by the desire to have a healthy child and to avoid termination of pregnancy. Those with a sick child or previous experience of termination were more likely to use PGT. Patients also felt compelled to make use of the technology available, either from a moral responsibility to do so or to avoid feelings of guilt if not. The main factors considered when deciding to use PGT were the need for IVF and the acceptability of the technology, the financial cost of the procedure and one's ethical standpoint on the creation and manipulation of embryos. There was a general consensus that PGT should be applied to lethal or severe childhood disease but less agreement on use for adult onset or variable expression conditions. There was an agreement that it should not be used to select for aesthetic traits and a frustration with the views of PGT in society. We report that couples find it difficult to consider all of the benefits and costs of PGT, resulting in ambivalence and prolonged indecision. After deciding on PGT use, we found that patients find the process extremely impractical and psychologically demanding., Wider Implications: This review aimed to summarize the current knowledge on how patients decide to use and experience PGT and to make suggestions to incorporate the findings into clinical practice. We cannot stress enough the importance of holistic evaluation of patients and thorough counselling prior to and during PGT use from a multidisciplinary team that includes geneticists, IVF clinicians, psychologists and also patient support groups. Large prospective studies using a validated psychological tool at various stages of the PGT process would provide an invaluable database for professionals to better aid patients in their decision-making and to improve the patient experience., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: What are the knowledge and views of UK-based women towards egg donation (ED) and egg sharing (ES)?, Summary Answer: Lacking knowledge of the practices of ED and ES could be an influential factor in donor egg shortages, rather than negative perceptions or lack of donor anonymity and financial incentives., What Is Known Already: The increasing age of women trying to conceive has led to donor egg shortages, with ED and ES failing to meet demand. Indeed, in recent years in the UK, ES numbers have fallen. This results in long waiting lists, forcing patients abroad for fertility treatment to take up cross border reproductive care. Previous research suggests a lack of knowledge of ED among members of the general public; however, no study has yet assessed knowledge or views of ES in the general public., Study Design, Size, Duration: Six hundred and thirty-five UK-based women over 18 years were voluntarily recruited from social media community groups by convenience sampling. The recruitment period was from February to April 2020., Participants/materials, Setting, Methods: Participants completed a previously validated questionnaire regarding female fertility, ED and ES, including knowledge, perceptions and approval of the practices and relevant legislation. This included ranking key benefits and issues regarding egg sharing. The questionnaire was completed using the online Qualtrics survey software. Statistical analysis was conducted using SPSS., Main Results and the Role of Chance: Regarding knowledge of ED and ES, 56.3% and 79.8%, respectively had little or no prior knowledge. Upon explanation, most approved of ED (85.8%) and ES (70.4%). A greater proportion of respondents would donate to a family member/friend (49.75%) than to an anonymous recipient (35.80%). Overall, ES was viewed less favourably than ED, with ethical and practical concerns highlighted. Women aged 18-30 years were significantly more likely to approve of egg donation practice compared to those aged >30 years (P < 0.0001). Those against ES found fears of financial coercion or negative psychological wellbeing the most concerning. About 35.8% and 49.7% would personally consider anonymous and known ED, respectively, whilst 56.7% would consider ES. Those answering in favour of egg sharing were significantly more likely to give higher benefit ratings compared to those against the practice (P < 0.001). Most agreed (55.8%) with and were not deterred to donate (60.1%) by the 'Disclosure of Donor Identity' legislation. Only 31.6% agreed with the compensatory cap; however, 52.7% would not be more motivated to donate by an increased cap., Limitations, Reasons for Caution: There were several limitations of the study, including the use of convenience sampling and the voluntary nature of participation opening the study up to sampling and participation bias. Finally, closed questions were predominantly used to allow the generation of quantitative data and statistical analysis. However, this approach prevented opinion justification and qualitative analysis, limiting the depth of conclusions drawn., Wider Implications of the Findings: To our knowledge, this is the first study to survey the general public's knowledge and views of ED/ES using a previously validated questionnaire. The conclusion that lack of knowledge could be contributing to the current donor shortfall in the UK demonstrates that campaigns to inform women of the practices are necessary to alleviate donor oocyte shortages., Study Funding/competing Interest(s): No external funds were used for this study. The authors have no conflicts of interest., Trial Registration Number: NA., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [ 11 C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy ( 1 H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [ 11 C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [ 11 C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [ 11 C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [ 11 C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1 H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia., (© 2021. The Author(s).)

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as K i cer value using [ 18 F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BP ND using [ 11 C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in K i cer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal K i cer values and time to relapse after antipsychotic discontinuation (R 2  = 0.518, p = 0.018). BP ND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

A new study explores the neural-circuit and synaptic processes that support the transition from general to specific aversive memory formation. A critical role for homeostatic synaptic down-scaling in shaping the specificity of an associative memory is identified., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multiarm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This biomimetic system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with a potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Sick sinus syndrome (SSS) encompasses a group of conduction disorders characterized by the inability of sinoatrial node to perform its pacemaker function. Our aim was to identify genetic predictors of SSS in a prospective cohort of patients admitted to the clinic for pacemaker implantation using single-locus and multilocus approaches. We performed genotyping for polymorphic markers of CLCNKA (rs10927887), SCN10A (rs6795970), FNDC3B (rs9647379), MIR146A (rs2910164), SYT10 (rs7980799), MYH6 (rs365990), and KCNE1 (rs1805127) genes in the group of 284 patients with SSS and 243 healthy individuals. Associations between the studied loci and SSS were tested using logistic regression under recessive genetic model using sex and age as covariates. Multilocus analysis was performed using Markov chain Monte Carlo method implemented in the APSampler program. Correction for multiple testing was performed using Benjamini-Hochberg procedure. We detected an individual association between KCNE1 rs1805127*A allele and SSS in the total study group (OR 0.43, P FDR  = 0.028) and in the subgroup of patients with 2nd or 3rd degree sinoatrial block (OR 0.17, P FDR  = 0.033), and identified seven allelic patterns associated with the disease. SCN10A rs6795970*T and MIR146A rs2910164*C alleles were present in all seven combinations associated with SSS. The highest risk of SSS was conferred by the combination SCN10A rs6795970*T+FNDC3B rs9647379*C+MIR146A rs2910164*C+SYT10 rs7980799*C+KCNE1 rs1805127*G (OR 2.98, CI 1.77-5.00, P = 1.27 × 10 -5 , P FDR  = 0.022). Our findings suggest that KCNE1 rs1805127 polymorphism may play a role in susceptibility to sinoatrial node dysfunction, particularly presenting as 2nd or 3rd degree sinoatrial block, and the risk-modifying effect of other studied loci is better detected using multilocus approach., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.

Introduction: The relationship between endometrioma and ovarian cancer is a topic of discussion in the field of endometriosis and to date it is still debated whether ovarian endometriosis may represent a risk factor for ovarian cancers., Evidence Acquisition: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to October 2020. Primary outcome of interest was ovarian cancer incidence in patients with endometriosis. Secondary outcome was ovarian cancer prognosis in patients with endometriosis compared to patient without endometriosis., Evidence Synthesis: Patients with ovarian endometriosis has a slight increase risk of developing ovarian cancer (merely 1.8%), being the general population risk for ovarian cancer 1.31%. In patient at postmenopausal age, long-lasting endometriosis, early-age diagnosis, infertility and/or infertility treatment the risk of developing ovarian cancer is higher. Endometriosis-related ovarian cancers are generally clear cell and endometrioid and are diagnosed at early stage compared to non-endometriosis related ovarian cancer., Conclusions: The lifetime risk for ovarian cancer is low in endometriosis patients in general and higher in subgroups of patients allowing a tailored management based on patient characteristics. Endometriosis is a chronic disease negatively affecting the quality of life, nonetheless, concerns on ovarian cancer should be avoided in order to reduce the burden of the disease on women's health.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10 -7 ; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits., (© 2021. The Author(s).)

The peptide hormone insulin is a key regulator of energy metabolism, proliferation and survival. Binding of insulin to its receptor activates the PI3K/AKT signalling pathway, which mediates fundamental cellular responses. Oxidants, in particular H 2 O 2 , have been recognised as insulin-mimetics. Treatment of cells with insulin leads to increased intracellular H 2 O 2 levels affecting the activity of downstream signalling components, thereby amplifying insulin-mediated signal transduction. Specific molecular targets of insulin-stimulated H 2 O 2 include phosphatases and kinases, whose activity can be altered via redox modifications of critical cysteine residues. Over the past decades, several of these redox-sensitive cysteines have been identified and their impact on insulin signalling evaluated. The aim of this review is to summarise the current knowledge on the redox regulation of the insulin signalling pathway., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Forkhead box M1 (FOXM1) is known to play a role in breast cancer progression. FOXM1 inhibition becomes one of the strategies in developing the novel cancer therapy. Recently, thiostrepton has been recognized as a potent FOXM1 inhibitor. To improve its potential, we aimed to develop a nanodelivery system for thiostrepton. Here, liposome-encapsulated thiostrepton (TSLP) was developed. Physiochemical properties were characterized by TEM and dynamic light scattering technique. The biological activities were also evaluated, by cellular internalization, MTT assay, spheroid formation assay and RT-PCR. The result showed that the range sizes of TSLP were 152 ± 2 nm, polydispersity index (PdI) of 0.23 ± 0.02 and zeta potential of -20.2 ± 0.1 mV. As expected, TSLP showed a higher potential in reducing FOXM1 levels in MCF-7 cells than free thiostrepton. Additionally, TSLP significantly improved the efficiently and specificity of thiostrepton in reducing cell viability of MCF-7, but not of the fibroblast (HDFn) cells. Interestingly, TSLP had an ability to induce MCF-7 cell death in both 2D monolayer and 3D spheroid culture. In conclusions, TSLP could possibly be one of the potential developments using nano-delivery system to improve abilities and specificity of thiostrepton in breast cancer cell inhibition and death inducing, with decreasing non-specific toxicity., (Copyright © 2021 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The adult neocortex is not hard-wired but instead retains the capacity to reorganise across multiple spatial scales long into adulthood. Plastic reorganisation occurs at the level of mesoscopic sensory maps, functional neuronal assemblies and synaptic ensembles and is thought to be a critical feature of neuronal network function. Here, we describe a series of approaches that use calcium imaging to measure network reorganisation across multiple spatial scales in vivo. At the mesoscopic level, we demonstrate that sensory activity can be measured in animals undergoing longitudinal behavioural assessment involving automated touchscreen tasks. At the cellular level, we show that network dynamics can be longitudinally measured at both stable and transient functional assemblies. At the level of single synapses, we show that functional subcellular calcium imaging approaches can be used to measure synaptic ensembles of dendritic spines in vivo. Finally, we demonstrate that all three levels of imaging can be spatially related to local pathology in a preclinical rodent model of amyloidosis. We propose that multi-scale in vivo calcium imaging can be used to measure parallel plasticity processes operating across multiple spatial scales in both the healthy brain and preclinical models of disease., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Microbes are an integral part of life on this planet. Microbes and their hosts influence each other in an endless dance that shapes how the meta-organism interacts with its environment. Although great advances have been made in microbiome research over the past 20 years, the mechanisms by which both hosts and their microbes interact with each other and the environment are still not well understood. The nematode Caenorhabditis elegans has been widely used as a model organism to study a remarkable number of human-like processes. Recent evidence shows that the worm is a powerful tool to investigate in fine detail the complexity that exists in microbe-host interactions. By combining the large array of genetic tools available for both organisms together with deep phenotyping approaches, it has been possible to uncover key effectors in the complex relationship between microbes and their hosts. In this perspective, we survey the literature for insightful discoveries in the microbiome field using the worm as a model. We discuss the latest conceptual and technological advances in the field and highlight the strengths that make C. elegans a valuable biosensor tool for the study of microbe-host interactions.

Study Question: Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer?, Summary Answer: Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer., What Is Known Already: Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious., Study Design, Size, Duration: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337)., Participants/materials, Setting, Methods: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence., Main Results and the Role of Chance: Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group., Limitations, Reasons for Caution: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias., Wider Implications of the Findings: The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence., Study Funding/competing Interest(s): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare., Prospero Registration Number: CRD42019153404., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To assess the variables associated with success of office hysteroscopy (OH) in pre-menopausal and post-menopausal women and to develop a clinical model for predicting the outcome of OH., Methods: This is a retrospective cohort study of consecutive patients ( n  = 3181) referred for an OH to a tertiary care university hospital between January 2018 and March 2020. Multivariate logistic regression analysis was used to investigate the variables for predicting the success of OH in all patients and in pre-menopausal and in post-menopausal patients separately. The logistic regression analysis of each variable was applied to develop a predictive model., Results: The overall success rate of the procedure was 92.2%; 95.4% in pre-menopausal women and 87.6% in post-menopausal women. In the general population, independent predictors of procedure success were previous vaginally delivery and hysteroscopy, while previous cervical or uterine surgery were associated with incomplete OH. In the pre-menopausal group, the independent predictors of failure were treatment with GnRH, estroprogestins and infertility. In 89% of cases, our developed model was able to predict whether an OH would be successful in a particular patient. ROC analysis showed an area under the curve of 0.8746 (95% CI: 0.85354-0.89557)., Conclusions: The present study demonstrates the development of a simple and reliable clinical model for the identification of both pre-menopausal and menopausal patients with a high chance of OH success.

Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60-70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD.

Aging is a complex process that differentially impacts multiple cognitive, sensory, neuronal and molecular processes. Technological innovations now allow for parallel investigation of neuronal circuit function, structure and molecular composition in the brain of awake behaving adult mice. Thus, mice have become a critical tool to better understand how aging impacts the brain. However, a more granular systems-based approach, which considers the impact of age on key features relating to neural processing, is required. Here, we review evidence probing the impact of age on the mouse brain. We focus on a range of processes relating to neuronal function, including cognitive abilities, sensory systems, synaptic plasticity and calcium regulation. Across many systems, we find evidence for prominent age-related dysregulation even before 12 months of age, suggesting that emerging age-related alterations can manifest by late adulthood. However, we also find reports suggesting that some processes are remarkably resilient to aging. The evidence suggests that aging does not drive a parallel, linear dysregulation of all systems, but instead impacts some processes earlier, and more severely, than others. We propose that capturing the more fine-scale emerging features of age-related vulnerability and resilience may provide better opportunities for the rejuvenation of the aged brain., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Graphene field-effect transistors (GFETs) are suitable building blocks for high-performance electrical biosensors, because graphene inherently exhibits a strong response to charged biomolecules on its surface. However, achieving ultralow limit-of-detection (LoD) is limited by sensor response time and screening effect. Herein, we demonstrate that the detection limit of GFET biosensors can be improved significantly by decorating the uncovered graphene sensor area with carbon dots (CDs). The developed CDs-GFET biosensors used for exosome detection exhibited higher sensitivity, faster response, and three orders of magnitude improvements in the LoD compared with nondecorated GFET biosensors. A LoD down to 100 particles/μL was achieved with CDs-GFET sensor for exosome detection with the capability for further improvements. The results were further supported by atomic force microscopy (AFM) and fluorescent microscopy measurements. The high-performance CDs-GFET biosensors will aid the development of an ultrahigh sensitivity biosensing platform based on graphene for rapid and early diagnosis of diseases.

Connexins oligomerise to form hexameric hemichannels in the plasma membrane that can further dock together on adjacent cells to form gap junctions and facilitate intercellular trafficking of molecules. In this study, we report the expression and function of an orphan connexin, connexin-62 (Cx62), in human and mouse (Cx57, mouse homolog) platelets. A novel mimetic peptide (62Gap27) was developed to target the second extracellular loop of Cx62, and 3-dimensional structural models predicted its interference with gap junction and hemichannel function. The ability of 62Gap27 to regulate both gap junction and hemichannel-mediated intercellular communication was observed using fluorescence recovery after photobleaching analysis and flow cytometry. Cx62 inhibition by 62Gap27 suppressed a range of agonist-stimulated platelet functions and impaired thrombosis and hemostasis. This was associated with elevated protein kinase A-dependent signaling in a cyclic adenosine monophosphate-independent manner and was not observed in Cx57-deficient mouse platelets (in which the selectivity of 62Gap27 for this connexin was also confirmed). Notably, Cx62 hemichannels were observed to function independently of Cx37 and Cx40 hemichannels. Together, our data reveal a fundamental role for a hitherto uncharacterized connexin in regulating the function of circulating cells., (© 2021 by The American Society of Hematology.)

The nematode Caenorhabditis elegans is commonly used as a model organism in studies of the host immune response. The worm encodes twelve peroxidase-cyclooxygenase superfamily members, making it an attractive model in which to study the functions of heme peroxidases. In previous work, loss of one of these peroxidases, SKPO-1 (ShkT-containing peroxidase), rendered C. elegans more sensitive to the human, Gram-positive pathogen Enterococcus faecalis. SKPO-1 was localized to the hypodermis of the animals where it also affected cuticle development as indicated by a morphological phenotype called "dumpy." In this work, a better understanding of how loss of skpo-1 impacts both sensitivity to pathogen as well as cuticle development was sought by subjecting a deletion mutant of skpo-1 to transcriptome analysis using RNA sequencing following exposure to control (Escherichia coli) and pathogenic (E. faecalis) feeding conditions. Loss of skpo-1 caused a general upregulation of genes encoding collagens and other proteins related to cuticle development. On E. faecalis, these animals also failed to upregulate guanylyl cyclases that are often involved in environmental sensing. Hoechst straining revealed increased permeability of the cuticle and atomic force microscopy exposed the misalignment of the cuticular annuli and furrows. These findings provide a basis for better understanding of the morphological as well as the pathogen sensitivity phenotypes associated with loss of SKPO-1 function., (© The Author(s) 2020. Published by Oxford University Press on behalf of Genetics Society of America.)

Human metabolism is influenced by genetic and environmental factors. Previous studies have identified over 23 loci associated with more than 26 urine metabolites levels in adults, which are known as urinary metabolite quantitative trait loci (metabQTLs). The aim of the present study is the identification for the first time of urinary metabQTLs in children and their interaction with dietary patterns. Association between genome-wide genotyping data and 44 urine metabolite levels measured by proton nuclear magnetic resonance spectroscopy was tested in 996 children from the Human Early Life Exposome project. Twelve statistically significant urine metabQTLs were identified, involving 11 unique loci and 10 different metabolites. Comparison with previous findings in adults revealed that six metabQTLs were already known, and one had been described in serum and three were involved the same locus as other reported metabQTLs but had different urinary metabolites. The remaining two metabQTLs represent novel urine metabolite-locus associations, which are reported for the first time in this study [single nucleotide polymorphism (SNP) rs12575496 for taurine, and the missense SNP rs2274870 for 3-hydroxyisobutyrate]. Moreover, it was found that urinary taurine levels were affected by the combined action of genetic variation and dietary patterns of meat intake as well as by the interaction of this SNP with beverage intake dietary patterns. Overall, we identified 12 urinary metabQTLs in children, including two novel associations. While a substantial part of the identified loci affected urinary metabolite levels both in children and in adults, the metabQTL for taurine seemed to be specific to children and interacted with dietary patterns., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: South Asians are at higher risk for diabetes (DM) than many other racial/ethnic groups. Circulating metabolites are measurable products of metabolic processes that may explain the aetiology of elevated risk. We characterized metabolites associated with prevalent DM and glycaemic measures in South Asians., Methods: We included 717 participants from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, aged 40-84 years. We used baseline fasting serum for metabolomics and demographic, behavioural, glycaemic data from baseline and at 5 years. We performed LC-MS untargeted metabolomic and lipidomic analysis with targeted integration of known signals. Individual linear and ordinal logistic regression models were adjusted for age, sex, BMI, diet, exercise, alcohol, smoking and family history of DM followed by elastic net regression to identify metabolites most associated with the outcome., Results: There were 258 metabolites with detectable signal in >98% of samples. Thirty-four metabolites were associated with prevalent DM in an elastic net model. Predominant metabolites associated with DM were sphingomyelins, proline (OR 15.86; 95% CI 4.72, 53.31) and betaine (OR 0.03; 0.004, 0.14). Baseline tri- and di-acylglycerols [DG (18:0/16:0) (18.36; 11.79, 24.92)] were positively associated with fasting glucose and long-chain acylcarnitines [CAR 26:1 (-0.40; -0.54, -0.27)] were inversely associated with prevalent DM and HbA 1c at follow-up., Discussion: A metabolomic signature in South Asians may help determine the unique aetiology of diabetes in this high-risk ethnic group. Future work will externally validate our findings and determine the effects of modifiable risk factors for DM., (© 2020 Diabetes UK.)

The intervertebral disc (IVD) plays a main role in absorbing and transmitting loads within the spinal column. Degeneration alters the structural integrity of the IVDs and causes pain, especially in the lumbar region. The objective of this study was to investigate non-invasively the effect of degeneration on human 3D lumbar IVD strains ( n = 8) and the mechanism of spinal failure ( n = 10) under pure axial compression using digital volume correlation (DVC) and 9.4 Tesla magnetic resonance imaging (MRI). Degenerate IVDs had higher ( p < 0.05) axial strains (58% higher), maximum 3D compressive strains (43% higher), and maximum 3D shear strains (41% higher), in comparison to the non-degenerate IVDs, particularly in the lateral and posterior annulus. In both degenerate and non-degenerate IVDs, peak tensile and shear strains were observed close to the endplates. Inward bulging of the inner annulus was observed in all degenerate IVDs causing an increase in the AF compressive, tensile, and shear strains at the site of inward bulge, which may predispose it to circumferential tears (delamination). The endplate is the spine's "weak link" in pure axial compression, and the mechanism of human vertebral fracture is associated with disc degeneration. In non-degenerate IVDs the locations of failure were close to the endplate centroid, whereas in degenerate IVDs they were in peripheral regions. These findings advance the state of knowledge on mechanical changes during degeneration of the IVD, which help reduce the risk of injury, optimize treatments, and improve spinal implant designs. Additionally, these new data can be used to validate computational models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tavana, Masouros, Baxan, Freedman, Hansen and Newell.)

Ultrasound is a readily available, safe and portable imaging modality that is widely applied in gynecology. However, there is limited guidance for its use intra-operatively especially with complex gynecological procedures. This narrative review examines the existing literature published on the use of intraoperative ultrasound (IOUS) in benign gynecology and in gynecological oncology. We searched for the following terms: 'intraoperative,' 'ultrasonography,' 'gynecology' and 'oncology' using Pubmed/Medline. IOUS can minimize complications and facilitate difficult benign gynecological procedures. There is also a role for its use in gynecological oncology surgery and fertility-sparing surgery. The use of IOUS in gynecological surgery is an emerging field which improves visualization in the surgical field and aids completion of minimally invasive techniques., Competing Interests: Financial & competing interests disclosure S Saso is a member of the journal editorial board. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2021 Karen Grewal, Benjamin Jones, Ariadne L'Heveder et al.)

Introduction: Pre-implantation genetic testing for aneuploidy (PGT-A) is in high demand worldwide, with ongoing debate among medical societies as to which patient groups it should be offered. The psychological aspects for patients regarding its use, lag behind the genomic technological advances, leaving couples with limited decision-making support. The development of this technology also leads to the possibility for its utilization in gender selection. Despite the controversy surrounding these issues, very few studies have investigated the psychological aspects of patients using PGT-A., Material and Methods: This systematic review provides an up-to-date analysis of the psychosocial aspects surrounding PGT for aneuploidy and sex selection, as well as decision-making factors. A systematic search of English peer-reviewed journals of three computerized databases were undertaken following PRISMA guidelines. The qualitative data were extracted using thematic analysis. PROSPERO Registration number: CRD42019126439., Results: The main outcome measures were patients' motivations, decision-making factors, attitudes and experiences surrounding the use of PGT for aneuploidy and sex selection. Ten studies were included, four for PGT-A and six for sex selection. Attitudes towards PGT-A were positive, with the main motivating factors being decreasing miscarriage rate, reducing the risk of termination of pregnancy and reducing the time to pregnancy. Consistently raised concerns regarding PGT-A were the financial burden and moral beliefs. The vast majority of patients felt sufficiently knowledgeable to make the decision; however, studies did reveal that a minority mis-interpreted certain potential benefits of PGT-A. Studies investigating PGT for sex selection predominantly reported the main motivation was to achieve gender balance within the family dynamic, with most studies finding no difference between couples using PGT for gender selection to have male or female offspring., Conclusions: Although this systematic review was limited by the small number of studies investigating this topic, a significant minority of patients appeared to misunderstand certain benefits and limitations of PGT-A. Fertility clinics must ensure they provide adequate counseling to all patients using PGT-A. With the use of PGT-A on the rise globally, there is a need to develop decision support tools for couples who have an increasing number of genetic testing options becoming available to them., (© 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7 th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1 st to 4 th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8 th ARDD meeting that is scheduled for the 31 st of August to 3 rd of September, 2021, at Columbia University, USA.

Roux-en-Y gastric bypass (RYGB) is an effective weight loss surgery, resulting in a characteristic increase of fecal Gammaproteobacteria The contribution of this compositional change to metabolic benefits of RYGB is currently debatable. Therefore, this study employed 16S rRNA gene sequencing and metabolic profiling to monitor the dynamic colonization of the RYGB microbial consortium and their metabolic impact on the host. Eleven Wistar rats received vancomycin and enrofloxacin, followed by fecal microbiota transplantation (FMT) of cecal slurry obtained from either RYGB- or sham-operated rats. Urine and feces from the microbiota recipients (RYGB microbiota recipients [RYGBr], n  = 6; sham microbiota recipients [SHAMr], n  = 5) were collected pre- and post-antibiotics and 1, 3, 6, 9, and 16 days post-FMT. No significant differences in body weight and food intake were observed between RYGBr and SHAMr. While neither group reached the community richness of that of their donors, by day 6, both groups reached the richness and diversity of that prior to antibiotic treatment. However, the typical signature of RYGB microbiome-increased Enterobacteriaceae -was not replicated in these recipients after two consecutive FMT, suggesting that the environmental changes induced by the anatomical rearrangements of RYGB could be key for sustaining such a consortium. The transplanted bacteria did not induce the same metabolic signature of urine and feces as those previously reported in RYGB-operated rats. Future work is required to explore environmental factors that shape the RYGB microbiota in order to further investigate the metabolic functions of the RYGB microbiota, thereby teasing out the mechanisms of the RYGB surgery. IMPORTANCE Roux-en-Y gastric bypass (RYGB) surgery results in a long-term gut bacterial shift toward Gammaproteobacteria in both patients and rodents. The contribution of this compositional shift, or the RYGB bacterial consortium, to the metabolic benefit of the surgery remains debatable. It is unclear how well these bacteria colonize in an anatomically normal gut. This is a fundamental question in both defining the function of the RYGB microbiota and evaluating its potential as a nonsurgical treatment for obesity. We monitored the dynamic colonization of the RYGB bacterial consortium and observed that while approximately one-third of the bacterial taxa from the RYGB donor colonized in the gut of the nonoperated recipients, Gammaproteobacteria were unable to colonize for longer than 3 days. The study highlighted that a successful long-term colonization of Gammaproteobacteria -rich RYGB microbiota in nonsurgical animals requires key environmental factors that may be dictated by the intestinal anatomical modification by the surgery itself., (Copyright © 2020 Liu et al.)

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10 -8 ), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Introduction: Police employees undertake challenging duties which may adversely impact their health. This study explored the prevalence of and risk factors for probable mental disorders amongst a representative sample of UK police employees. The association between mental illness and alterations in blood pressure was also explored., Methods: Data were used from the Airwave Health Monitoring Study which was established to monitor the possible physical health impacts of a new communication system on police employees. Data included sociodemographic characteristics, lifestyle habits, depression, anxiety, and post-traumatic stress disorder (PTSD) symptoms and blood pressure. Descriptive statistics were used to explore the prevalence of probable mental disorders and associated factors. Stepwise linear regression was conducted, controlling for confounding variables, to examine associations between mental disorders and blood pressure., Results: The sample included 40,299 police staff, police constable/sergeants and inspectors or above. Probable depression was most frequently reported (9.8%), followed by anxiety (8.5%) and PTSD (3.9%). Groups at risk for probable mental disorders included police staff, and police employees who reported drinking heavily. Police employees exposed to traumatic incidents in the past six months had a doubling in rates of anxiety or depression and a six-fold increase in PTSD compared to those with no recent trauma exposure. Adjusted logistic regression models did not reveal any significant association between probable mental disorders and systolic blood pressure but significantly elevated diastolic blood pressure (≈1mmHg) was found across mental disorders., Conclusions: These results show lower rates of probable mental disorders, especially PTSD, than reported in other studies focusing on police employees. Although mental ill health was associated with increased diastolic blood pressure, this was unlikely to be clinically significant. These findings highlight the importance of continued health monitoring of members of the UK police forces, focusing on employees recently exposed to traumatic incidents, heavy drinkers and police staff., Competing Interests: The authors have read the journal's policy and have the following conflicts: SAMS and NTF salaries are part funded by the UK Ministry of Defence (MoD). NTF is a trustee (unpaid) of The Warrior Programme and the ADVANCE study charity, and is an independent advisor to the Independent Group Advising on the Release of Data (IGARD) for NHS Digital. NG is a trustee with two military charities, undertakes voluntary roles with the Royal College of Psychiatrists and runs his own psychological health consultancy. PE is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.

Background: Pancreaticoduodenectomy is performed using an open technique (OPD) as the gold standard. An increase in those performed laparoscopically (LPD) and robotically (RPD) are now reported. We compared the short-term outcomes of RPD cases with LPD and OPD., Methods: A retrospective review of a prospectively collected database was undertaken of our first consecutive RPD, our first LPD and consecutive OPD cases. Those requiring venous and/or arterial resection were excluded., Results: RPD (n = 25) had longer median operating times (461 (IQR 358-564) mins) than LPD (n = 41) (330 (IQR 262.5-397.5) mins) and OPD (n = 37) (330 (IQR 257-403) mins, p < 0.0001). Estimated blood loss and transfusion requirement was less after RPD and LPD compared to OPD (p = 0.012 and p < 0.0001 respectively). No RPD cases required conversion to open operation compared to 24.4% of LPD. Morbidity was comparable with a Clavien Dindo score ≥3 in 20.00%, 24.39% and 18.92% for RPD, LPD and OPD respectively (p = 0.83). Post-operative pancreatic fistula rates were seen in 16.00%, 29.27% and 21.62% of our RPD, LPD and OPD cohorts respectively (p = 0.81). 90-day mortality was seen in 0.97% of the total cohort. Length of hospital stay (LOS) was shorter for RPD compared to both LPD (p = 0.030) and OPD (p = 0.002)., Conclusion: RPD is safe to perform with comparable outcomes to LPD and OPD. Further evidence is provided that a randomised controlled trial for PD techniques is required., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)