mTOR inhibition attenuates cTfh cell dysregulation and chronic T-cell activation in multilineage immune cytopenias.

mTOR inhibitors such as sirolimus are increasingly used in the management of multilineage immune cytopenia (m-IC) in children. Although sirolimus is effective in improving IC, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC. We profiled T- and B-cell subsets longitudinally and measured cytokines and chemokines before and after sirolimus treatment. Eleven of the 12 patients with m-IC who tolerated sirolimus were followed for a median duration of 17 months. All patients had an improvement in IC, and sirolimus therapy did not result in significant decreases in T-, B- and NK-cell numbers. However, the expansion and activation of circulating T follicular helper and the Th1 bias noted before the initiation of sirolimus were significantly decreased. Features of chronic T-cell activation and exhaustion within effector memory compartments of CD4+ and CD8+ T cells decreased with sirolimus therapy. Corresponding to these changes, plasma levels of CXCL9 and CXCL10 also decreased. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4+ naive T cells were noted. Longer follow-up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B-cell maturation.

Implementing a Clinical Decision Support Tool to Increase Early Peanut Introduction Guidance.

BACKGROUND: General pediatric providers are the frontline for early peanut introduction discussions, but many feel ill-equipped to handle such discussions as guidelines have quickly changed. OBJECTIVE: We hypothesized that a clinical decision support (CDS) tool could improve peanut introduction discussions. METHODS: CDS tools were designed by stakeholders, improved through usability testing, and integrated into the current note templates. Based on queries of electronic health record (EHR), we did a pre-post performance evaluation of peanut introduction conversations, barriers for introduction, and percentage of 12-month WCC visits that had successfully introduced peanut. Providers completed surveys before and after intervention to assess awareness of early peanut introduction and comfort using CDS. RESULTS: Providers' awareness of early peanut introduction guidelines increased from 17.8% to 66.7% after the CDS tool was implemented. 79.1% were comfortable using the tool. The CDS tool improved peanut introduction conversations at the 4-month well-child (WCC) care visit from 2.4% to 81.2%, at the 6-month WCC visit from 3.0% to 84.2%, and at the 12-month WCC visit from 2.7% to 82.9%. 56.6% of families had a plan to introduce peanut at the 4-month WCC visit. Of those who did not have a plan, the most common barrier was family's unawareness of the benefits of early peanut introduction. At the 12-month visit, 62.8% of families had introduced peanut without concerns. CONCLUSION: A point-of-care CDS tool encouraged more discussions by general pediatric providers on early peanut introduction to all patients. CDS tools should be considered in quality improvement projects as an implementation method for the most up-to-date guidelines.

Frequency of HLA-DR+CD38hi T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders.

BACKGROUND: Quantifying T-cell activation is essential for the diagnosis and evaluation of treatment response in various hyperinflammatory and immune regulatory disorders, including hemophagocytic lymphohistiocytosis. Plasma soluble IL-2 receptor (sIL-2R) is a well-established biomarker for evaluating systemic T-cell activation. However, the limited availability of sIL-2R testing could result in delayed diagnosis. Furthermore, high sIL-2R levels may not always reflect T-cell activation. OBJECTIVES: To address these limitations, this study investigated whether cell surface markers of T-cell activation, HLA-DR, and CD38, as assessed by flow cytometry, could be used to quantify systemic T-cell activation in a variety of inflammatory disease states and examine its correlation with sIL-2R levels. METHODS: Results for sIL-2R, CXCL9, and ferritin assays were obtained from patient's medical records. Frequency of HLA-DR+CD38high(hi) T-cells was assessed in different T-cell subsets using flow cytometry. RESULTS: In this study's cohort, activation in total CD8+ T (r = 0.65; P < .0001) and CD4+ (r = 0.42; P < .0001) T-cell subsets significantly correlated with plasma sIL-2R levels. At the disease onset, the frequency of HLA-DR+CD38hi T cells in CD8+ T (r = 0.65, P < .0001) and CD4+ T (r = 0.77; P < .0001) effector memory (TEM) compartments correlated strongly with sIL-2R levels. Evaluation of T-cell activation markers in follow-up samples also revealed a positive correlation for both CD4+ TEM and CD8+ TEM activation with sIL-2R levels; thus, attesting its utility in initial diagnosis and in evaluating treatment response. The frequency of HLA-DR+CD38hi T-cells in the CD8+ TEM compartment also correlated with plasma CXCL9 (r = 0.42; P = .0120) and ferritin levels (r = 0.32; P = .0037). CONCLUSIONS: This study demonstrates that flow cytometry-based direct T-cell activation assessed by HLA-DR+CD38hi T cells accurately quantifies T-cell activation and strongly correlates with sIL-2R levels across a spectrum of hyperinflammatory and immune dysregulation disorders.

Generation of High-Affinity Aptamers for Indazole Synthetic Cannabinoids.

Synthetic cannabinoids are a widely abused class of dangerous psychoactive substances, especially among youths and young adults. Dozens of such drugs have been identified to date, and new ones continue to emerge. The ability to detect these drugs is important for interdiction efforts and the diagnosis of drug overdose, but existing analytical methods lack broad cross-reactivity to diverse members of this drug family. Here, we have utilized library-immobilized SELEX to generate DNA aptamers that can broadly recognize various members of the indazole-3-carboxamide synthetic cannabinoid family. Using two representatives of this family, AB-FUBINACA and 5F-AMB, we identify two aptamers FUB4 and AMB2F with respective dissociation constants (KDs) of 138 ± 15 and 411 ± 20 nM for their targets. These aptamers can recognize many indazole-based synthetic cannabinoids with high affinity and excellent specificity against natural cannabinoids as well as other structurally similar interferents like serotonin and tryptophan. We use these two aptamers to develop fluorescence strand-displacement sensors that successfully detect these synthetic cannabinoids at concentrations as low as 50 nM in human serum. The sensors can also detect up to 14 different drugs from this family─a major improvement over the six recognized by an existing commercial immunoassay.

Surface Chemistry in Environmental Degradation of Polymeric Solids.

Microplastics (MPs) cause significant adverse environmental effects. To address this issue, a scientific approach for understanding the formation of MPs is essential. In this Perspective, we summarize the three typical degradation behaviors of polymeric solids from a surface chemistry perspective: chemical degradation, biodegradation, and mechanical degradation. These three degradation processes can occur consecutively or simultaneously in poorly managed polymeric materials, ultimately resulting in their disintegration into the environment. This Perspective provides valuable insights into controlling the degradation of polymeric solids and designing eco-friendly polymers for a sustainable future.

Outcomes for pregnant women with Borderline Personality Disorder who attended a specialist antenatal service.

OBJECTIVE: Our study focussed on the obstetric and psychosocial outcomes of pregnant women with Borderline Personality Disorder (BPD) who received care via a specialist antenatal clinic in Western Australia. METHOD: This study is a retrospective examination of outcomes for 80 women with a confirmed diagnosis of BPD, with findings compared with published population outcome data for the state. RESULTS: Pregnant women with BPD appeared to be at a risk of complications including pre-eclampsia and special care nursery admission for their newborns when compared to population data. Furthermore, the studied women had elevated rates of psychiatric admissions during pregnancy, child protection involvement, and domestic violence. Polypharmacy exposure was frequent, with the likely impact on obstetric and neonatal outcomes requiring further study. CONCLUSION: The findings reinforced the notion that pregnant women with BPD experience complex multifaceted vulnerabilities and require enhanced multidisciplinary care. Our study further calls for the development of clinical practice guidelines for managing BPD in the perinatal period.

Calcium Intake Contributed by Whole Foods and Gastric Cancer in Viet Nam: A Case­Control Study.

BACKGROUND: Recent studies revealed the potential tumor-suppressive effects of calcium. We aimed to investigate the association between dietary calcium intake contributed by whole foods and gastric cancer. METHODS: 466 gastric cancer cases and 1531 controls were extracted from the completed case-control studies in hospitals in Hanoi from 2017 to 2019. A validated semi-quantitative food frequency questionnaire was used to obtain data via face-to-face interviews with the trained interviewer. Calcium intake was calculated based on the food frequency intake per year. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. RESULTS: The study participants consumed less than 50% of 700 mg/day compared to the recommended calcium intake. With increasing calcium intake, we found a reduction in gastric cancer in both genders, men and women (adjusted OR and 95%CI, 5th vs. 1st quintile: 0.50 (0.36, 0.70), p_trend 0.000; 0.62 (0.42, 0.92), p_trend 0.019; and 0.30 (0.16, 0.57), p_trend 0.000, respectively). The inverse association remained in the subgroups of never-smokers and those with positive H. pylori infection. CONCLUSION: We observed substantial benefits of calcium intake from whole foods against gastric cancer in the Vietnamese population with a low nutritious status.

General practitioner perceptions and experiences of managing perinatal mental health: a scoping review.

BACKGROUND: General Practitioners (GPs) are involved in preconception, pregnancy, and postnatal care. Overall, mental health remains a significant contributor to disease burden affecting 1 in 4 pregnant women. Psychotropic medication prescribing occurs in almost 1 in 12 pregnancies, and appears to be increasing, along with the prevalence of mental health disorders in women of reproductive age. Perinatal mental health management is therefore not an unlikely scenario within their clinical practice. This scoping review aims to map current research related to GPs perceptions and experiences of managing perinatal mental health. METHOD: A comprehensive search strategy using nine electronic databases, and grey literature was undertaken between December 2021 and February 2023. Relevant studies were sourced from peer review databases using key terms related to perinatal mental health and general practitioners. Search results were screened on title, abstract and full text to assess those meeting inclusion criteria and relevance to the research question. RESULTS: After screening, 16 articles were included in the scoping review. The majority focused on perinatal depression. Findings support that GPs express confidence with diagnosing perinatal depression but report issues of stigma navigating a diagnosis. Over the last two decades, prescribing confidence in perinatal mental health remains variable with concerns for the safety profile of medication, low level of confidence in providing information and a strong reliance on personal experience. Despite the establishment of perinatal guidelines by countries, the utilisation of these and other existing resources by GPs appears from current literature to be infrequent. Many challenges exist for GPs around time pressures, a lack of information and resources, and difficulty accessing referral to services. CONCLUSION: Recommendations following this scoping review include targeted perinatal education programs specific for GPs and embedded within training programs and the development of practice guidelines and resources specific to general practice that recognises time, services, and funding limitations. To achieve this future research is first needed on how guidelines and resources can be developed and best delivered to optimise GP engagement to improve knowledge and enhance patient care.

Dynamic indoor free-space optical communication enabled by beam steering and beam shaping.

Indoor free-space optical communication (FSO) provides orders of magnitude larger usable bandwidth compared to radio-frequency links but suffers from an intrinsic trade-off between areal coverage and received power. In this paper, we report a dynamic indoor FSO system enabled by a line-of-sight optical link featuring advanced beam control capabilities. The optical link herein utilizes a passive target acquisition scheme by combining a beam steering and beam shaping transmitter with a receiver adorned with a ring-shaped retroreflector. When controlled by an efficient beam scanning algorithm, the transmitter is capable of locating the receiver with millimeter-scale accuracy over a distance of 3 m with a full viewing angle of ±11.25∘ in the vertical direction and ±18.75∘ in the horizontal direction within 1.162±0.005s, regardless of the receiver's positions. We also demonstrate 1 Gbit/s data rate with bit error rates below 4×10-7 using an 850 nm laser diode with only 2 mW of output power.

Distinguishing immune activation and inflammatory signatures of multisystem inflammatory syndrome in children (MIS-C) versus hemophagocytic lymphohistiocytosis (HLH).

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening sequela of severe acute respiratory syndrome coronavirus 2 infection characterized by hyperinflammation and multiorgan dysfunction. Although hyperinflammation is a prominent manifestation of MIS-C, there is limited understanding of how the inflammatory state of MIS-C differs from that of well-characterized hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH). OBJECTIVES: We sought to compare the qualitative and quantitative inflammatory profile differences between patients with MIS-C, coronavirus disease 2019, and HLH. METHODS: Clinical data abstraction from patient charts, T-cell immunophenotyping, and multiplex cytokine and chemokine profiling were performed for patients with MIS-C, patients with coronavirus disease 2019, and patients with HLH. RESULTS: We found that both patients with MIS-C and patients with HLH showed robust T-cell activation, markers of senescence, and exhaustion along with elevated TH1 and proinflammatory cytokines such as IFN-γ, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10. In comparison, the amplitude of T-cell activation and the levels of cytokines/chemokines were higher in patients with HLH when compared with patients with MIS-C. Distinguishing inflammatory features of MIS-C included elevation in TH2 inflammatory cytokines such as IL-4 and IL-13 and cytokine mediators of angiogenesis, vascular injury, and tissue repair such as vascular endothelial growth factor A and platelet-derived growth factor. Immune activation and hypercytokinemia in MIS-C resolved at follow-up. In addition, when these immune parameters were correlated with clinical parameters, CD8+ T-cell activation correlated with cardiac dysfunction parameters such as B-type natriuretic peptide and troponin and inversely correlated with platelet count. CONCLUSIONS: Overall, this study characterizes unique and overlapping immunologic features that help to define the hyperinflammation associated with MIS-C versus HLH.

The Patterns of Antipsychotic Use for Pregnant Women Over a 16-year Timeframe in an Australian Principal Referral and Specialist Women and Newborn Hospital.

The purpose of the study is to analyse the patterns of antipsychotic use for pregnant women in an Australian Principal Referral and Specialist Women and Newborn Hospital. This retrospective, observational study involved an analysis of dispensing data of antipsychotics from 1998 to 2014 extracted from the pharmacy dispensing systems. The study included 282 antipsychotic dispensings in the years 1999 to 2006 and 3041 dispensings in the years 2007 to 2014. Second-generation antipsychotic use during pregnancy increased over time, while first-generation-antipsychotics showed declining trend. The use of quetiapine has increased from 2.9% of total antipsychotic dispensings in 2002 up to 77.9% of total antipsychotic dispensings in 2008. Olanzapine use decreased from 78.1% in 2003 to around 20% since 2006. When comparing the age distribution, there was an increased proportion of patients receiving antipsychotics in the 30-39 age range in the second period of 2007 to 2014 compared to 1999 to 2006. The proportion of women on more than one antipsychotic increased from 5% (n = 8) to 9.8% (n = 81) when comparing between 1999 and 2006 and between 2007 and 2014. Our findings indicate a significant shift in prescribing patterns over the study period, with the increased use of antipsychotics, particularly the emergence of SGAs from 2007, changing trends in the use of specific medications as published findings on their safety profiles becomes evident, and more polypharmacy prescribing.

A combination of intrinsic and extrinsic features improves prognostic prediction in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a lung pleural cancer with very poor disease outcome. With limited curative MPM treatment available, it is vital to study prognostic biomarkers to categorise different patient risk groups. METHODS: We defined gene signatures to separately characterise intrinsic and extrinsic features, and investigated their interactions in MPM tumour samples. Specifically, we calculated gene signature scores to capture the downstream pathways of major mutated driver genes (BAP1, NF2, SETD2 and TP53) as tumour-intrinsic features. Similarly, we inferred the infiltration levels for major immune cells in the tumour microenvironment to characterise tumour-extrinsic features. Lastly, we integrated these features with clinical factors to predict prognosis in MPM. RESULTS: The gene signature scores were more prognostic than the corresponding genomic mutations, mRNA and protein expression. High immune infiltration levels were associated with prolonged survival. The integrative model indicated that tumour features provided independent prognostic values than clinical factors and were complementary with each other in survival prediction. CONCLUSIONS: By using an integrative model that combines intrinsic and extrinsic features, we can more correctly predict the clinical outcomes of patients with MPM.

The sexual and reproductive health of female psychiatric inpatients: An area needing more attention?

OBJECTIVE: Trauma-informed care and physical (including sexual and reproductive) health screening is standard in Western Australian mental health settings. We sought to determine the rates of reported sexual trauma and domestic violence (DV), the rates of sexual and reproductive health screening, and associations between sexual trauma and reproductive health screening in a sample of women of child-bearing age (WOCBA), that is, 18-49 years, admitted to an inpatient psychiatric unit (IPU). METHODS: A retrospective study on 12 months of admissions to an outer metropolitan IPU (2017-2018), using descriptive analysis. RESULTS: Review of 160 admissions demonstrated high rates of reported sexual trauma (49.4%) and DV (38.8%). Rates of screening for pregnancy (56.9%) and sexually-transmitted infection risk (18.8%) were low. 5 out of 25 (20.0%) patients prescribed a mood stabiliser had documented discussions regarding reproductive risks of their medication. An overall lack of effect (p > .6) was found between sexual trauma history and reproductive health screening. CONCLUSIONS: WOCBA admitted to an IPU are vulnerable to having experienced sexual trauma and DV, with low rates of documented reproductive health screening despite existing clinical guidelines.

Genome-wide analysis of SARS-CoV-2 strains circulating in Vietnam: Understanding the nature of the epidemic and role of the D614G mutation.

Genome-wide analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains is essential to better understand infectivity and virulence and to track coronavirus disease 2019 (COVID-19) cases and outbreaks. We performed whole-genome sequencing of 27 SARS-CoV-2 strains isolated between January 2020 and April 2020. A total of 54 mutations in different genomic regions was found. The D614G mutation, first detected in March 2020, was identified in 18 strains and was more likely associated with a lower cycle threshold (<25) in real-time reverse-transcription polymerase chain reaction diagnostic tests than the original D614 (prevalence ratio = 2.75; 95% confidence interval, 1.19-6.38). The integration of sequencing and epidemiological data suggests that SARS-CoV-2 transmission in both quarantine areas and in the community in Vietnam occur at the beginning of the epidemic although the country implemented strict quarantine quite early, with strict contact tracing, and testing. These findings provide insights into the nature of the epidemic, as well as shape strategies for COVID-19 prevention and control in Vietnam.

The O6-methyguanine-DNA methyltransferase inhibitor O6-benzylguanine enhanced activity of temozolomide + irinotecan against models of high-risk neuroblastoma.

DNA-damaging chemotherapy is a major component of therapy for high-risk neuroblastoma, and patients often relapse with treatment-refractory disease. We hypothesized that DNA repair genes with increased expression in alkylating agent resistant models would provide therapeutic targets for enhancing chemotherapy. In-vitro cytotoxicity of alkylating agents for 12 patient-derived neuroblastoma cell lines was assayed using DIMSCAN, and mRNA expression of 57 DNA repair, three transporter, and two glutathione synthesis genes was assessed by TaqMan low-density array (TLDA) with further validation by qRT-PCR in 26 cell lines. O6-methylguanine-DNA methyltransferase (MGMT) mRNA was upregulated in cell lines with greater melphalan and temozolomide (TMZ) resistance. MGMT expression also correlated significantly with resistance to TMZ+irinotecan (IRN) (in-vitro as the SN38 active metabolite). Forced overexpression of MGMT (lentiviral transduction) in MGMT non-expressing cell lines significantly increased TMZ+SN38 resistance. The MGMT inhibitor O6-benzylguanine (O6BG) enhanced TMZ+SN38 in-vitro cytotoxicity, H2AX phosphorylation, caspase-3 cleavage, and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling. TMZ+IRN+O6BG delayed tumor growth and increased survival relative to TMZ+IRN in two of seven patient-derived xenografts established at time of death from progressive neuroblastoma. We demonstrated that high MGMT expression was associated with resistance to alkylating agents and TMZ+IRN in preclinical neuroblastoma models. The MGMT inhibitor O6BG enhanced the anticancer effect of TMZ+IRN in vitro and in vivo. These results support further preclinical studies exploring MGMT as a therapeutic target and biomarker of TMZ+IRN resistance in high-risk neuroblastoma.

Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies.

T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. There exist some key differences between HDAC inhibitors. Therefore, we determined if the pan-HDAC inhibitor vorinostat synergizes with fenretinide. We demonstrated cytotoxic synergy between vorinostat and fenretinide in nine TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, vorinostat + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous TCLM xenograft models than other groups. Fenretinide + vorinostat increased reactive oxygen species (ROS, measured by 2',7'-dichlorodihydrofluorescein diacetate dye), resulting in increased apoptosis (via transferase dUTP nick end labeling assay) and histone acetylation (by immunoblotting). The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + vorinostat was abrogated by the antioxidant vitamin C. Like romidepsin, vorinostat combined with fenretinide achieved synergistic cytotoxic activity and increased histone acetylation in preclinical models of TCLMs, but not in non-malignant cells. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs.

Emotional availability in women with bipolar disorder and major depression: A longitudinal pregnancy cohort study.

OBJECTIVE: Poorer mother-infant interaction quality has been identified among women with major depression; however, there is a dearth of research examining the impact of bipolar disorder. This study sought to compare mother-infant emotional availability at 6 months postpartum among women with perinatal major depressive disorder, bipolar disorder and no disorder (control). METHODS: Data were obtained for 127 mother-infant dyads from an Australian pregnancy cohort. The Structured Clinical Interview for the DSM-5 was used to diagnose major depressive disorder (n = 60) and bipolar disorder (n = 12) in early pregnancy (less than 20 weeks) and review diagnosis at 6 months postpartum. Prenatal and postnatal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale, along with self-report psychotropic medication use. Mother and infant's interaction quality was measured using the Emotional Availability Scales when infants reached 6 months of age. Multivariate analyses of covariance examining the effects of major depressive disorder and bipolar disorder on maternal emotional availability (sensitivity, structuring, non-intrusiveness, non-hostility) and child emotional availability (responsiveness, involvement) were conducted. RESULTS: After controlling for maternal age and postpartum depressive symptoms, perinatal disorder (major depressive disorder, bipolar disorder) accounted for 17% of the variance in maternal and child emotional availability combined. Compared to women with major depressive disorder and their infants, women with bipolar disorder and their infants displayed lower ratings across all maternal and child emotional availability qualities, with the greatest mean difference seen in non-intrusiveness scores. CONCLUSIONS: Findings suggest that perinatal bipolar disorder may be associated with additional risk, beyond major depressive disorder alone, to a mother and her offspring's emotional availability at 6 months postpartum, particularly in maternal intrusiveness.

Reproductive planning, vitamin knowledge and use, and lifestyle risks of women attending pregnancy care with a severe mental illness.

OBJECTIVE: Women with severe mental illnesses are a vulnerable population and little is known about their reproductive planning needs. The aim of our study was to describe rates of unintended pregnancies, postpartum contraception, identify use and knowledge of prenatal/pregnancy vitamins and identify modifiable lifestyle risks. DESIGN: Mixed methods study incorporating a cross-sectional survey and prospective pregnancy data collection. SETTING: A multidisciplinary antenatal clinic in Australia. METHOD: Thirty-eight pregnant women with severe mental illnesses: schizophrenia, schizoaffective, bipolar and severe post-traumatic stress disorder. MAIN OUTCOME MEASURES: Unintended pregnancy rates, immediate postpartum contraception, use of prenatal and pregnancy vitamins and knowledge sources, obesity, and use and cessation rates for smoking, and substances, and comorbid medical conditions. RESULTS: Overall 42% of women had unintended pregnancy, with those with schizophrenia at most risk (56%). A long acting reversible contraception was inserted in 5 women (13%), with 45% having no immediate contraception prescribed prior to postnatal discharge. Women's main source of vitamin supplementation for pregnancy was from general practitioners. Prenatal folic acid use occurred in 37%, with rates differing for those with a diagnosis of bipolar disorder (52%) and schizophrenia (25%). Vitamin deficiencies occurred in pregnancy, with iron deficiency (ferritin <30 ng/mL) (n = 27, 73%) the most frequent. Overall 21% of women smoked cigarettes and 35% were obese. DISCUSSION: Addressing gaps in use of effective contraception, proactive reproductive planning and lifestyle management may improve outcomes for women with mental illnesses and their babies.Key pointsWomen with severe mental illnesses have complex health needs that require targeted reproductive counselling. This study adds to what is known by highlighting that:•Women with schizophrenia appear more likely to have unintended pregnancy.•Prenatal counselling for women with severe mental disorders should include recognition and optimisation of management for the high rates of pre-existing medical comorbidities, obesity and elevated nicotine and substance use.•Many women with severe mental illness need increased doses (5 mg) of prenatal folic acid due to psychotropic medication risk and obesity, as well as treatment for high rates of iron and vitamin D deficiency in pregnancy.

Lithocholic Acid Induces miR21, Promoting PTEN Inhibition via STAT3 and ERK-1/2 Signaling in Colorectal Cancer Cells.

Micro-RNA-21 (miR-21) is a vital regulator of colorectal cancer (CRC) progression and has emerged as a potential therapeutic target in CRC treatment. Our study using real-time PCR assay found that a secondary bile acid, lithocholic acid (LCA), stimulated the expression of miR21 in the CRC cell lines. Promoter activity assay showed that LCA strongly stimulated miR21 promoter activity in HCT116 cells in a time- and dose-dependent manner. Studies of chemical inhibitors and miR21 promoter mutants indicated that Erk1/2 signaling, AP-1 transcription factor, and STAT3 are major signals involved in the mechanism of LCA-induced miR21 in HCT116 cells. The elevation of miR21 expression was upstream of the phosphatase and tensin homolog (PTEN) inhibition, and CRC cell proliferation enhancement that was shown to be possibly mediated by PI3K/AKT signaling activation. This study is the first to report that LCA affects miR21 expression in CRC cells, providing us with a better understanding of the cancer-promoting mechanism of bile acids that have been described as the very first promoters of CRC progression.

A review of technologies for collaborative online information seeking: On the contribution of collaborative argumentation.

In everyday life, people seek, evaluate, and use online sources to underpin opinions and make decisions. While education must promote the skills people need to critically question the sourcing of online information, it is important, more generally, to understand how to successfully promote the acquisition of any skills related to seeking online information. This review outlines technologies that aim to support users when they collaboratively seek online information. Upon integrating psychological-pedagogical approaches on trust in and the sourcing of online information, argumentation, and computer-supported collaborative learning, we reviewed the literature (N = 95 journal articles) on technologies for collaborative online information seeking. The technologies we identified either addressed collaborative online information seeking as an exclusive process for searching for online information or, alternatively, addressed online information seeking within the context of a more complex learning process. Our review was driven by three main research questions: We aimed to understand whether and how the studies considered 1) the role of trust and critical questioning in the sourcing of online information, 2) the learning processes at play when information seekers engage in collaborative argumentation, and 3) what affordances are offered by technologies that support users' collaborative seeking of online information. The reviewed articles that focused exclusively on technologies for seeking online information primarily addressed aspects of cooperation (e.g., task management), whereas articles that focused on technologies for integrating the processes of information seeking into the entire learning processes instead highlighted aspects of collaborative argumentation (e.g., exchange of multiple perspectives and critical questioning in argumentation). Seven of the articles referred to trust as an aspect of seekers' sourcing strategies. We emphasize how researchers', users', and technology developers' consideration of collaborative argumentation could expand the benefits of technological support for seeking online information.