Body mass index and inflammation in depression and treatment-resistant depression: a Mendelian randomisation study.

BACKGROUND: Major depressive disorder (MDD) has a significant impact on global burden of disease. Complications in clinical management can occur when response to pharmacological modalities is considered inadequate and symptoms persist (treatment-resistant depression (TRD)). We aim to investigate inflammation, proxied by C-reactive protein (CRP) levels, and body mass index (BMI) as putative causal risk factors for depression and subsequent treatment resistance, leveraging genetic information to avoid confounding via Mendelian randomisation (MR). METHODS: We used the European UK Biobank subcohort ([Formula: see text]), the mental health questionnaire (MHQ) and clinical records. For treatment resistance, a previously curated phenotype based on general practitioner (GP) records and prescription data was employed. We applied univariable and multivariable MR models to genetically predict the exposures and assess their causal contribution to a range of depression outcomes. We used a range of univariable, multivariable and mediation MR models techniques to address our research question with maximum rigour. In addition, we developed a novel statistical procedure to apply pleiotropy-robust multivariable MR to one sample data and employed a Bayesian bootstrap procedure to accurately quantify estimate uncertainty in mediation analysis which outperforms standard approaches in sparse binary outcomes. Given the flexibility of the one-sample design, we evaluated age and sex as moderators of the effects. RESULTS: In univariable MR models, genetically predicted BMI was positively associated with depression outcomes, including MDD ([Formula: see text] ([Formula: see text] CI): 0.133(0.072, 0.205)) and TRD (0.347(0.002, 0.682)), with a larger magnitude in females and with age acting as a moderator of the effect of BMI on severity of depression (0.22(0.050, 0.389)). Multivariable MR analyses suggested an independent causal effect of BMI on TRD not through CRP (0.395(0.004, 0.732)). Our mediation analyses suggested that the effect of CRP on severity of depression was partly mediated by BMI. Individuals with TRD ([Formula: see text]) observationally had higher CRP and BMI compared with individuals with MDD alone and healthy controls. DISCUSSION: Our work supports the assertion that BMI exerts a causal effect on a range of clinical and questionnaire-based depression phenotypes, with the effect being stronger in females and in younger individuals. We show that this effect is independent of inflammation proxied by CRP levels as the effects of CRP do not persist when jointly estimated with BMI. This is consistent with previous evidence suggesting that overweight contributed to depression even in the absence of any metabolic consequences. It appears that BMI exerts an effect on TRD that persists when we account for BMI influencing MDD.

Weak and pleiotropy robust sex-stratified Mendelian randomization in the one sample and two sample settings.

BACKGROUND: Mendelian randomization (MR) leverages genetic data as an instrumental variable to provide estimates for the causal effect of an exposure X on a health outcome Y that is robust to confounding. Unfortunately, horizontal pleiotropy-the direct association of a genetic variant with multiple phenotypes-is highly prevalent and can easily render a genetic variant an invalid instrument. METHODS: Building on existing work, we propose a simple method for leveraging sex-specific genetic associations to perform weak and pleiotropy-robust MR analysis. This is achieved by constructing an MR estimator in which pleiotropy is perfectly removed by cancellation, while placing it within the powerful machinery of the robust adjusted profile score (MR-RAPS) method. Pleiotropy cancellation has the attractive property that it removes heterogeneity and therefore justifies a statistically efficient fixed effects model. We extend the method from the typical two-sample summary-data MR setting to the one-sample setting by adapting the technique of Collider-Correction. Simulation studies and applied examples are used to assess how the sex-stratified MR-RAPS estimator performs against other common approaches. RESULTS: The sex-stratified MR-RAPS method is shown to be robust to pleiotropy even in cases where all genetic variants violated the standard Instrument Strength Independent of Direct Effect assumption. In some cases where the strength of the pleiotropic effect additionally varied by sex (and so perfect cancellation was not achieved), over-dispersed MR-RAPS implementations can still consistently estimate the true causal effect. In applied analyses, we investigate the causal effect of waist-hip ratio (WHR), an important marker of central obesity, on a range of downstream traits. While the conventional approaches suggested paradoxical links between WHR and height and body mass index, the sex-stratified approach obtained a more realistic null effect. Nonzero effects were also detected for systolic and diastolic blood pressure as well as high-density and low-density lipoprotein cholesterol. DISCUSSION: We provide a simple but attractive method for weak and pleiotropy robust causal estimation of sexually dimorphic traits on downstream outcomes, by combining several existing approaches in a novel fashion.

Myocarditis following mRNA Covid-19 vaccination: A pooled analysis.

BACKGROUND: Post-marketing surveillance studies have raised concerns of increased myocarditis rates following coronavirus disease-19 (Covid-19) mRNA vaccines. The present study aims to accumulate the published mRNA Covid-19 vaccine-associated myocarditis cases, describe their clinical characteristics and determine the factors predisposing to critical illness. METHODS: Medline, Scopus, Web of Science, CENTRAL and Google Scholar were systematically searched from inception. Studies reporting adult myocarditis cases following BNT162b2 or mRNA-1273 vaccination were included. Individual participant data coming from case reports/series were pooled. Proportional random-effects meta-analysis was conducted by combining the pooled cohort and observational studies with aggregated data. RESULTS: Overall, 39 studies were included with a total of 129 patients. Most cases occurred in young males after the second vaccine dose. Myocarditis after the first dose was significantly associated with prior Covid-19 (p-value: 0.025). The most common electrocardiographic finding was ST-segment elevation, while late gadolinium enhancement was invariably observed in cardiac magnetic reasoning. Logistic regression analysis demonstrated that signs of heart failure were predictive of subsequent critical illness (Odds ratio: 19.22, 95% confidence intervals-CI: 5.57-275.84). Proportion meta-analysis indicated that complete resolution of symptoms is achieved in 80.5% of patients (95% CI: 59.3-92.1), while the proportion of participants necessitating intensive care unit admission is 7.0% (95% CI: 3.8-12.9). CONCLUSIONS: Myocarditis following mRNA Covid-19 vaccination is typically mild, following an uncomplicated clinical course with rapid improvement of symptoms. Future research is needed to define its exact incidence, clarify its pathophysiology and determine the optimal management plan depending on its severity. Protocol registration: dx.https://doi.org/10.17504/protocols.io.bxwtppen.

Mean platelet volume and neonatal sepsis: a systematic review and meta-analysis of diagnostic accuracy.

AIM: To determine the diagnostic accuracy of Mean Platelet Volume in neonatal sepsis. METHODS: We systematically searched MEDLINE, Clinicaltrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar and WHO (International Clinical Trials Register Platform) databases from inception using a structured algorithm. All observational studies were deemed eligible. Meta-analysis was performed using the RevMan 5.3 software and heterogeneity was assessed through subgroup and meta-regression analysis. Studies included in the meta-analysis were assessed using the Newcastle-Ottawa scale while studies used for the calculation of the diagnostic accuracy were evaluated using the Quality Assessment of Diagnostic Accuracy tool. RESULTS: MPV levels were found significantly higher than in healthy neonates (SMD: 1.62, 95% CI 0.97-2.27 and p < 10-5). Subgroup analysis based on hematological analyzer, EDTA usage and venipuncture to analysis time below 120 min also showcased significantly higher SMD's in neonates with sepsis than in healthy. Sensitivity and specificity of MPV in neonatal sepsis were found to be 0.675 (95% CI: 0.536-0.790) and 0.733 (95% CI: 0.589-0.840), respectively, at an optimal cutoff point of 9.28fL. CONCLUSION: MPV appears to have a fair diagnostic accuracy in sepsis investigation. Given its ready availability it may constitute an attractive adjunct for clinicians, especially in low-resource environments.

Peritoneal dialysis in very low and extremely low birthweight infants: A pooled analysis.

BACKGROUND: Peritoneal dialysis (PD) represents an important therapeutic option in neonatal acute kidney injury (AKI), although evidence regarding its effects in preterm neonates remains unclear. The present study aims to evaluate the feasibility of PD in very low birthweight (VLBW) and extremely low birthweight (ELBW) infants and clarify the association of catheter choice with clinical outcomes. METHODS: Medline, Scopus, Web of Science, Clinicaltrials.gov and CENTRAL databases were systematically searched from inception to 15 January 2021. Studies reporting individual participant data of VLBW and ELBW infants treated with PD were selected. RESULTS: Overall, 20 studies were included comprising 101 patients. Catheter-related complications were significantly more frequent among ELBW infants (odds ratio: 5.18, 95% confidence intervals (CI): 1.23-29.09). After inverse probability treatment weighting, compared to drainage catheters, death risk was significantly lower with the use of PD (hazard ratio: 0.42, 95% CI: 0.19-0.90) but not vascular catheters (hazard ratio: 0.58, 95% CI: 0.28-1.20). Similarly, kidney function loss was significantly lower only with the implementation of PD catheters (hazard ratio: 0.44, 95% CI: 0.21-0.94). CONCLUSIONS: PD is a feasible kidney replacement therapy modality in VLBW and ELBW infants with AKI. The use of drainage catheters may be linked to significantly worse kidney recovery and overall survival rates, compared to PD catheters. Future cohorts should confirm the most appropriate catheter type and contribute to the standardisation of PD procedures.

An age-period-cohort study of completed suicides in Greece: Patterns and implications for suicide prevention.

Suicide is a dynamic phenomenon. Psychiatric medication intake, illicit drug and alcohol use or the preference for particular suicide methods shift continuously over time. To capture such variations -and their potential implications for suicide prevention-, we researched the forensic records of suicide cases for the period 1992-2016 at a large department of forensic medicine and conducted age-period-cohort (APC) analyses of our sample (1162 suicides, 77.45% males, 22.25% females). We primarily investigated socio-demographic and toxicological parameters. Benzodiazepine, alcohol and illicit drug use increased considerably towards the younger cohorts. The segment of individuals of foreign nationality raised significantly too; likewise, the proportion of prison suicides. Hanging appears increasingly preferred by the younger APCs (the opposite is true for jumping). Hanging seems more popular among males, prisoners, and those under the influence of illicit drugs; jumping by females and those less likely to have consumed alcohol or illicit drugs. Given that the method of a prior attempt, if a highly lethal one, usually gets repeated in the completed suicide, a history of an attempt by hanging should never be underestimated. The mental health needs of immigrants and prisoners look inadequately addressed. Young-middle aged immigrant prisoners appear a group at high suicide risk.

Investigating the impact of different strategies for endometrial preparation in frozen cycles considering normal responders undergoing IVF/ICSI cycles: a multicenter retrospective cohort study.

Uncertainty exists concerning the type, adjunct, or dose of regimen to offer in frozen cycles in infertile women undergoing IVF/ICSI. Current systematic reviews have failed to identify one method of endometrial preparation as being more effective than another, whereas many IVF Units use variable and mixed protocols mainly based on their experience and convenience of use. Thus, we performed a four-center two-arm retrospective cohort study, encompassing 439 cycles in 311 women. The modalities analyzed were: Modified natural cycle without and with luteal support (Groups 1,2) and Hormone Replacement cycle (HRC) with and without GnRHa suppression (Groups 3,4). Various schemes of progesterone and estradiol were used and compared. χ2 tests for categorical data and t-tests for continuous data were employed, stratifying by exposure, along with univariate and multivariable Logistic Regression models and subgroup analyses, according to the number of embryos transferred (1 vs. ≥2) and day of transfer (d2 vs. d5). Group 3 presented with statistically significant higher live birth and miscarriage rates in comparison to Group 4 (RR = 5.87, 95%CI: 2.44-14.14 and RR = 0.19, 95%CI: 0.06-0.60, respectively), findings that persisted in subgroup analyses according to the day of transfer and the number of embryos transferred. Progesterone administration through the combination of vaginal tabs and gel was associated with lower clinical pregnancy rates when compared to tabs (RR = 0.19, 95%CI: 0.05-0.71). The stable estrogen protocol compared to increasing estrogen at day 5 was associated with a higher positive hCG test and clinical pregnancy rate, while the progesterone through vaginal tabs was linked with lower miscarriages compared either with gel or combinations. In conclusion, HRC with GnRHa appears to be superior to HRC without GnRHa, concerning live birth and miscarriage, especially when the number of embryos transferred are ≥2 and irrespective of day of transfer. The use of progesterone vaginal tabs compared to gel or combinations is associated with better outcomes. Age is a significant predictor of a negative hCG test and clinical pregnancy rates. A properly conducted RCT is needed to evaluate the optimal frozen embryo transfer preparation strategy.Abbreviations: SD: standard deviation; BMI: body mass index; PCOS: polycystic ovarian syndrome; IQR: interquartile range; FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid-stimulating hormone.

Current Issues on Research Conducted to Improve Women's Health.

There are varied lessons to be learned regarding the current methodological approaches to women's health research. In the present scheme of growing medical literature and inflation of novel results claiming significance, the sheer amount of information can render evidence-based practice confusing. The factors that classically determined the impact of discoveries appear to be losing ground: citation count and publication rates, hierarchy in author lists according to contribution, and a journal's impact factor. Through a comprehensive literature search on the currently available data from theses, opinion, and original articles and reviews on this topic, we seek to present to clinicians a narrative synthesis of three crucial axes underlying the totality of the research production chain: (a) critical advances in research methodology, (b) the interplay of academy and industry in a trial conduct, and (c) review- and publication-associated developments. We also provide specific recommendations on the study design and conduct, reviewing the processes and dissemination of data and the conclusions and implementation of findings. Overall, clinicians and the public should be aware of the discourse behind the marketing of alleged breakthrough research. Still, multiple initiatives, such as patient review and strict, supervised literature synthesis, have become more widely accepted. The "bottom-up" approach of a wide dissemination of information to clinicians, together with practical incentives for stakeholders with competing interests to collaborate, promise to improve women's healthcare.

Characteristics of completed suicides after Greek financial crisis onset: A comparative time-series analysis study.

Severe financial crises could influence a country's suicide trends and characteristics. We aimed to highlight differences among suicide completers before and after the onset of Greece's serious debt crisis of 2010 based exclusively on forensic data. The sample's size permitted a further elaboration by means of a time series analysis too. Data were collected from the Piraeus Department of Forensic Medicine for the period 1992-2016. We extracted information on sociodemographic parameters, psychiatric medication and alcohol intake, suicide method, place and month of suicide. The "after crisis onset" group (2011-2016) was significantly older (p = 0.039)-primarily due to differences in the 55-64 age group-, had more frequently used psychiatric medications (p < 0.001), less often alcohol (p = 0.001) and died more frequently by immolation (p = 0.001). These differences were-almost exclusively-due to changes regarding male suicidal behavior. Time series analysis indicates that no strong increasing trend in total (male + female) suicide count can be observed, despite a local increase in 2009-2010. Antidepressant-positive suicides show an increase after 2010, whereas alcohol-positive suicides show a decrease. Future predicted forecasts for antidepressant-positive suicides indicate a decrease (from 5.6 per year in 2018 to 4.3 per year in 2025) whereas an increase is predicted in alcohol-positive suicides (7.7 per year in 2017, 9.36 per year in 2025). Middle-aged men, compared to middle-aged women, presumably found it harder to adjust to economic hardship after the crisis onset. Finally, comparatively more men than women who died by suicide appear to have started and/or complied with psychiatric treatment after 2010.

Knowledge, Attitudes and Perceptions about Cervical Cancer Risk, Prevention and Human Papilloma Virus (HPV) in Vulnerable Women in Greece.

Cervical cancer can be largely preventable through primary and secondary prevention activities. Following the financial crisis in Greece since 2011 and the increased number of refugees/migrants since 2015 the proportion of vulnerable population groups in Greece increased greatly and the ability of the healthcare sector to respond and to cover the health needs of the population is put under tremendous stress. A cross-sectional study was designed to assess the characteristics of vulnerable women in Greece regarding cervical cancer risk factors, prevention through screening activities and Human Papilloma Virus (HPV) knowledge. Two cohorts of women aged 18 to 70 years were studied (142 in 2012 and 122 in 2017) who completed an interviewer-administered questionnaire based on the behavioural model for vulnerable populations. According to this model, the factors that affect the behaviour of women in relation with their knowledge, attitudes and beliefs towards cervical cancer and the HPV vaccine in our study sample are categorised in predisposing factors (age, educational status, nationality menopausal status and housing) and enabling factors (lack of insurance coverage). Results from both univariate and multivariate analyses show that older age, low educational background, refugee/migrant or ethnic minority (Roma) background, menopausal status, housing conditions and lack of insurance coverage are linked with insufficient knowledge on risk factors for cervical cancer and false attitudes and perceptions on cervical cancer preventive activities (Pap smear and HPV vaccine). This is the first study in Greece showing the lack of knowledge and the poor attitudes and perceptions on cervical cancer screening and the HPV vaccine in various groups of vulnerable women. Our results indicate the need of health education and intervention activities according to the characteristics and needs of each group.

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction.

BACKGROUND: Despite substantial improvements in the success of assisted reproduction techniques (ART), live birth rates may remain consistently low, and practitioners may look for innovative treatments to improve the outcomes. The injection of embryo culture supernatant in the endometrial cavity can be undertaken at various time intervals before embryo transfer. It provides an altered endometrial environment through the secretion of factors considered to facilitate implantation. It is proposed that injection of the supernatant into the endometrial cavity prior to embryo transfer will stimulate the endometrium and provide better conditions for implantation to take place. An increased implantation rate would subsequently increase rates of clinical pregnancy and live birth, but current robust evidence on the efficacy of injected embryo culture supernatant is lacking. OBJECTIVES: To evaluate the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing ART. SEARCH METHODS: Our search strategies were designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist. We sought to identify all published and unpublished randomised controlled trials (RCTs) meeting inclusion criteria. Searches were performed on 2 December 2019. We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, CINAHL, trials registries and grey literature. We made further searches in the UK National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with searches of PubMed and Google for any recent trials that have not yet been indexed in the major databases. We had no language or location restrictions. SELECTION CRITERIA: We included RCTs testing the use of endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle, compared with the non-use of this intervention, the use of placebo or the use of any other similar drug. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We pooled studies using a fixed-effect model. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found five RCTs suitable for inclusion in the review (526 women analysed). We made two comparisons: embryo culture supernatant use versus standard care or no intervention; and embryo culture supernatant use versus culture medium. All studies were published as full-text articles. Data derived from the reports or through direct communication with investigators were available for the final meta-analysis performed. The GRADE evidence quality of studies ranged from very low-quality to moderate-quality. Factors reducing evidence quality included high risk of bias due to lack of blinding, unclear risk of publication bias and selective outcome reporting, serious inconsistency among study outcomes, and serious imprecision due to wide confidence intervals (CIs) and low numbers of events. Comparison 1. Endometrial injection of embryo culture supernatant before embryo transfer versus standard care or no intervention: One study reported live birth only and two reported the composite outcome live birth and ongoing pregnancy. We are uncertain whether endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle improves live birth/ongoing pregnancy rates compared to no intervention (odds ratio (OR) 1.11, 95% CI 0.73 to 1.70; 3 RCTs; n = 340, I2 = 84%; very low-quality evidence). Results suggest that if the chance of live birth/ongoing pregnancy following placebo or no treatment is assumed to be 42%, the chance following the endometrial injection of embryo culture supernatant before embryo transfer would vary between 22% and 81%. We are also uncertain whether the endometrial injection of embryo culture supernatant could decrease miscarriage rates, compared to no intervention (OR 0.89, 95% CI 0.44 to 1.78, 4 RCTs, n = 430, I2 = 58%, very low-quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 9%, the chance following injection of embryo culture supernatant would vary between 3% and 30%. Concerning the secondary outcomes, we are uncertain whether the injection of embryo culture supernatant prior to embryo transfer could increase clinical pregnancy rates (OR 1.13, 95% CI 0.80 to 1.61; 5 RCTs; n = 526, I2 = 0%; very low-quality evidence), decrease ectopic pregnancy rates (OR 0.32, 95% CI 0.01 to 8.24; n = 250; 2 RCTs; I2 = 41%; very low-quality evidence), decrease multiple pregnancy rates (OR 0.70, 95% CI 0.26 to 1.83; 2 RCTs; n = 150; I2 = 63%; very low-quality evidence), or decrease preterm delivery rates (OR 0.63, 95% CI 0.17 to 2.42; 1 RCT; n = 90; I2 = 0%; very low-quality evidence), compared to no intervention. Finally, there may have been little or no difference in foetal abnormality rates between the two groups (OR 3.10, 95% CI 0.12 to 79.23; 1 RCT; n = 60; I2 = 0%; low-quality evidence). Comparison 2. Endometrial injection of embryo culture supernatant versus endometrial injection of culture medium before embryo transfer We are uncertain whether the use of embryo culture supernatant improves clinical pregnancy rates, compared to the use of culture medium (OR 1.09, 95% CI 0.48 to 2.46; n = 96; 1 RCT; very low-quality evidence). No study reported live birth/ongoing pregnancy, miscarriage, ectopic or multiple pregnancy, preterm delivery or foetal abnormalities. AUTHORS' CONCLUSIONS: We are uncertain whether the addition of endometrial injection of embryo culture supernatant before embryo transfer as a routine method for the treatment of women undergoing ART can improve pregnancy outcomes. This conclusion is based on current available data from five RCTs, with evidence quality ranging from very low to moderate across studies. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of endometrial injection of embryo culture supernatant before embryo transfer.

Menopause in women with multiple sclerosis: A systematic review.

AIM: Sex hormones have been suggested to have neuroprotective effects in the natural history of multiple sclerosis (MS), particularly in animal studies. The aim of the present review was to retrieve and systematically synthesize the evidence on the effect of menopause and hormonal replacement treatment (HRT) on the course of MS. METHODS: A systematic literature search was conducted in the databases MEDLINE (accessed through PubMed), Scopus, clinicaltrials.gov and Cochrane Controlled Register of Trials (CENTRAL). Eligible studies were all those that included women with MS and reported on at least one of the following: a) disability and MS relapse rate before and after menopause, b) serum sex hormone concentrations, c) sexual function, d) age at menopause onset. Effects of HRT on MS clinical outcomes were also assessed. RESULTS: Of the 4,102 retrieved studies, 28 were included in the systematic review. Of these, one reported the age at menopause for both controls and women with MS and found no difference between the two groups. There was no difference in the rates of relapse before and after menopause (risk ratio 1.21, 95 % confidence interval 0.91-1.61, p = 0.218). Two intervention studies reported beneficial effects of estrogen therapy on women with MS; however, the majority of women were premenopausal. Three studies addressed the issue of sexual dysfunction in women with MS, but information on hormonal parameters was limited. CONCLUSIONS: The age at menopause is not associated with the presence of MS. The evidence on a potential causal effect of estrogen depletion on disability is inconclusive; still, relapse rate seems not be associated with menopause. The effect of HRT on the natural course of the disease remains to be defined.

Retinal Changes in Schizophrenia: A Systematic Review and Meta-analysis Based on Individual Participant Data.

BACKGROUND: Retinal assessment has indicated the presence of neuronal loss in neurodegenerative disorders, but its role in schizophrenia remains unclear. We sought to synthesize the available evidence considering 3 noninvasive modalities: optical coherence tomography, electroretinography, and fundus photography, and examine their diagnostic accuracy based on unpublished individual participant data, when provided by the primary study authors. METHODS: We searched MEDLINE, SCOPUS, clinicaltrials.gov, PSYNDEX, Cochrane Controlled Register of Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and Google Scholar, up to October 30, 2018. Authors were contacted and invited to share anonymized participant-level data. Aggregate data were pooled using random effects models. Diagnostic accuracy meta-analysis was based on multiple cutoffs logistic generalized linear mixed modeling. This study was registered with PROSPERO, number CRD42018109344. RESULTS: Pooled mean differences of peripapillary retinal nerve fiber layer thickness in micrometer between 694 eyes of 432 schizophrenia patients and 609 eyes of 358 controls, from 11 case-control studies, with corresponding 95% confidence intervals (CIs) by quadrant were the following: -4.55, 95% CI: -8.28, -0.82 (superior); -6.25, 95% CI: -9.46, -3.04 (inferior); -3.18, 95% CI: -5.04, -1.31 (nasal); and -2.7, 95% CI: -4.35, -1.04 (temporal). Diagnostic accuracy, based on 4 studies, was fair to poor, unaffected by age and sex; macular area measurements performed slightly better. CONCLUSION: The notion of structural and functional changes in retinal integrity of patients with schizophrenia is supported with current evidence, but diagnostic accuracy is limited. The potential prognostic, theranostic, and preventive role of retinal evaluation remains to be examined.

Management of depressive symptoms in peri- and postmenopausal women: EMAS position statement.

INTRODUCTION: Globally, the total number of people with depression exceeds 300 million, and the incidence rate is 70 % greater in women. The perimenopause is considered to be a time of increased risk for the development of depressive symptoms and major depressive episodes. AIM: The aim of this position statement is to provide a comprehensive model of care for the management of depressive symptoms in perimenopausal and early menopausal women, including diagnosis, treatment and follow-up. The model integrates the care provided by all those involved in the management of mild or moderate depression in midlife women. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Awareness of depressive symptoms, early detection, standardized diagnostic procedures, personalized treatment and a suitable follow-up schedule need to be integrated into healthcare systems worldwide. Recommended treatment comprises antidepressants, psychosocial therapies and lifestyle changes. Alternative and complementary therapies, although widely used, may help with depression, but a stronger evidence base is needed. Although not approved for this indication, menopausal hormone therapy may improve depressive symptoms in peri- but not in postmenopausal women, especially in those with vasomotor symptoms.

Adipokines in anorexia nervosa: A systematic review and meta-analysis.

OBJECTIVE: The association between adipokine dysregulation and weight loss of patients with anorexia nervosa (AN) has been long investigated, in search of a causal relationship. We sought to: a) synthesize the available evidence on potential differences between AN patients and controls with regards to adipokine measurements (namely, leptin, adiponectin, resistin, soluble leptin receptor, visfatin, vaspin and omentin), b) estimate the potential differences between constitutionally thin (CT) subjects and AN patients, and c) present the available evidence with regards to biomarker efficacy of adipokines in AN. METHODS: A structured literature search, last updated in 2/2019, was conducted in the following databases: MEDLINE, clinicaltrials.gov, PsycINFO, PSYNDEX and WHO Registry Network. The primary outcome was the standardized mean difference of each adipokine between AN patients and controls of normal BMI. Secondary outcomes included the correlation of leptin with BMI and bone mineral density among AN patients. The study protocol is published in PROSPERO (CRD42018116767). RESULTS: In a total of 622 screened studies, after exclusion of non-relevant articles and duplicates, 84 reports on leptin, 31 reports on adiponectin, 12 on resistin, 10 on soluble leptin receptor, 5 on visfatin, 3 on vaspin and omentin were finally included in the meta-analysis. Publication bias assessment underlined the possibility of non-significant studies being underrepresented; still, significant heterogeneity renders this statement inconclusive. Leptin [ELISA: SMD (95% CI): -3.03 (-4, -2.06)], radioimmunoassay [RIA: -3.84 (-4.71, -2.98)] and resistin [-1.67 (-2.85, -0.48)] were significantly lower in patients with AN compared with controls, whereas visfatin decrease did not reach significance (-2.03 (-4.38, 0.3). Mean adiponectin, vaspin and soluble leptin receptor levels were significantly higher. In subgroup analysis, a significantly attenuated SMD was reported in ELISA studies compared with RIA studies. Leptin was significantly lower in AN patients compared to CT subjects and BMI marginally did not appear to confound the result. In all analyses, except for the correlation of leptin with BMI in AN patients, high heterogeneity was present. Meta-regression analysis indicated a potential confounding action of controls' BMI and age on leptin SMD and between-assay differences. Publication bias assessment underlined the possibility of nonsignificant studies being underrepresented; still, further investigation did not corroborate this and significant heterogeneity renders this statement inconclusive. CONCLUSION: A distinct profile of adipokine dysregulation is apparent in AN patients, following the anticipated pattern of low BMI. A precise estimation of the magnitude is hindered by heterogeneity, partly caused by varying assays and methodologies. Interestingly, while mean leptin levels are lower in AN subjects compared with constitutionally thin women, there is an overlap in individual levels between the two groups and therefore, they cannot be used to differentiate between these states.

Red cell distribution width to platelet ratio for liver fibrosis: a systematic review and meta-analysis of diagnostic accuracy.

Introduction: Red cell distribution width to platelet ratio (RPR) may be a useful marker for the evaluation of liver fibrosis in chronic liver disease (CLD). We sought to investigate its value in fibrosis-related outcomes in a meta-analysis of diagnostic accuracy. Areas covered: We searched MEDLINE (1966-2019), Clinicaltrials.gov (2008-2019), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2019), Google Scholar (2004-2019) and WHO (International Clinical Trials Register Platform) databases using a structured algorithm. The articles were assessed by Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). In over 1,800 patients for each outcome, pooled sensitivity and specificity for a) significant fibrosis, b) advanced fibrosis and c) cirrhosis were: a) 0.635 and 0.769 with an AUC of 0.747, b) 0.607 and 0.783 with an AUC of 0.773, c) 0.739 and 0.768 with an AUC of 0.818 respectively. Similar results were found for chronic hepatitis B in all outcomes. Subgroup analysis indicated a high specificity for advanced fibrosis detection in primary biliary cirrhosis. Sensitivity analysis did not alter the results. Expert opinion: RPR is a good predictor of fibrosis, especially as severity of chronic liver disease progresses. Future research should elucidate its value in specific etiologies of chronic liver disease.

Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis.

There is evidence showing a positive correlation between prenatal androgens and their effect on the development of central nervous system and the autistic spectrum disorder (ASD) phenotype in offspring of mothers with polycystic ovary syndrome (PCOS). We applied a systematic review to investigate whether women with PCOS have increased odds of having a child with ASD, while, secondarily, if these women themselves are at high risk of having the disease. Major databases from inception until 14th October 2018 were searched. The primary outcome measure was the odds of an ASD diagnosis in children of mothers with diagnosed PCOS, while the secondary outcome was the odds of ASD diagnosis in women with PCOS. Scheduled subgroup analyses were according to the time of birth and maternal age. We assessed the odds ratio (OR), using a random-effects model; heterogeneity was assessed by I2 and τ2 statistics. The quality of the evidence was evaluated using the Newcastle-Ottawa Scale. Ten studies were eligible for inclusion, including a total of 33,887 ASD children and 321,661 non-ASD children. Diagnosed PCOS was associated with a 1.66 times increase in the odds of ASD in the offspring [95% CI: 1.51, 1.83, p = 1.99 × 10-25, 7 studies, I2 = 0%, τ2 = 0]. Women with PCOS were 1.78 times more likely to be diagnosed with ASD (95% CI: 1.10, 2.87, p = 0.0179, 5 studies, I2 = 85.4%, τ2 = 0.2432). Additional analyses did not change the initial result. The overall quality of the evidence was high. The pooled effects size displayed low heterogeneity (I2 = 0%) for the primary outcome. While the heterogeneity in the secondary outcome appears to attenuate when only high quality studies are synthesized, still the result exhibits significant heterogeneity. Τhe available data allowed a subgroup analysis only for classification system for PCOS diagnosis and showed a significant increase of ASD diagnosis in the offspring of women with Read Code and ICD diagnosed PCOS. In conclusion, the available evidence suggests that women with PCOS have increased odds of having a child with ASD, an effect size estimate based on a large number of patients from studies of good quality. Regarding the evidence on the prevalence of ASD in PCOS women, results suggest that women with PCOS are more likely to be diagnosed with ASD.

Association of menopausal symptoms with sociodemographic factors and personality traits.

AIM OF THE STUDY: To investigate the association of personality traits with the severity of vasomotor symptoms (VMS) in a predominantly Greek population. MATERIAL AND METHODS: A questionnaire-based study of women from the Menopause Clinic of a University Hospital in Athens, Greece. Sociodemographic parameters were documented through a structured interview. All women completed the Menopause Rating Scale (MRS) for the assessment of severity of menopausal symptoms, the Hot Flush Beliefs Scale (HFBS) for the assessment of how women were coping with their symptoms and the Big Five Inventory questionnaires for the assessment of personality traits. Associations between baseline parameters and menopausal symptoms were assessed with univariate and multivariate regression analyses. RESULTS: One hundred women were included. Employed women had lower MRS sub-scores (psychological p< 0.001, somatic p< 0.047, urogenital p< 0.008). Married women scored higher in the psychological and somatic domains. Women of university educational level coped significantly better with hot flushes (ß coefficient [SE]: 0.72 [0.25], p< 0.01) and night sweats (0.57 [0.19], p< 0.01) than women of primary education, although the significance of these findings was not replicated when taking into account confounders. Regarding personality traits, women with low openness (-0.33 [0.11], p< 0.01) and empathy (-0.83 [0.37], p = 0.03) and high agreeableness (1.13 [0.21], p< 0.001) had more severe menopausal symptoms. In contrast, women with high agreeableness could better cope with their menopausal symptoms (-0.75 [0.36], p = 0.04). These associations were independent of sociodemographic factors. CONCLUSIONS: Personality traits, especially agreeableness, openness and empathy are associated with menopausal symptoms and functionality in postmenopausal women. These associations might serve as indicators of women at risk of experiencing more severe VMS.

Effectiveness of artificial pancreas in the non-adult population: A systematic review and network meta-analysis.

OBJECTIVE: Artificial pancreas is a technology that minimizes user input by bridging continuous glucose monitoring and insulin pump treatment, and has proven safety in the adult population. The purpose of this systematic review and meta-analysis is to evaluate the efficacy of closed-loop (CL) systems in the glycemic control of non-adult type 1 diabetes patients in both a pairwise and network meta-analysis (NMA) context and investigate various parameters potentially affecting the outcome. METHODS: Literature was systematically searched using the MEDLINE (1966-2018), Scopus (2004-2018), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2018), Clinicaltrials.gov (2008-2018) and Google Scholar (2004-2018) databases. Studies comparing the glycemic control in CL (either single- or dual-hormone) with continuous subcutaneous insulin infusion (CSII) in people with diabetes (PWD) aged <18 years old were deemed eligible. The primary outcome analysis was conducted with regard to time spent in the target glycemic range. All outcomes were evaluated in NMA in order to investigate potential between-algorithm differences. Pairwise meta-analysis and meta-regression were performed using the RevMan 5.3 and Open Meta-Analyst software. For NMA, the package pcnetmetain R 3.5.1 was used. RESULTS: The meta-analysis was based on 25 studies with a total of 504 PWD. The CL group was associated with significantly higher percentage of time spent in the target glycemic range (Mean (SD): 67.59% (SD: 8.07%) in the target range and OL PWD spending 55.77% (SD: 11.73%), MD: -11.97%, 95% CI [-18.40, -5.54%]) and with lower percentages of time in hyperglycemia (MD: 3.01%, 95% CI [1.68, 4.34%]) and hypoglycemia (MD: 0.67%, 95% CI [0.21, 1.13%]. Mean glucose was also decreased in the CL group (MD: 0.75 mmol/L, 95% CI [0.18-1.33]). The NMA arm of the study showed that the bihormonal modality was superior to other algorithms and standard treatment in lowering mean glucose and increasing time spent in the target range. The DiAs platform was superior to PID in controlling hypoglycemia and mean glucose. Time in target range and mean glucose were unaffected by the confounding factors tested. CONCLUSIONS: The findings of this meta-analysis suggest that artificial pancreas systems are superior to the standard sensor-augmented pump treatment of type 1 diabetes mellitus in non-adult PWD. Between-algorithm differences are also addressed, implying a superiority of the bihormonal treatment modality. Future large-scale studies are needed in the field to verify these outcomes and to determine the optimal algorithm to be used in the clinical setting.