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• Surgical menopause is associated with faster cognitive decline and worse cognitive performance later in life. • The younger the age at surgery, the more rapid the decline in cognitive function. • Early surgical menopause at ≤45 years of age is further associated with higher risk of dementia. • The limited number of available studies highlights the need for large cohorts to further examine this research question. Experimental and epidemiological studies suggest female sex hormones to have long-lasting neuroprotective and anti-ageing properties. Surgically-induced menopause leads to a premature cessation of exposure to female sex hormones and could thus impact late-life cognitive function. Yet, evidence remains controversial. We systematically reviewed literature for articles investigating the association of surgical menopause (defined as bilateral oophorectomy before the onset of menopause) with risk of dementia, cognitive performance, cognitive decline, and Alzheimer's disease neuropathological indices later in life. We evaluated study quality with the Newcastle-Ottawa scale and performed random-effects meta-analyses. We identified 11 eligible studies (N = 18,867). Although surgical menopause at any age was not associated with risk of dementia (4 studies; HR: 1.16, 95%CI: 0.96–1.43), early surgical menopause (≤45 years of age) was associated with a statistically significantly higher risk (2 studies; HR: 1.70, 95%CI: 1.07–2.69). Surgical menopause at any age was associated with faster decline in verbal memory, semantic memory, and processing speed, whereas early surgical menopause was further associated with faster global cognitive decline. No heterogeneity was noted. Among women undergoing surgical menopause, a younger age at surgery was associated with faster decline in global cognition, semantic and episodic memory, worse performance in verbal fluency and executive function, and accumulation of Alzheimer's neuropathology. Current evidence is limited, but suggests surgical menopause induced by bilateral oophorectomy at ≤45 years of age to be associated with higher risk of dementia and cognitive decline. Additional large-scale cohort studies are necessary to replicate these findings. [ABSTRACT FROM AUTHOR]

Background Gliomatosis cerebri (GC) is a fatal diffusely infiltrating glioma. Because of its rarity, only scarce evidence is available regarding outcome predictors and the proper management of GC. Methods Reported studies of patients with histologically confirmed GC were systematically reviewed and individual patient-level data (n = 523) extracted. Multivariable Cox proportional hazard models were fit for overall survival (OS) and progression-free survival (PFS). Results The median OS and PFS were 13 and 10 months, with 5-year rates of 18% and 13%, respectively. Age ≥65 years at diagnosis (hazard ratio for OS [HR OS ], 2.32; 95% confidence interval [CI], 1.62–3.31), high-grade tumor (HR PFS for grade III, 1.57; 95% CI, 1.02–2.40; HR PFS for grade IV, 1.74; 95% CI, [0.98–3.10), GC type II (HR OS , 1.49; 95% CI, 1.12–1.98; HR PFS , 1.56; 95% CI, 1.04–2.34), more central nervous system (CNS) regions involved (HR OS , 1.09; 95% CI, 1.01–1.18), focal neurological deficits (HR OS , 1.41; 95% CI, 1.07–1.86), cerebellar symptoms (HR PFS , 2.20; 95% CI, 1.42–3.39), more symptoms at presentation (HR OS , 1.21; 95% CI, 1.05–1.40), Karnofsky performance scale score <70 (HR OS , 3.58; 95% CI, 1.73–7.39; HR PFS , 4.48; 95% CI, 1.39–14.4), magnetic resonance imaging contrast enhancement (HR OS , 1.48; 95% CI, 1.12–1.96; HR PFS , 1.74; 95% CI, 1.18–2.55), symmetric bilateral CNS invasion (HR OS , 1.42; 95% CI, 1.03–1.96), and high proliferation index (Ki-67 >5%; HR OS , 2.32; 95% CI, 1.11–4.86) were independent predictors of poor outcomes. In contrast, seizure occurrence (HR OS , 0.77; 95% CI, 0.60–1.00; HR PFS , 0.68; 95% CI, 0.47–0.95), isocitrate dehydrogenase 1 mutation (HR OS , 0.16; 95% CI, 0.05–0.49), and O6-methylguanine-DNA-methyltransferase promoter methylation (HR OS , 0.23; 95% CI, 0.09–0.59) were associated with prolonged survival. Chemotherapy and surgical resection were associated with improved outcomes, but radiotherapy, whether monotherapy or combined with chemotherapy, was not superior to chemotherapy alone. Conclusions In the largest study to date on GC, we have identified clinical, imaging, and molecular outcome predictors that are similar to other gliomas and highlight the beneficial effect of chemotherapy and surgical resection, when feasible, on outcomes. Highlights • We performed an individual-patient level data meta-analysis of 532 patients with GC. • Older age, high-grade tumor, and widespread CNS invasion were negative prognostic factors. • Contrast-enhanced mass, more severe symptoms, and high proliferation index were negative prognostic factors. • Seizure at diagnosis, IDH1 mutation, and MGMT promoter methylation were associated with prolonged survival. • Chemotherapy and, when feasible, surgical resection, but not radiotherapy, were associated with improved outcomes. [ABSTRACT FROM AUTHOR]

Aim Neuroblastoma outcomes vary with disease characteristics, healthcare delivery and socio-economic indicators. We assessed survival patterns and prognostic factors for patients with neuroblastoma in 11 Southern and Eastern European (SEE) countries versus those in the US, including—for the first time—the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumours (NARECHEM-ST)/Greece. Methods Overall survival (OS) was calculated in 13 collaborating SEE childhood cancer registries (1829 cases, ∼1990–2016) and Surveillance, Epidemiology, and End Results (SEER), US (3072 cases, 1990–2012); Kaplan–Meier curves were used along with multivariable Cox regression models assessing the effect of age, gender, primary tumour site, histology, Human Development Index (HDI) and place of residence (urban/rural) on survival. Results The 5-year OS rates varied widely among the SEE countries (Ukraine: 45%, Poland: 81%) with the overall SEE rate (59%) being significantly lower than in SEER (77%; p < 0.001). In the common registration period within SEE (2000–2008), no temporal trend was noted as opposed to a significant increase in SEER. Age >12 months (hazard ratio [HR]: 2.8–4.7 in subsequent age groups), male gender (HR: 1.1), residence in rural areas (HR: 1.3), living in high (HR: 2.2) or medium (HR: 2.4) HDI countries and specific primary tumour location were associated with worse outcome; conversely, ganglioneuroblastoma subtype (HR: 0.28) was associated with higher survival rate. Conclusions Allowing for the disease profile, children with neuroblastoma in SEE, especially those in rural areas and lower HDI countries, fare worse than patients in the US, mainly during the early years after diagnosis; this may be attributed to presumably modifiable socio-economic and healthcare system performance differentials warranting further research. [ABSTRACT FROM AUTHOR]

Aim To present incidence of central nervous system (CNS) tumours among adolescents and young adults (AYAs; 15–39 years) derived from registries of Southern and Eastern Europe (SEE) in comparison to the Surveillance, Epidemiology and End Results (SEER), US and explore changes due to etiological parameters or registration improvement via evaluating time trends. Methods Diagnoses of 11,438 incident malignant CNS tumours in AYAs (1990–2014) were retrieved from 14 collaborating SEE cancer registries and 13,573 from the publicly available SEER database (1990–2012). Age-adjusted incidence rates (AIRs) were calculated; Poisson and joinpoint regression analyses were performed for temporal trends. Results The overall AIR of malignant CNS tumours among AYAs was higher in SEE (28.1/million) compared to SEER (24.7/million). Astrocytomas comprised almost half of the cases in both regions, albeit the higher proportion of unspecified cases in SEE registries (30% versus 2.5% in SEER). Similar were the age and gender distributions across SEE and SEER with a male-to-female ratio of 1.3 and an overall increase of incidence by age. Increasing temporal trends in incidence were documented in four SEE registries (Greater Poland, Portugal North, Turkey-Izmir and Ukraine) versus an annual decrease in Croatia (−2.5%) and a rather stable rate in SEER (−0.3%). Conclusion This first report on descriptive epidemiology of AYAs malignant CNS tumours in the SEE area shows higher incidence rates as compared to the United States of America and variable temporal trends that may be linked to registration improvements. Hence, it emphasises the need for optimisation of cancer registration processes, as to enable the in-depth evaluation of the observed patterns by disease subtype. [ABSTRACT FROM AUTHOR]

Background The aetiology of primary central nervous system (CNS) tumours remains largely unknown, but their childhood peak points to perinatal parameters as tentative risk factors. In this meta-analysis, we opted to quantitatively synthesise published evidence on the association between birth anthropometrics and risk of primary CNS tumour. Methods Eligible studies were identified via systematic literature review; random-effects meta-analyses were conducted for the effect of birth weight and size-for-gestational-age on childhood and adult primary CNS tumours; subgroup, sensitivity, meta-regression and dose–response by birth weight category analyses were also performed. Results Forty-one articles, encompassing 53,167 CNS tumour cases, were eligible. Birth weight >4000 g was associated with increased risk of childhood CNS tumour (OR: 1.14, [1.08–1.20]; 22,330 cases). The risk was higher for astrocytoma (OR: 1.22, [1.13–1.31]; 7456 cases) and embryonal tumour (OR: 1.16, [1.04–1.29]; 3574 cases) and non-significant for ependymoma (OR: 1.12, [0.94–1.34]; 1374 cases). Increased odds for a CNS tumour were also noted among large-for-gestational-age children (OR: 1.12, [1.03–1.22]; 10,339 cases), whereas insufficient data for synthesis were identified for other birth anthropometrics. The findings remained robust across subgroup and sensitivity analyses controlling for several sources of bias, whereas no significant heterogeneity or publication bias were documented. The limited available evidence on adults (4 studies) did not reveal significant associations between increasing birth weight (500-g increment) and overall risk CNS tumour (OR: 0.99, [0.98–1.00]; 1091 cases) or glioma (OR: 1.03, [0.98–1.07]; 2052 cases). Conclusions This meta-analysis confirms a sizeable association of high birth weight, with childhood CNS tumour risk, particularly astrocytoma and embryonal tumour, which seems to be independent of gestational age. Further research is needed to explore underlying mechanisms, especially modifiable determinants of infant macrosomia, such as gestational diabetes. [ABSTRACT FROM AUTHOR]

Background Low circulating levels of adiponectin, an anti-inflammatory and vasculoprotective adipokine, are associated with obesity, type 2 diabetes, and atherosclerotic disease. Presence of unstable plaques in the carotid artery is a known etiological factor causing ischemic strokes. Herein, we systematically reviewed the association between circulating adiponectin and progression of carotid atherosclerotic disease, particularly evaluating the occurrence of (1) carotid atherosclerotic plaques, (2) ischemic stroke, and (3) mortality in subjects who suffered a previous ischemic stroke. Methods Medline, Embase, Biosis, Scopus, Web of Science, and Pubmed were searched for published studies and conference abstracts. The effect size and 95% confidence intervals (CIs) of the individual studies were pooled using fixed-effect or random-effect models. The quality of the eligible studies was evaluated using the Newcastle–Ottawa quality assessment scale. Sensitivity, subgroup, and meta-regression analyses were performed to address the impact of various risk factors on the association between adiponectin and ischemic stroke risk. Results Twelve studies fulfilled the inclusion criteria for 3 independent meta-analyses. The association of increasing circulating adiponectin levels (5 μg/mL-increment) with presence of carotid plaque was not conclusive (n = 327; OR: 1.07; 95% CI: 0.85–1.35; 2 studies), whereas high adiponectin levels showed a significant 8% increase in risk of ischemic stroke (n = 13,683; 7 studies), with a more sizable association observed among men compared to women. HDL was observed to have a marginal effect on the association between adiponectin and ischemic stroke, while other evaluated parameters were not found to be effect modifiers. A non-significant association of adiponectin with mortality was yielded (n = 663; OR: 2.58; 95% CI: 0.69–9.62; 3 studies). Although no publication bias was evident, there was significant between-study heterogeneity in most analyses. Conclusion It appears that the direction of the relationship between adiponectin and carotid atherosclerotic plaque presence is dependent on the duration, severity, and nature of the underlying disease, while increased adiponectin levels were associated with an increase in risk for ischemic stroke. Lastly, the results from the mortality meta-analysis remain inconclusive. Future properly designed studies are necessary to further elucidate the role of adiponectin on atherosclerotic plaque development, and its related outcomes. [ABSTRACT FROM AUTHOR]

We employed Mendelian randomization to determine whether genetically predicted circulating levels of endothelial-derived adhesion molecules (soluble intercellular adhesion molecule-1 [sICAM-1]), soluble vascular-leukocyte adhesion molecule-1 [sVCAM-1], and soluble-endothelial-leukocyte adhesion molecule [sE-selectin]) were associated with functional outcome after ischemic stroke. Independent genetic variants robustly associated with soluble adhesion molecules, located at or close to the coding gene (cis), were used as genetic instruments. The functional outcome was evaluated using the 3-month modified Rankin Scale (mRS) score after ischemic stroke. A poor functional outcome was defined as mRS ≥ 3 at 3 months. We extracted summary data for functional outcome after ischemic stroke from the Genetics of Ischaemic Stroke Functional Outcome network (n = 6,021). Genetically elevated sICAM-1 (OR 1.28, 95% CI 1.05-1.56) and sE-selectin (OR 2.69, 95% CI 1.23-5.86) levels were related with poor post-stroke outcome. However, we found no evidence that genetically elevated sVCAM-1 were associated with post-stroke outcome (OR 1.36, 95% CI 0.39-4.66). We found that genetically elevated higher sICAM-1 and sE-selectin levels are associated with poor post-stroke outcome. Further studies are warranted to evaluate the potential of ICAM-1 and E-selectin to be drug targets for post-stroke recovery. [ABSTRACT FROM AUTHOR]

Introduction The preponderance of dementia among postmenopausal women compared with same-age men and the female sex hormones neuroprotective properties support a tentative role of their deficiency in the dementia pathogenesis. Methods Pairs of independent reviewers screened 12,323 publications derived from a search strategy for MEDLINE to identify articles investigating the association of age at menopause/reproductive period with (i) dementia and (ii) cognitive function; a snowball of eligible articles and reviews was conducted and authors were contacted for additional information. Random-effect models were used for the meta-analysis. Results Age at menopause (13 studies; 19,449 participants) and reproductive period (4 studies; 9916 participants) in the highest categories were not associated with odds of dementia (effect size [ES]: 0.97 [0.78–1.21]) and Alzheimer’s disease (ES: 1.06 [0.71–1.58]). Significant heterogeneity was however noted in both analyses ( I 2 : 63.3%, p = 0.003 and I 2 : 72.6%, p = 0.01, respectively). Subgroup analyses by outcome assessment, study design, level of adjustment and study quality did not materially change the findings. In 9/13 studies assessing cognitive function, advanced age at menopause/longer reproductive period was significantly associated with better cognitive performance/lower decline. Due to statistical differences, no meta-analysis was possible for cognitive function. Conclusions Existing evidence does not support an association between indices of prolonged exposure to female hormones and lower dementia risk. There are indications, however, for better cognitive performance and delayed cognitive decline, supporting a link between female hormone deficiency and cognitive aging. Current literature limitations, indicated by the heterogeneous study-set, point towards research priorities in this clinically relevant area. [ABSTRACT FROM AUTHOR]

• Current evidence does not support an adverse impact of gender-affirming hormone therapy on cognitive performance in birth-assigned either male or female transgender individuals • An enhanced effect on visuospatial ability following post-pubertal hormone therapy was shown in assigned females • Pooling data from cross-sectional studies showed a higher performance in verbal working memory in treated assigned males • New longitudinal studies with longer follow-up should explore the long-term effects of hormone therapy, especially the effects on younger individuals, where there is greater scarcity of data Previous studies have examined whether steroid hormone treatment in transgender individuals may affect cognitive function; yet, their limited power does not allow firm conclusions to be drawn. We leveraged data from to-date literature aiming to explore the effect of gender-affirming hormone administration on cognitive function in transgender individuals. A search strategy of MEDLINE was developed (through June 1, 2019) using the key terms transgender, hormone therapy and cognitive function. Eligible were (i) cohort studies examining the longitudinal effect of hormone therapy on cognition, and (ii) cross-sectional studies comparing the cognitive function between treated and non-treated individuals. Standardized mean differences (Hedges' g) were pooled using random-effects models. Study quality was evaluated using the Newcastle-Ottawa Scale. Ten studies (seven cohort and three cross-sectional) were eligible representing 234 birth-assigned males (aM) and 150 birth-assigned females (aF). The synthesis of cohort studies (n = 5) for visuospatial ability following hormone treatment showed a statistically significant enhancement among aF (g = 0.55, 95% confidence intervals [CI]: 0.29, 0.82) and an improvement with a trend towards statistical significance among aM (g = 0.28, 95%CI: -0.01, 0.58). By contrast, no adverse effects of hormone administration were shown. No heterogeneity was evident in most meta-analyses. Current evidence does not support an adverse impact of hormone therapy on cognitive function, whereas a statistically significant enhancing effect on visuospatial ability was shown in aF. New longitudinal studies with longer follow-up should explore the long-term effects of hormone therapy, especially the effects on younger individuals, where there is greater scarcity of data. [ABSTRACT FROM AUTHOR]

Purpose: Season of birth has been considered a proxy of seasonally varying exposures around perinatal period, potentially implicated in the etiology of several health outcomes, including malignancies.Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we have systematically reviewed published literature on the association of birth seasonality with risk of central nervous system tumors in children and adults.Results: Seventeen eligible studies using various methodologies were identified, encompassing 20,523 cases. Eight of 10 studies in children versus four of eight in adults showed some statistically significant associations between birth seasonality and central nervous system tumor or tumor subtype occurrence, pointing to a clustering of births mostly in fall and winter months, albeit no consistent pattern was identified by histologic subtype. A plethora of perinatal factors might underlie or confound the associations, such as variations in birth weight, maternal diet during pregnancy, perinatal vitamin D levels, pesticides, infectious agents, immune system maturity, and epigenetic modifications.Conclusions: Inherent methodological weaknesses of to-date published individual investigations, including mainly underpowered size to explore the hypothesis by histological subtype, call for more elegant concerted actions using primary data of large datasets taking also into account the interplay between the potential underlying etiologic factors. [ABSTRACT FROM AUTHOR]

Post hoc analyses of clinical trials show that PCSK9 inhibitors might lower lipoprotein(a), but whether this effect contributes to reductions in cardiovascular risk remains unknown. We aimed to assess whether genetically proxied PCSK9 inhibition influences lipoprotein(a) (Lp(a)), and whether any such effect could mediate its effects on coronary artery disease (CAD) and ischemic stroke (IS). To explore associations between the genetic proxies for PCSK9 inhibitors and Lp(a) levels, we used UK Biobank data (310,020 individuals). We identified 10 variants in the PCSK9 gene associated with lower PCSK9 and LDL-C levels as proxies for PCSK9 inhibition. We explored the effects of genetically proxied PCSK9 inhibition on Lp(a) levels, as well as on odds of CAD (60,801 cases, 184,305 controls) and IS (60,341 cases, 454,450 controls) in two-sample Mendelian randomization analyses. In mediation analyses, we assessed the effects of genetically proxied PCSK9 inhibition on CAD and IS mediated through reductions in Lp(a) levels. Genetically proxied PCSK9 inhibition (1-SD decrement in PCSK9 concentration; corresponding to 20.6 mg/dl decrement in LDL-C levels) was associated with a 4% decrease in log-Lp(a) levels (beta: −0.038, 95%CI: −0.053 to −0.023). We estimated a 0.8% reduction in the odds for CAD (OR: 0.992, 95%CI: 0.989–0.995) and a 0.5% reduction in the odds for atherosclerotic IS (OR: 0.995, 95%CI: 0.992–0.998) due to reductions in Lp(a) levels through genetically proxied PCSK9 inhibition, corresponding to 3.8% and 3.2% of the total effects, respectively. Genetic proxies for PCSK9 inhibition are associated with lower Lp(a) levels. However, Lp(a) lowering explains only a small proportion of the total effects of genetic proxies for PCSK9 inhibitors on risk of CAD and IS. [Display omitted] • 12 genetic variants in the PCSK9 gene were identified as proxies for PCSK9 inhibition. • Genetically proxied PCSK9 inhibition is associated with lower Lp(a) levels. • Lp(a) lowering explains only a small proportion of the effects of genetically proxied PCSK9 inhibition on cardiovascular risk. [ABSTRACT FROM AUTHOR]