Causal associations between female reproductive behaviors and psychiatric disorders: a lifecourse Mendelian randomization study.

BACKGROUND: The timings of reproductive life events have been examined to be associated with various psychiatric disorders. However, studies have not considered the causal pathways from reproductive behaviors to different psychiatric disorders. This study aimed to investigate the nature of the relationships between five reproductive behaviors and twelve psychiatric disorders. METHODS: Firstly, we calculated genetic correlations between reproductive factors and psychiatric disorders. Then two-sample Mendelian randomization (MR) was conducted to estimate the causal associations among five reproductive behaviors, and these reproductive behaviors on twelve psychiatric disorders, using genome-wide association study (GWAS) summary data from genetic consortia. Multivariable MR was then applied to evaluate the direct effect of reproductive behaviors on these psychiatric disorders whilst accounting for other reproductive factors at different life periods. RESULTS: Univariable MR analyses provide evidence that age at menarche, age at first sexual intercourse and age at first birth have effects on one (depression), seven (anxiety disorder, ADHD, bipolar disorder, bipolar disorder II, depression, PTSD and schizophrenia) and three psychiatric disorders (ADHD, depression and PTSD) (based on p<7.14×10-4), respectively. However, after performing multivariable MR, only age at first sexual intercourse has direct effects on five psychiatric disorders (Depression, Attention deficit or hyperactivity disorder, Bipolar disorder, Posttraumatic stress disorder and schizophrenia) when accounting for other reproductive behaviors with significant effects in univariable analyses. CONCLUSION: Our findings suggest that reproductive behaviors predominantly exert their detrimental effects on psychiatric disorders and age at first sexual intercourse has direct effects on psychiatric disorders.

Plasticity of the spinal glymphatic system in male SD rats with painful diabetic neuropathy induced by type 2 diabetes mellitus.

The glymphatic system is a recently discovered glial-dependent macroscopic interstitial waste clearance system that promotes the efficient elimination of soluble proteins and metabolites from the central nervous system. Its anatomic foundation is the astrocytes and aquaporin-4 (AQP4) water channels on the endfeet of astrocytes. The aim of this study is to evaluate the plasticity of the spinal glymphatic system in male SD rats with painful diabetic neuropathy (PDN) induced by type 2 diabetes mellitus. PDN rats were modeled under a high-fat and high-glucose diet with a low dose of streptozotocin. MRI was applied to observe the infiltration and clearance of contrast to indicate the functional variability of the glymphatic system at the spinal cord level. The paw withdrawal threshold was used to represent mechanical allodynia. The numerical change of glial fibrillary acidic protein (GFAP) positive astrocytes was assessed and the polarity reversal of AQP4 protein was measured by immunofluorescence. As a result, deceased contrast infiltration and clearance, enhanced mechanical allodynia, increased number of GFAP positive astrocytes, and reversed polarity of AQP4 protein were found in the PDN rats. The above molecular level changes may contribute to the impairment of the spinal glymphatic system in PDN rats. This study revealed the molecular and functional variations of the spinal glymphatic system in PDN rats and for the first time indicated that there might be a correlation between the impaired spinal glymphatic system and PDN rats.

Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study.

In our previous study, we have shown that number of synapses in the L5 segment of spinal dorsal horn increased significantly in a rat model of painful diabetic neuropathy (PDN) induced by high-dose of streptozotocin (an animal model of type 1 diabetes). The aims of this study were: (1) to determine whether high fat diet/low dose streptozotocin-diabetes, a rat model for type 2 diabetes, related PDN was also associated with this synaptic plasticity, (2) to reveal the range of this synaptic plasticity change occurred (in the whole length of spinal dorsal horn or only in the L5 lumbar segment of spinal dorsal horn) and (3) to discover whether treatment with metformin had effect on this synaptic plasticity. Male adult Sprague-Dawley rats were randomly allocated into the control group (n = 7), the PDN group (n = 6) and the PDN treated with metformin (PDN + M) group (n = 7), respectively. 28 days after medication, synaptic and neuronal numbers in the whole length of spinal dorsal horn or in 1 mm length of the L5 segment of spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group and the PDN + M group, number of synapses in the L5 segment of spinal dorsal horn increased significantly in the PDN group (P < 0.05). There was no significant change between the control group and the PDN + M group in terms of the parameters in the L5 segment of the spinal dorsal horn (P > 0.05). Parameters of the whole length of spinal dorsal horn showed no significant changes (P > 0.05). Our results suggest that high fat diet/low dose streptozotocin diabetes related PDN is also associated with a numerical increase of synapses in the L5 segment of spinal dorsal horn but not in the whole length of spinal dorsal horn. Furthermore, the analgesic effect of metformin against PDN is related to its inhibition of numerical increase of synaptic number in the rat spinal dorsal horn.

Association between dietary habits and the risk of migraine: a Mendelian randomization study.

Objective: The important contribution of dietary triggers to migraine pathogenesis has been recognized. However, the potential causal roles of many dietary habits on the risk of migraine in the whole population are still under debate. The objective of this study was to determine the potential causal association between dietary habits and the risk of migraine (and its subtypes) development, as well as the possible mediator roles of migraine risk factors. Methods: Based on summary statistics from large-scale genome-wide association studies, we conducted two-sample Mendelian randomization (MR) and bidirectional MR to investigate the potential causal associations between 83 dietary habits and migraine and its subtypes, and network MR was performed to explore the possible mediator roles of 8 migraine risk factors. Results: After correcting for multiple testing, we found evidence for associations of genetically predicted coffee, cheese, oily fish, alcohol (red wine), raw vegetables, muesli, and wholemeal/wholegrain bread intake with decreased risk of migraine, those odds ratios ranged from 0.78 (95% CI: 0.63-0.95) for overall cheese intake to 0.61 (95% CI: 0.47-0.80) for drinks usually with meals among current drinkers (yes + it varies vs. no); while white bread, cornflakes/frosties, and poultry intake were positively associated with the risk of migraine. Additionally, genetic liability to white bread, wholemeal/wholegrain bread, muesli, alcohol (red wine), cheese, and oily fish intake were associated with a higher risk of insomnia and (or) major depression disorder (MDD), each of them may act as a mediator in the pathway from several dietary habits to migraine. Finally, we found evidence of a negative association between genetically predicted migraine and drinking types, and positive association between migraine and cups of tea per day. Significance: Our study provides evidence about association between dietary habits and the risk of migraine and demonstrates that some associations are partly mediated through one or both insomnia and MDD. These results provide new insights for further nutritional interventions for migraine prevention.

Ultrasound Evaluation of the Diaphragm in Clinical Anesthesia.

When the human body is anesthetized, the human nerve tissue will be greatly affected, which also affects the breathing of the human body. The respiration during anesthesia is a lack of initiative, and the energy efficiency of the diaphragm in the lungs is very important to the safety of anesthesia. In this paper, the application of the ultrasound evaluation of the diaphragm in clinical anesthesia was studied. In this paper, 24 patients who underwent lung examination under medical anesthesia at our hospital were evaluated by the ultrasound vertical mixed echo method. Through patient voluntary selection and consent, 16 patients were examined with B-mode ultrasound and the other 8 patients with M-mode ultrasound to compare the effects of different ultrasounds on diaphragm image quality. In addition, this paper also analyzes the differences between different ultrasounds and the strengths and weaknesses of diaphragmatic ultrasound evaluation in clinical anesthesia. The suggestions of using different ultrasounds in ultrasonic evaluation are given. The study showed that 16 cases of B-mode ultrasound evaluation of the diaphragm obtained ultrasound images which showed a large field of vision, acoustic frequency between 7 and 18 MHz, and thickness difference between 0.35 and 0.52 cm. In 8 patients with the diaphragm evaluated by M-mode ultrasound, the local features of M-mode ultrasound images were clearer than those of B-mode ultrasound images, but the visual field area was smaller, the acoustic frequency was between 10 and 15 MHz, and the thickness difference was between 0.12 and 0.18 cm. Based on the above data, this paper suggests that, in the ultrasonic evaluation of the diaphragm, B-mode ultrasound should be used to check the patients first, and then M-mode ultrasound should be used to check the parts with poor quality so that the accurate diaphragm quality of patients can be obtained in the vast majority of patients.

Comparative efficacy and safety of glucose-lowering drugs in children and adolescents with type 2 diabetes: A systematic review and network meta-analysis.

Objective: Type 2 diabetes is more common in adults, but is becoming the major concern in children and adolescent recently. This study aimed to provide additional pharmaceutical management for children and adolescents with type 2 diabetes by assessing the efficacy and safety of several glucose-lowering drugs. Methods: Searches were performed in PubMed, Medline, Ovid, Cochrane Controlled Register of Trials (CENTRAL), and ClinicalTrials.gov that reported the efficacy and safety of drugs for children and adolescents with type 2 diabetes. Pooled effects were calculated by frequentist fixed effects network meta-analyses and additive network meta-analyses. Results: A total of 12 trials assessing eight glucose-lowering drugs were included, which compose of seven trials with monotherapy and five trials with combination therapies. Network meta-analysis results showed compared to placebo, saxagliptin+metformin (mean difference (MD) -1.91% [-2.85%, -0.97%]), liraglutide+metformin (MD -1.45% [-1.65%, -1.26%]), and liraglutide (MD -0.90% [-1.35%, -0.45%]) were the top 3 drugs that significantly reduced hemoglobin A1c (HbA1c). Sitagliptin+metformin, dapagliflozin, exenatide-2mcg, linagliptin-5mg, metformin, exenatide-5/10mcg, glimepiride, and sitagliptin also showed significant reduction in HbA1c. There were no significant differences between treatments in the incidence of adverse events, except that liraglutide+metformin had significant adverse effect such as abdominal pain. In addition, dapagliflozin, sitagliptin+metformin, and saxagliptin+metformin showed better efficacy compared with FDA-approved drugs. Conclusions: The top 10 treatments of type 2 diabetes in children and adolescents aged 10-17 years were saxagliptin+metformin, liraglutide+metformin, liraglutide, dapagliflozin, exenatide-2 mcg, sitagliptin+metformin, linagliptin-5 mg, linagliptin-1 mg, metformin, and exenatide-5/10 mcg. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=284897, identifier CRD42021284897.

Lipids, Anthropometric Measures, Smoking and Physical Activity Mediate the Causal Pathway From Education to Breast Cancer in Women: A Mendelian Randomization Study.

PURPOSE: We aimed to investigate whether obtaining a higher level of education was causally associated with lower breast cancer risk and to identify the causal mechanism linking them. METHODS: The main data analysis used publicly available summary-level data from 2 large genome-wide association study consortia. Mendelian randomization (MR) analysis used 65 genetic variants derived from the Social Science Genetic Association Consortium as instrumental variables for years of schooling. The outcomes from the Breast Cancer Association Consortium (BCAC) were the overall breast cancer risk (122,977 cases/105,974 controls in women) and the two subtypes: estrogen receptor (ER)-positive breast cancer and ER-negative breast cancer. Fixed and random effects inverse variance weighted methods were used to estimate the causal effects, along with other additional MR methods for sensitivity analyses. RESULTS: Results showed that each additional standard deviation of 4.2 years of education was causally associated with a 27% lower risk of ER-negative breast cancer (odds ratio, 0.73; 95% confidence interval, 0.64-0.84; p-value < 0.001). This finding was consistent with the results of the sensitivity analyses. Physical activities can help improve the protective effect of education against breast cancer, with relatively large mediation proportions. Education increases the risk of ER-positive breast cancer due to alterations in high-density lipoprotein level, triglyceride level, height, waist-to-hip ratio, body mass index, and smoking status, with relative medium mediation proportions. Other mediators including low-density lipoprotein, hip circumference, number of cigarettes smoked per day, time spent performing light physical activity, and performing vigorous physical activity for > 10 minutes explain a small part of the causal effect of education on the risk of developing breast cancer, and their mediation proportion is approximately 1%. CONCLUSION: A low level of education is a causal risk factor in the development of breast cancer as it is associated with poor lipid profile, obesity, smoking, and types of physical activity.

Stereological study on the numerical plasticity of myelinated fibers and oligodendrocytes in the rat spinal cord with painful diabetic neuropathy.

Painful diabetic neuropathy may associate with nerve morphological plasticity in both peripheral and central nervous system. The aim of this study was to determine numerical changes of myelinated fibers in the spinothalamic tract region and oligodendrocytes in the spinal dorsal horn of rats with painful diabetic neuropathy and the effects of metformin on the above changes. Male Sprague-Dawley rats were randomly allocated into the control group (n = 7), the painful diabetic neuropathy group (n = 6) and the painful diabetic neuropathy treated with metformin group (the PDN + M group, n = 7), respectively. Twenty-eight days after medication, numbers of myelinated fibers in the spinothalamic tract and oligodendrocytes in the spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group, number of myelinated fibers in the spinothalamic tract increased significantly in the painful diabetic neuropathy and PDN + M group, compared to the painful diabetic neuropathy group, number of myelinated fibers decreased in the PDN + M group (P < 0.05). As the oligodendrocyte in the spinal dorsal horn was considered, its number increased significantly in the painful diabetic neuropathy group compared to the control and the PDN + M group (P < 0.05), there was no significant difference between the control and the PDN + M group (P > 0.05). Our results indicate that painful diabetic neuropathy is associated with a serial of morphometric plasticity in the rat spinal cord including the numerical increase of the myelinated fibers in the spinothalamic tract and the oligodendrocytes in the spinal dorsal horn. The analgesic effect of metformin against painful diabetic neuropathy might be related to its adverse effects on the above morphometric plasticity.