The complement system plays an important role in the development of left ventricular hypertrophy. Complement C1q is an initial component of the classical complement pathway and is related to many inflammatory diseases. We aimed to determine whether there was an association between serum complement C1q and left ventricular hypertrophy induced by coarctation of the aorta (CoA).n = 15) and a complex CoA group (n = 13). Meanwhile, we selected simple large VSD (n = 14) patients and normal children (n = 28) as the control group. The serum complement C1q level was compared using immunity transmission turbidity among different groups.Based on whether CoA was combined with a large ventricular septal defect (VSD) or patent ductus arteriosus (PDA), the patients were divided into a simple CoA group (P < 0.05). There was no significant difference in the preoperative content of C1q between the complex CoA group and the large VSD group (P > 0.05). There was a negative correlation between the preoperative complement C1q content and the interventricular septal thickness and left ventricular posterior wall thickness . The percentage of postoperative decrease in C1q in children with simple CoA or complex CoA was positively correlated with the time of cardiopulmonary bypass and aortic cross clamp, respectively . There was no significant difference in the content of preoperative triglycerides (TG), total cholesterol (TCHO), high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C) among the different groups (P > 0.05). In the simple CoA group and complex CoA group, the preoperative complement C1q, TG, TCHO, HDL-C and LDL-C levels were significantly higher than those after the operation (P < 0.05). There was no significant correlation between preoperative complement C1q and TG, TCHO, HDL-C or LDL-C (P > 0.05).The preoperative content of C1q in the simple CoA group was significantly lower than that in the complex CoA group and normal group (96.97 ± 20.66 vs. 130.73 ± 35.78, 96.97 ± 20.66 vs. 156.21 ± 29.14, Complement C1q has an inhibitory effect on the formation of left ventricular hypertrophy, which may not be mediated by regulating lipid metabolism. During cardiac surgery, complement C1q may have a protective effect against myocardial injury. Congenital coarctation of the aorta (CoA) is a common congenital heart disease. Its incidence is approximately 1/2500 live birth infants, and it accounts for 6 ~ 8% . Accordiβ-Catenin pathway [The complement system is an essential part of innate and adaptive immunity. It comprises of a group of proteins with enzyme activity in the blood, body fluids and on the surface of the cell membrane. It plays a biological function in regulating phagocytosis, clearing aging apoptotic cells, participating in the immune response and mediating the inflammatory response . C1q is  pathway .ThereforTherefore, determining the level of complement C1q in patients with CoA will be of great significance to further clarify the pathogenesis of left ventricular hypertrophy induced by CoA. In this study, we analyzed the content of complement C1q and the changes in complement C1q before and after surgery in patients with CoA and clarified the regulatory effect of complement C1q on CoA-induced left ventricular hypertrophy and the correlation between operation-related factors and complement C1q.Patients with CoA hospitalized in the pediatric heart center of Beijing Anzhen Hospital between January 1, 2017 and December 31, 2019 were included in this study. Inclusion criteria: (1) Meets the diagnostic criteria of CoA; (2) Clinical diagnosis of simple CoA or complex CoA  (defect diameter ≥ 10 mm) or CoA with a thick patent ductus arteriosus (PDA) , and a left to right shunt at ventricular level or large artery level); (3) Complement C1q examination was performed before and 24 h after the operation, and the clinical data were complete; (4) There were no other systemic diseases. Exclusion criteria: (1) patients with CoA who did not undergo surgery; (2) patients with an early death; (3) CoA with a small ventricular septal defect (defect diameter < 5 mm) or a small patent ductus arteriosus (pulmonary end of the ductus arteriosus < 2 mm), or CoA with other cardiovascular malformations; (4) CoA with a large ventricular septal defect or a thick patent ductus arteriosus and a right to left shunt at the ventricular or large artery level; (5) combined with other systemic diseases; (6) incomplete clinical data before and after the operation. Meanwhile, we selected children with simple large VSD with complete clinical data  and normal children as controls. The institutional review board for clinical research at Beijing Anzhen Hospital approved the use of patient medical records for this retrospective review.Based on whether CoA patients had a large VSD or PDA, the patients were divided into a simple CoA group and a complex CoA group . The control group was divided into a simple large VSD group and normal group.All patients were measured by transthoracic echocardiography with an ultrasonic instrument (PHILIP IE33) one day before the operation. The position and length of the aortic constriction were measured by two-dimensional echocardiography through the long axis section of the suprasternal aortic arch, and the blood flow velocity at the constriction was measured by color Doppler flow imaging. Left ventricular end diastolic diameter (LVDd), interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were measured by M-mode echocardiography through the parasternal left ventricular long axis section. The diameter of the VSD and the left to right shunt velocity at the ventricular level were measured through multiple sections by two-dimensional echocardiography and color Doppler flow imaging. The diameter, length and left to right shunt velocity of the patent ductus arteriosus were measured by two-dimensional echocardiography and color Doppler flow imaging through the short axis section of the parasternal artery.IVST, LVPWT and LVDd were converted to Z scores (number of standard deviations from the expected mean) using the formula from Sluymans and Colan .Venous blood was taken from patients with an empty stomach in the case group one day before the operation and 24 h after the operation in the morning. Venous blood was taken from the children in the control group with an empty stomach in the morning. The serum was separated from the blood samples. The content of complement C1q was determined by a complement C1q determination kit (immunoturbidimetry) .The venous blood of patients with an empty stomach was taken before the operation, and serum samples were used to determine the contents of TG, TCHO, HDL-C and LDL-C.The intraoperative cardiopulmonary bypass time, aortic cross clamp time and mechanical ventilation time were collected.χ2 test was performed to analyze the sex distribution. A t-test was used to compare the differences between the two groups of normally distributed measurement data, and one-way ANOVA was used to compare the differences among three or more groups. The Mann–Whitney U test was used to compare the nonnormally distributed measurement data between the two groups. For the correlation between complement C1q and IVSTZ, LVPWTZ, LVDdZ, TG, TCHO, HDL-C, LDL-C, cardiopulmonary bypass time, aortic cross clamp time and mechanical ventilation time, if the data conformed to a normal distribution, pearson correlation analysis was used; if the data did not conform to a normal distribution, rank correlation analysis was used. P < 0.05 was considered statistically significant.SPSS 20.0 was used for statistical analysis. Measurement data are presented as the mean ± standard deviation  in the simple CoA group and 13 cases (46.4%) in the complex CoA group (11 cases (39.3%) were CoA combined with large VSD, and 2 cases (7.1%) were CoA combined with thick PDA). There were 42 cases in the control group, including 14 cases (33.3%) in the simple large VSD group and 28 cases (66.7%) in the normal group.There was no significant difference in sex, age, weight or height among the simple CoA group, complex CoA group, simple large VSD group and normal group (P > 0.05) Table .Table 1TP < 0.05). There was no significant difference in LVDdZ between the complex CoA group and the normal group (P > 0.05). There was no significant difference in IVSTZ and LVPWTZ between patients in the complex CoA group and the large VSD group (P > 0.05), but the LVDdZ in the complex CoA group was significantly lower than that in the large VSD group (P < 0.05)  Table .Table 2TP < 0.05)    (Table P < 0.05) (Table P > 0.05) (Table P > 0.05)   Table . In simp5) Table . There w5) Table . In the 5) Table .However,5) Table .Table 4Tr = − 0.035, r = − 0.288, P < 0.05)   Fig. .Fig. 2Tht = 0.515, P > 0.05). There was no significant difference in cardiopulmonary bypass time, aortic cross clamp time or mechanical ventilation time between the simple CoA group and the complex CoA group (P > 0.05)  (Table P < 0.05)   is a kind of localized aortic stenosis near the arterial catheter that was first described by Morgagni in 1760 . CoA canThe mechanisms of cardiac hypertrophy include cellular metabolism, proliferation, noncoding RNAs, immune responses, translational regulation, and epigenetic modifications . Immune β-catenin activation [The complement system is an important part of innate and adaptive immunity. Under physiological conditions, the activation and regulation of the complement system are in a balanced state. When the balance is broken, the complement system will attack the body’s own cells and tissues, which will lead to a variety of inflammatory reactions and autoimmune diseases . C1q is tivation . The C1qtivation . In 2019tivation . TherefoBased on our study, we found that the content of complement C1q in the plasma of patients with simple CoA was significantly lower, and their IVSTZ and LVPWTZ were significantly higher. By further analyzing the relationship between complement C1q and left ventricular hypertrophy, we found that the content of complement C1q before the operation was negatively correlated with IVSTZ and LVPWTZ. These data indicate that complement C1q has a certain inhibitory effect on the formation of left ventricular hypertrophy. Meanwhile, we also found that the IVSTZ and LVPWTZ were not significantly different between the complex CoA group and the large VSD group, which may be related to the large left to right shunts at the ventricular level, but the LVDdZ in the complex CoA group was significantly lower than that in the large VSD group. We think that this may be related to the reduction in the left to right shunt flow through the ventricular septum, which was induced by the obstruction of the left ventricular outflow tract caused by CoA.During cardiac surgery with cardiopulmonary bypass and aortic cross clamp, the heart is isolated from the circulation. This inevitably induces myocardial ischemia. In addition to this ischemic insult, an additional hit will occur upon reperfusion, which may worsen the extent of tissue damage and organ dysfunction . In 2020Mechanical ventilation can also promote the release of inflammatory mediators and activate the inflammatory response. Silvia Marchesi et al. reported that the blood IL6 and TNF-α ratio increased significantly in patients on mechanical ventilation . DhanireBy analyzing complement C1q in children with CoA before and 24 h after the operation, we found that the decreased percentage of C1q in children with simple CoA or complex CoA was positively correlated with the time of cardiopulmonary bypass and aortic cross clamp. In the simple CoA group, the percentage of postoperative decrease in C1q was positively correlated with the time of mechanical ventilation. However, in the complex CoA group, there was no significant correlation between the percentage of postoperative decrease in C1q and the time of mechanical ventilation. These results show that with the extension of cardiopulmonary bypass time and aortic cross clamp time, complement C1q is gradually consumed and reduced. Complement C1q may have a certain protective effect on myocardial ischemia reperfusion during cardiopulmonary bypass and aortic cross clamp. In terms of mechanical ventilation time, with the extension of mechanical ventilation time, complement C1q gradually decreases, which may be due to mechanical ventilation causing inflammatory reactions, and complement C1q protects other organs and tissues by inhibiting inflammatory reactions. The continuous activation and consumption of complement C1q in this process eventually leads to a gradual decrease in complement C1q.Abnormal lipid metabolism of cardiomyocytes can cause left ventricular hypertrophy. Celentano A found that hypercholesterolemia in normotensive nondiabetic adults is independently associated with a mildly concentric left ventricular geometry . IncreasIn 2004, Wong GM et al. identified C1q complement/TNF-related protein (CTRP) . To dateIn conclusion, in this study, by analyzing the content of complement C1q in the plasma of children with simple and complex CoA and the relationship between the content of complement C1q and LVPW, IVS and LVDd, we found that complement C1q has an inhibitory effect on CoA-induced left ventricular hypertrophy, which is negatively correlated with left ventricular myocardial hypertrophy. By analyzing the content of complement C1q in children with CoA before and 24 h after the operation, it was found that the decreased percentage of complement C1q after the operation was positively correlated with the time of cardiopulmonary bypass, aortic cross clamp and mechanical ventilation. We also found that there was no significant correlation between complement C1q and related indicators of lipid metabolism. The above results have certain clinical significance for clarifying the pathogenesis of left ventricular hypertrophy caused by congenital CoA and the role of complement C1q in myocardial injury during cardiac surgery.There were some limitations in our study. First, this was a retrospective study, there was only the value of complement C1q at 24 h after operation, and the values at other times after operation were incomplete. Therefore, we only analyzed the complement C1q level at 24 h after the operation. The time of echocardiogram reexamination after operation was inconsistent, so the correlation between postoperative complement C1q and LVDd, IVST and LVPWT could not be analyzed. Second, the number of patients included in this study is small. In the future, we will conduct a large clinical prospective study to further investigate the correlation between complement C1q levels and left ventricular hypertrophy induced by coarctation of the aorta.C1q is an important promoter of the classical complement pathway. In our study, we found that serum complement C1q levels in simple CoA patients showed lower level. In CoA patients, serum complement C1q had a negative association with interventricular septal thickness and left ventricular posterior wall thickness. The decreasing of serum complement C1q was an unfavorable factor for acute myocardial injury during cardiac surgery. Complement C1q may be related to the process of left ventricular hypertrophy induced by CoA and have a protective effect against myocardial injury during cardiac surgery.


Patients with Alzheimer’s disease show a sex-dependent decline of cognitive and behavioral performance. It is controversially discussed whether general anesthesia itself can aggravate or even cause this neurocognitive decline. Therefore, we investigated the effect of general anesthesia on neurocognitive and behavioral function and amyloidopathy in a mouse model of early-stage Alzheimer’s disease with respect to sex.After governmental approval 10 months old Tg2576 mice and wild type  either underwent general anesthesia with 1.0 minimal alveolar concentration of isoflurane for 2 h or were not exposed to isoflurane (controls). Following cognitive and behavioral testing using the modified hole board test (mHBT), brains were investigated regarding amyloidopathy, inflammation, and apoptosis. Data were analyzed using repeated measure analysis of variance (ANOVA) and univariate analysis of variance (UNIANOVA).p < 0.001), less anxiety (p = 0.022 and p = 0.024), increased locomotor activity (p = 0.025), and impaired fine motor skills (p < 0.001). Amyloid precursor protein (p < 0.001), soluble amyloid-beta (p < 0.001) and insoluble amyloid deposits (p < 0.001) were increased in Tg2576 animals. Neither sex nor exposure to isoflurane had an effect on cognitive or behavioral testing or expression of amyloid-related biomarkers.Tg2576 mice showed a decline in memory function (We found that 10 months old Tg2576 showed typical signs of early-stage Alzheimer’s disease and corresponding histopathological alterations. Relevant sex-specific differences or an effect of isoflurane anesthesia could not be detected at this early stage of the disease. Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Due to medical progress and a rising life expectancy, the prevalence is increasing with an estimated total number of people living with AD dementia of 13.8 million in the U.S. in 2050 . While tAccording to epidemiological studies, women have a higher lifetime risk for developing AD . NeurodeWhile an interaction between anesthetics and amyloid-beta has been demonstrated , the relMice and humans are analogous regarding higher cognitive functions such as cognition, behavior and fine motor skills . The Tg2This study aimed to investigate the effects of general anesthesia on cognitive function and behavioral parameters in a model of early-stage AD with respect to sex. We therefore decided to expose 10 months old Tg2576 to general anesthesia with isoflurane and afterward compare them to their non-transgenic littermates  using the modified hole board test (mHBT). In order to assess amyloidopathy, neuroinflammation, and apoptosis we examined the brains for corresponding biomarkers.This study was carried out in strict accordance with the recommendations of the Federation of European Laboratory Animal Science Associations (FELASA). The following experimental procedures on animals were approved by the Governmental Animal Care Committee . All surgical procedures were performed under isoflurane anesthesia, and all efforts were made to minimize suffering. Animal welfare was assessed daily.°C, 60% humidity and free access to water and standard mouse chow) 2576Kha mouse model of AD, also referred to as Tg2576. With the approval of Taconic , male B6;SJL-Tg(APPSWE)2576Kha mice were crossed with female C57B6/SJL mice  in a separate breeding facility. The genotype was confirmed by PCR, using DNA from tail tissues . Mice homozygous for the rd1-mutation were excluded from the analysis as these mice suffer from blindness. At least 14 days prior to anesthesia and cognitive and behavioral testing, mice were transferred to a test facility for acclimatization. Mice were housed under standard laboratory conditions  .n = 9–12 mice per group) regarding isoflurane anesthesia or sham procedure using a computer-generated randomization list. The experimental groups were designed as depicted in For this study, 85 mice with 10 months of age were used , 44 Tg2576; 41 male, 44 female). Mice were randomly assigned to one of eight groups (°C ± 0.5°C). General anesthesia was maintained for 2 h with 1.6 Vol% isoflurane (MAC 1.0) and a fraction of inspired oxygen of 50% (FiO2 0.5) administered via a nose chamber. Mice breathed spontaneously with an applied positive end-expiratory pressure of 5 mbar.For induction of general anesthesia mice were placed in an acrylic glass chamber that had been pre-flushed with 4.5 Vol% isoflurane  and 50% oxygen. After loss of postural reflexes, mice were placed on a warming pad , gas concentrations, and rectal temperature were measured .After 2 h mice were again placed in the acrylic glass chamber with 50% oxygen now without isoflurane until full recovery from anesthesia. Afterward the animals were weighed and placed in single cages. During general anesthesia respiratory rate, heart rate .We evaluated two different parameters regarding behavior, cognition and motor skills, respectively. Parameters focusing on behavior are the latency with which the mice first visited the holes on the area of interest . Each brain was separated into hemicortices. One hemicortex was sliced into 21 sagittal slides of 50 μm and 21 sagittal slides of 10 μm . The other hemicortex was separated into prefrontal motor cortex, sensory cortex, and hippocampus. A total of 56 brains  were further analyzed.On day 9 after general anesthesia mice were anesthetized deeply using isoflurane and brains were harvested by decapitation using a guillotine . The samples were stored at −80n = 56 brains), we homogenized brain slices of prefrontal motor cortex in 10 volumes of cold guanidine–HCl buffer  and mixed them for 3–4 h at room temperature. The homogenates were diluted in 10 volumes of cold casein buffer , centrifuged , and the supernatant stored at −80°C  was used for the following ELISA. Samples and the standard solution were diluted with standard diluent buffer (Sample concentration: 0.075 μg/μl) and 100 μl of each were added to the appropriate wells and the plate was incubated in the refrigerator at 8°C on a 3D-shaker  overnight. The next day the wells were washed four times with washing solution, 100 μl of HRP-conjugated antibody solution were dispensed into the wells and the plate was incubated at room temperature on a different 3D-shaker  for 30 min. Wells were washed another four times with wash buffer and 100 μl Chromogen (Tetramethybenzidin) solution was added.To determine the total amount of Aβ per brain  and the standard curve was generated using the Magellan® software . We performed two determinations for each brain region and averaged the results for the final analysis.After then adding 100 μl of stop solution, the absorbance at 450 nm optical density was determined using the Sunrisen = 21 per brain) were investigated. The slices including sensory cortex and hippocampus were fixed on microscope slides  in −20°C acetone for 20 min. The staining protocol has been described previously  were suspended separately in grinding tubes  and 300 μl extraction-solution were added . The samples were then homogenized using pestles  for 2–3 min and afterward centrifuged for 30 min (13.000 rounds per minute at 4°C). After centrifugation the supernatant was stored at −80°C. The protein-concentration (by Bradford Assay) was standardized with Laemmli buffer . The samples were transferred onto the gel  in equal amounts (20 μl) and equal protein-concentrations (1 μg/μl) per lane for separation by gel electrophoresis and blotted onto a membrane . The membrane was blocked for 1 h and incubated afterward with the first antibody  overnight at 8°C on a 3D-shaker. After washing with TBS/T  the membrane was incubated with the second antibody  for 1 h on a 3D-shaker.Sensory cortex and hippocampus of seven animals per group . For analysis and normalization ImageLab® was used in addition to the Stain-Free® Technology to assess the total protein amount . A standard lane was included in every blot.Following another washing step, the membrane was incubated in the dark with Clarity™ Western ECL Substrate  for 1 min. The labeled proteins were detected with camera imaging . The material was then observed under a light microscope  with a 10×, 40×, and 100× objective. The full cycle in mice can be divided into 4 stages: Proestrus, estrus, metestrus, and diestrus. The determination of the respective cycle phase is based on the proportion among epithelial cells, cornified cells and leukocytes.Following decapitation and preparation of the brains, the reproductive cycle of each female mouse was assessed by vaginal cytology . TherefoParameters obtained in the mHBT were analyzed using repeated measure analysis of variance (ANOVA) to represent the learning process over eight consecutive days as well as univariate analysis of variance (UNIANOVA) to assess the mice’ performance on day 8 of neurocognitive and behavioral testing.Using repeated measure ANOVA, the dependent variables were tested by the between-group factors sex , genotype (Tg2576 and wild type), intervention (isoflurane anesthesia and sham), the within-group factor time (day 1–8), and their interaction terms. The values of testing on eight consecutive days are included in the model and effects of time were analyzed in a linear fashion (time) due to the strictly monotonic character of learning curves in these tests.In calculations using UNIANOVA sex , genotype (Tg2576 and wild type) and intervention (isoflurane anesthesia and sham) served as independent variables while parameters obtained in the mHBT on day 8 served as dependent variables.Post-hoc tests were performed if the interaction terms sex × intervention or genotype × intervention had proven to be significant.For determination of the effect size, we calculated mean differences with 95% confidence interval. post hoc comparisons, nine animals per group were found to be sufficient. In order to account for drop-outs we decided to aim for 12 animals per group in accordance with the Governmental Animal Care Committee.Regarding sample-size calculations, variables of the mHBT are considered relevant if two groups differ two times the given standard deviation. We planned a hierarchical model addressing three between-subject factors  resulting in eight randomized groups. Based on a type I error of 0.05, a type II error of 0.20 and with 64 possible Since distribution of the amount of amyloid-beta, the concentration of APP, Tumor necrosis factor (TNF) alpha and Caspase 3 in the western blot analysis, and as the percentage of brain area covered with amyloid deposits were positively skewed, the statistical analyses were performed following logarithmic transformation.Results of ELISA (amyloid-beta), western blot  and methoxy staining (amyloid deposits) (dependent variable) were compared using UNIANOVA with the additional factors sex, genotype and intervention, and their interaction terms (independent variable).p < 0.05. Calculations were done with SPSS Statistics® .The significance level was set at p < 0.001). Tg2576 visited a hole earlier during the trials than WT throughout the 8 days of testing  and on day 8 . Tg2576 spent more time on board than WT over the course of the mHBT  and on day 8  on the gray board of the mHBT and the time spent on this board  evaluated exploratory motivation and anxiety. Mice underwent 4 trials per day on 8 consecutive days. Each trial ended as soon as the mice found and ate the third bait or after a maximum of 300 s. LFHV decreased from day 1 to day 8 , irrespective of sex or intervention. On day 8 of the mHBT, Tg2576 visited more already emptied holes compared to WT . Tg2576 did less WCT compared to WT over the course of day 1 to day 8  as well as on day 8  and wrong choices total  were evaluated. If an animal revisited a previously emptied baited hole again, it counted as RC. If an animal did not visit a baited hole  or visited a non-baited hole (= wrong choice (WC), [number per trial]) it was later summed up as wrong choices total . Tg2576 did more RC than WT  and on day 8  during one trial and time for food intake . The floor of the four-sided mHBT apparatus is divided into 9 squares by two parallel lines between opposite walls and the gray board with the cylinders is placed in the middle . Wheneven = 44, WT = 21, Tg2576 = 23). Fourteen mice  were in estrus, 4 mice  in metestrus, 25 mice  in pro-estrus and 1 WT mouse (2.3%) in diestrus.The reproductive cycle of each female mouse was assessed . There were no significant differences regarding sex or intervention (The expression of APP was significantly higher in both the sensory cortex (SC) and hippocampus (HC) of Tg2576  than WT, where no amyloid deposits were present, irrespective of sex or intervention (The area [%] of isocortex (IC) and hippocampus (HC) covered with amyloid deposits was higher in Tg2576  of Tg2576 contained significantly more soluble amyloid-beta 1–42 compared to WT (mean difference = 1.23 × 106 units) in the HC was higher in male mice (Tg2576 and WT) compared to female mice (Tg2576 and WT) irrespective of genotype or intervention  in the HC was higher in Tg2576 compared to WT irrespective of sex or intervention , less anxiety (reduced LFHV and increased TOB), increased locomotor activity (increased LC), and impaired fine motor skills (increased TFI). The animals had pathognomonic signs of Alzheimer’s disease in the brains like increased APP, soluble amyloid-beta, and insoluble amyloid deposits. At this early stage of the disease, we did not detect any relevant sex-specific differences nor an effect of general anesthesia.During the course of behavioral testing all mice showed signs of habituation to the test situation : increasAPP was expressed significantly more in the HC and SC in Tg2576 regardless of sex or intervention . This reCaspase 3 as a marker for apoptosis was found significantly more in the HC of male mice, regardless of genotype or intervention . Female TNF alpha as a sign of neuroinflammation was expressed higher in the HC in Tg2576 . This fiThere is not only controversy whether or not general anesthesia might influence neurodegenerative diseases but also which anesthetics and what duration of exposure might be harmful or even beneficial . Han et The lack of sex-differences and the missing effect of isoflurane might be explained by our study conception. In a previous study from our department, female Tg2576 showed a pronounced cognitive decline at the age of 12 months when compared to male Tg2576 at 12 months. A female sex-dependent correlation of cognitive impairment to the amount of soluble amyloid-beta and amyloid deposits has also been demonstrated . We therBesides the missing effect of our intervention our study has other limitations. We chose to use an AD mouse model restricted to amyloidopathy, although in humans living with AD both amyloidopathy and tauopathy are found . Recent Tg2576 mice show typical signs of early-stage Alzheimer’s disease at 10 months of age: decline in working and declarative memory, less anxiety, increased locomotor activity, and impaired fine motor skills. We also found histopathological alterations in the brains typical for Alzheimer’s disease. Sex or general anesthesia do not seem to have an effect on cognition, behavior, or motor skills at this early stage of the disease.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Regierung von Oberbayern, Maximilianstr. 39, 80538 Munich, Germany, Chair: Dr. B. Wirrer, Registration number: 55.2-1-54-2532-67-2016, July 28th, 2016.LB: investigation, formal analysis, validation, writing – original draft and review, and editing. SB: investigation, writing – review, and editing. MB: methodology, resources, formal analysis, supervision, writing – review, and editing. CP: investigation and formal analysis. BU: formal analysis and validation. BJ: conceptualization, methodology, formal analysis, validation, supervision, writing – review, and editing. SS: conceptualization, methodology, investigation, formal analysis, validation, data curation, writing – original draft and review, and editing. All authors contributed to the article and approved the submitted version.


To study the clinical effect and influencing factors of kyphoplasty in the treatment of osteoporotic thoracolumbar compression fractures (OTCF) complicated with type 2 diabetes mellitus (T2DM).A total of 472 patients with OTCF complicated with diabetes who were enrolled in our hospital from January to December 2019 were selected as the study subjects, and all patients were treated with percutaneous kyphoplasty (PKP). The effects of gender, age, smoking, drinking, body mass index (BMI), bone mass density (T score), fasting blood glucose level, fasting C-peptide, glycosylated hemoglobin, course of T2DM, vertebral segment and surgical instrument on postoperative improvement were analyzed. The quality of life was evaluated by visual analog score (VAS) and Oswestry disability index (ODI) before PKP and 7 days, and 6 months after PKP, and the patient satisfaction was assessed by the modified Macnab criteria at 6 months postoperatively.P = 0.025), fasting blood glucose ≥8 mmol/L , glycosylated hemoglobin ≥6.5 mmol/L , duration ≥8 years  and Kyphon instrument  were independent influencing factors of OTCF complicated with DM.The overall excellent and good rate of evaluation result was satisfactory. In multivariate regression, independent risk factors for poor patient satisfaction included: age ≥70 years (odds ratio (OR) = 2.298, 95% confidence interval [CI] 1.290–4.245, Kyphoplasty for patients with osteoporotic thoracolumbar compression fractures complicated with diabetes can achieve a satisfactory clinical effect, the curative effect is affected by many factors, attention to these factors can improve the clinical effect. Diabetes mellitus (DM) and osteoporosis are major public health problems in the aging population affecting people all over the world and are of serious health and financial concern . DM can This was a retrospective cohort study, which included 472 patients with OTCF complicated with diabetes at our hospital from January to December 2019. We reviewed each patient's clinical records and built the database.Inclusion criteria: (1) OTCF was confirmed by low-intensity signal changes on T1-weighted image, high-intensity changes on T2-weighted image preoperatively; (2) bone mass density (BMD) T score≤−2.5 SD; (3) OTCF patients who underwent PKP surgery; (4) patients with T2DM; (5) follow-up time >6 months; (6) complete clinical and imaging data.Exclusion criteria: (1) acute vertebral compression fracture caused by severe trauma such as car accidents and falling injury; (2) primary or metastatic tumors; (3) multiple myeloma or other systemic diseases; (4) infection; (5) previous spinal surgery; (6) allergic to surgical supplies. This study was approved by the Ethics Committee of Xi'an Honghui Hospital, and all patients obtained preoperative informed consent.All patients were placed in prone position on a spinal reduction stent prior to surgery to maximize reduction of the compressed vertebra. Routine skin disinfection was carried out in the surgical area, sterile towel sheets were laid down and skin care membranes were pasted. The compressed vertebral body was fluoroscopically located, local anesthesia was performed with 1% lidocaine, and incisions about 5 mm long were made on either side of the injured vertebral body. Under fluoroscopy, the pedicle surface of the injured vertebral body was slotted using the apex, and the apex was driven into the pedicle. Pull out the inner core of the apex and insert the guide wire into the vertebral body under fluoroscopy. At this point, pull out the sleeve of the apex vertebra and insert it into the channel along the direction of the guide needle under fluoroscopy. Pull out the guide pin and insert the drill bit into the channel to drill. After that, the drill bit was taken and put into the dilator, and the contrast agent was injected into the balloon. Under fluoroscopy, whether the contrast agent leaked into the blood vessel was observed. After seeing the balloon, it was opened to make the fracture part reset. Remove the contrast agent from the balloon and draw out the dilator. The bone cement sleeve was inserted into the channel, and an appropriate amount of bone cement was injected into the vertebra from both sides of the pedicle under fluoroscopy, and satisfactory filling effect was achieved. The sleeve and channel were pulled out after the cement hardened. The incision was sutured and covered with compresses. All patients were prescribed calcium tablets , calcitriol (0.25–0.5 μg/day) and alendronate (70 mg/week), postoperatively.The effects of gender, age, smoking, drinking, BMI, BMD T score, fasting blood glucose level, fasting C-peptide, glycosylated hemoglobin, course of T2DM, vertebral segment and surgical instrumentation postoperative improvement were analyzed. The Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI) were routinely administered to all patients. Meanwhile, the quality of life was evaluated by VAS scores for low back pain and ODI indices for the functional assessment preoperatively, 7 days and 6 months postoperatively, and the modified Macnab criteria were used to assess the patient satisfaction . Accordit-test, Mann–Whitney U-test, chi-square test, and Fisher exact test were used to evaluate differences between these groups. Multivariate binary Logistic regression analysis were performed under single factor. P-value < 0.05 was considered statistically significant.EpiData3.5 software  was used to establish the database. All analyses were conducted using SPSS version 26  and GraphPad Prism version 9.3.0 . Specifically, Student 2 and −3.0 ± 0.3 SD, respectively. The mean fasting blood glucose, fasting C-peptide and glycosylated hemoglobin were 8.0 ± 2.4 mmol/L, 0.67 ± 0.24 nmol/L and 6.5 ± 1.3 mmol/L. The mean course of disease was 8 ± 1.5 years. In terms of instrumentation, KMC system was used in 334 patients and Kyphon was used in 138 patients. There were 108 cases with T11 fracture, 120 cases with T12 fracture, 138 cases with L1 fracture, 106 cases with L2 fracture.In this study, a total of 472 patients meeting the criteria were included with a follow-up period of 6 months. The general characteristics of the patients are summarized in P < 0.001). The ODI score was 72.5 ± 17.7 preoperatively, which declined to 30.2 ± 16.8 at the final follow-up with a mean decrease of 42.3 ± 9.8 (P < 0.05). According to the modified Macnab criteria for patient satisfaction, the clinical good-to-excellent rate was 93.6% for all parentis: excellent- 228 (48.3%), good- 214 (45.3%), fair- 20 (4.2%), and poor- 10 (2.1%). Among the follow-up cases, there were 26 cases of adjacent vertebral body fracture and 4 cases of distal vertebral body fracture.All patients were followed up for 6 months. Preoperative and postoperative VAS scores of low back pain and ODI evaluations are shown in P > 0.05). Age, fasting blood glucose, fasting C-peptide, glycosylated hemoglobin, duration and instrument were correlated with patient satisfaction after PKP (P < 0.05). As shown in P = 0.025], fasting blood glucose , glycosylated hemoglobin , duration  and instrument .The results of univariate analysis were shown in In this study, it was found in the 6-month follow-up after surgery that the overall excellent and good rate of patient satisfaction was 93.6%, indicating that the use of kyphoplasty can achieve relatively satisfactory clinical results, but there were 15 patients with poor results, and it was found that the blood glucose control of these 15 patients was not ideal, all of them were severe osteoporosis. Furthermore, during the follow-up of this study, 13 cases of compression fractures occurred in the adjacent vertebrae of surgically reshaped vertebrae and 2 cases of distal vertebral fractures. Therefore, effective control of blood glucose is an effective prerequisite for preventing fractures in diabetic patients. In addition, the results of this study showed that age ≥70 years, fasting blood glucose ≥8 mmol/L, glycosylated hemoglobin ≥6.5 mmol/L, duration ≥8 years and Kyphon instrument were independent influencing factors of OTCF complicated with T2DM.Age is an important factor affecting the degree of osteoporosis, and bone loss increases with age . PreviouFasting blood glucose is one of the most frequently used factors reflecting blood glucose level in patients with T2DM. Previous studies have shown that long-term poor blood glucose control can lead to an increase in advanced glycation end products, while the continuous accumulation of advanced glycation end products can inhibit osteoblast differentiation, thus promote osteoblast apoptosis and osteoclast formation, resulting in a decrease in bone mass and aggravation of osteoporosis , 15. In At present, most studies have confirmed that glycosylated hemoglobin ≥6.5% (≥48 mmol/mol) can irremediable long-term risk for diabetic complications and mortality . Lim et The present study demonstrated that the duration of diabetes ≥8 years was an independent risk factor for poor patient satisfaction after PKP treatment in OTCF patients with diabetes. An increasing number of studies have shown that the longer duration of diabetes affects the health-related quality of life , 23. TakIn our study, patients who used surgical instruments using KMC had a higher recovery rate after surgery than those who used Kyphon. Combined with the result of logistic regression analysis in this study, Kyphon instrument was independent influencing factor of OTCF complicated with T2DM. After analyzing for underlying reasons, we found some possibilities as follows: (1) When KMC was used in surgery to expand the coronal surface centered on the channel, it was not easy to produce pressure on the lateral wall of the vertebral body, so the possibility of bone cement exudating and pressing blood vessels and nerves could be minimized to the greatest extent. (2) KMC mainly expands in the height direction of the vertebral body, which can effectively restore the height of the compressed vertebral body. It is point-shaped when opened, so that the bone cement can pour into the vertebral body from all directions, while Kyphon evenly spreads the balloon, which is not easy to control in the direction and the permeability of the bone cement is not satisfactory , 26. TheThe limitations of the present study mainly include the following items: (1) the clinical data were collected in our hospital, so it lacked comparison with different centers. (2) The patient was followed up for a short time, so the results of long-term follow-up are needed to support our conclusions. (3) The clinical efficacy of kyphoplasty is affected by many factors, the indicators used in this study are not comprehensive, so the results are inevitably biased.To sum up, kyphoplasty for treatment of OTCF with diabetes can play a more satisfactory clinical effect, its curative effect is affected by age, duration, fasting blood glucose levels, glycosylated hemoglobin, duration and type of instrument.


This cross-sectional study uses health administrative data to examine trends in diabetes incidence among children during the COVID-19 pandemic in Ontario, Canada. There is no clear mechanism by which COVID-19 infection might cause new-onset diabetes.2 Kamrath et al3 recently reported an increase in type 1 diabetes incidence among children in Germany during the pandemic. They did not observe an association of COVID-19 and increased type 1 diabetes incidence in the months after infection or an increase in the frequency of autoantibody-negative type 1 diabetes, which prompts the question of whether COVID-19 infection is associated with incident type 1 diabetes.3 Given the challenges of ascertaining a COVID-19 infection history for children with new-onset diabetes, additional population-based studies investigating changes in diabetes incidence among children during the pandemic are needed. Canada has one of the highest incident rates of type 1 diabetes worldwide. Therefore, this study examined whether diabetes incidence increased during the COVID-19 pandemic among children and youths (aged <18 years) in Ontario, Canada.A recent study reported an association between COVID-19 infection and new-onset diabetes among people younger than 18 years in the US.STROBE reporting guideline.For this population-based, repeated cross-sectional study, data use was authorized under Section 45 of Ontario’s Personal Health Information Protection Act and therefore did not require research ethics board review or informed consent. The study followed the We used health administrative data (January 2017 to September 2021) linked using unique encoded identifiers, held and analyzed at ICES  in Ontario, Canada. We included all children and youth (aged 1-17 years) eligible for universal health care insurance  on January 1 of each year (2017 to -2021).4 We used generalized estimating equations for Poisson regression to model 3-year pre–COVID-19 rates adjusting for age group, sex, pre–COVID-19 month, and secular trend. We then used these models to estimate expected post–COVID-19 monthly rates (95% CIs) using 2-sided hypothesis tests .Ontario has a population of approximately 14.8 million people; 3 million are younger than 18 years. Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had SARS-CoV-2 infection.There were 2 700 178 children in the 2021 cohort; the mean (SD) age was 9.2 (4.9) years, and 48.7% were girls. Overall, there was no difference in observed vs expected relative rates (RRs) of new diabetes presentations  . However3 who reported a 1.15-fold increase in type 1 diabetes incidence among children in Germany during the pandemic.3 Limitations of our study include its smaller population and therefore lower power; thus, we cannot rule out a 1.3-fold increase in RRs. An advantage of our study is that we report monthly variations in post–COVID-19 diabetes incidence showing a decline then an increase in rates, suggesting possible delays in diabetes diagnosis for children early in the pandemic with a catch-up effect. Although we are unable to differentiate type 1 and 2 diabetes, 95% of children with diabetes in Ontario have type 1.6 The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions and a plausible biological mechanism calls into question an association between COVID-19 and new-onset diabetes. Given the variability in monthly RRs, additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children.In this cross-sectional study, we observed a slightly higher but nonsignificant increase in diabetes incidence among children during the COVID-19 pandemic. Our overall rate ratio is similar to that of Kamrath et al,


HighlightsWe question certain aspects of the recent Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report (January 2022) showing a significant increase in the incidence of diabetes in children after COVID‐19 infection.We are concerned at the source of data being limited to commercial health insurances and lack of factoring race, ethnicity, social determinants of health, body mass index, type of diabetes, and viral variants in the interpretation of these data. It is well known that multiple viruses  are associated with triggering development of type 1 diabetes in genetically susceptible individuals. In January 2022, the CDC, in their Morbidity and Mortality Weekly Report, published a study suggesting that youth under 18 years old had a higher rate of developing diabetes more than 30 days after COVID‐19 infection.Significantly higher rates of diabetic ketoacidosis (DKA) were noted in patients with a previous COVID‐19 diagnosis who went on to develop diabetes, 40.2%  and 48.5% (IQVIA), compared to DKA reported in patients with new onset diabetes who did not have a recent COVID‐19 diagnosis .The report's strengths are that it utilizes large sample sizes  and captures data in the USA since the advent of the pandemic for at least 12 months. Having age‐ and sex‐matched control groups adds to the strengths of the study. It also corroborates with prior US data showing an increased risk for diabetes in the adult population with COVID‐19 and is consistent with studies from Europe that similarly report an increased incidence of pediatric diabetes associated with COVID‐19 infection. Further, the incidence of diabetes in the non‐COVID cohort in the IQVIA database was 32.6/100000 children, consistent with data from the SEARCH study, which reported incidence of diabetes in youth at 36.1/100000 children.The authors appropriately list several limitations that are important to consider. Significant details regarding glycosylated hemoglobin levels, presence of autoantibodies, and characterization of diabetes into type 1 or type 2 were not presented. Patients were only followed for limited periods of time and longer‐term follow up would be required to assess whether diabetes was transient or persistent. It is well established that the risk for both types of diabetes varies significantly between different racial and ethnic groups and that COVID‐19 has disproportionately affected disadvantaged groups.Additionally, the data do not represent uninsured children (5%) or those on Medicaid (29%), who encompass over one‐third of the pediatric population in the USA, a substantial portion that may be disproportionately affected by COVID‐19 and type 2 diabetes. Thus, the true incidence of diabetes may be much higher, and risk of developing type 1 vs type 2 diabetes is likely quite different and considerably more complex than what we can glean from the data presented.The timing of presentation for diagnosis of diabetes should also be considered. Because children with prediabetes and diabetes are often asymptomatic, diabetes may have been incidentally diagnosed when presenting to the clinician with COVID‐19 symptoms. Thus, the acute infection may have brought children to medical attention sooner, allowing for the diagnosis of diabetes to be made at presentation.Also, this report is only applicable to the COVID‐19 viral variants present from March 2020 to June 2021 and does not represent the omicron surge that has been sweeping our country and has affected larger numbers of children than any prior wave of the pandemic.Lastly, while the conclusions in the article highlight vaccination as a strategy to prevent new onset diabetes after COVID‐19 infection, this study did not evaluate how vaccination status affected diagnoses of new onset diabetes in the pediatric population. While vaccination is important to help prevention of well‐documented sequelae, to our knowledge, there are no data to support that vaccination will prevent diabetes, and this takeaway message should be interpreted with caution.In conclusion, this observational study presents preliminary data of an association between new onset diabetes and recent COVID‐19 infection; it does not establish causation. Further prospective studies are required to confirm these findings.None.The authors have no conflicts of interest to disclose.


Bile cast nephropathy (BCN) or cholemic nephropathy (CN) is an acute renal dysfunction, including acute kidney injury (AKI) in the setting of liver injury. It is a common phenomenon in patients with liver disease and is associated with significant morbidity and mortality. CN is characterized by hemodynamic changes in the liver, kidney, systemic circulation, intratubular cast formation, and tubular epithelial cell injury. CN has been overlooked as a differential diagnosis in chronic liver disease patients due to more importance to hepatic injury. However, frequent and considerable reporting of case reports recently has further investigated this topic in the last two decades. This review determines the evidence behind the potential role of bile acids and bilirubin in acute renal dysfunction in liver injury, summarizing the implied pathophysiology risk factors, and incorporating the therapeutic mechanisms and outcomes. The term bile cast nephropathy (BCN), also known as cholemic nephropathy, icteric nephrosis, or cholemic nephrosis, is described as acute renal dysfunction, including acute kidney injury (AKI) in the setting of liver injury . QuinckeThe AKI in cholestatic liver dysfunction is usually linked with other unfavorable factors such as hypovolemia, endotoxemia, and exposure to nephrotoxins . On the BCN is underdiagnosed and is witnessed as a neglected injury found in the autopsy of patients with hyperbilirubinemia and renal dysfunction. The pathophysiology of AKI in the setting of hyperbilirubinemia is multifactorial and involves a wide range of mechanisms. This review aims to determine the evidence behind the potential role of bile acids and bilirubin in acute renal dysfunction in liver injury. It also summarizes the implied pathophysiology risk factors and incorporates the therapeutic mechanisms and outcomes.Bilirubin and cholemic nephropathyExcess bilirubin has detrimental effects on kidney tubule function and intracellular mitochondrial function. Bilirubin aids in oxidative stress to kidney tubular epithelium leading to damage to the tubules and associated renal structures ,4,8. A sMoreover, hyperbilirubinemia can cause uncoupling oxidative phosphorylation in the mitochondria ,8. OxidaIn contrast to bilirubin’s harmful effects, it also exhibits debatable renoprotective effects . It is aBile acids and cholemic nephropathyMost bile acids are usually reabsorbed in the ileum and transported via portal blood circulation back to the liver. It is estimated that the liver does not take up about 10-50% of reabsorbed bile acids, making them escape in the peripheral circulation leaving behind 100 μmol bile acids per day prone to glomerular filtration . OrganicWith the above theory in context, it is worth noting how these mechanisms are affected in the event of cholestatic diseases such as obstructive jaundice, primary biliary cirrhosis, and primary sclerosing cholangitis. To counteract the rising bile salts in these pathologies, hepatocytes heighten basolateral hepatocellular export and enhance renal filtration and tubular secretion in the proximal tubules via organic anion transporters and multidrug resistance-associated proteins ,6. ThereHemodynamic changes due to hyperbilirubinemiaHRS is a life-threatening complication that compromises renal function, especially in patients with advanced liver disease -10. The Moreover, in patients with liver cirrhosis, endotoxins are released due to the translocation of bacteria and pathogen-associated molecular patterns (PAMPs) from the gut and prompt systemic inflammation ,4. SpeciApproach and diagnosisCurrently, a kidney biopsy is the gold standard diagnostic test for CN. In autopsy evaluations of CN patients, the kidney’s cortex and medulla appear yellow due to bilirubin. After fixation with formalin, color changes to green due to bilirubin oxidation and conversion to biliverdin ,27. On hBiomarkersAKI is associated with high morbidity and mortality and can occur in patients with severe liver disease. Proximal tubule cells are sensitive to hypoxic injury, leading to a release of proteins into the urine. Several promising urinary biomarkers may be used to evaluate AKI. The most studied is neutrophil gelatinase-associated lipocalin (NGAL), a 25 kDa iron-transporting protein excreted in nephrotoxic or ischemic kidney injury. Urinary(u) NGAL levels in CN were shown to be suitable to monitor tubular epithelial damage and therapeutic effects under experimental conditions ,45. The Treatment strategies and outcomesThe definitive diagnosis and subsequent treatment of CN are challenging, especially considering that a few case reports are diagnosed postmortem through autopsy, and adequate treatment was not provided. Treatment of CN is primarily based on treating the underlying cause of hyperbilirubinemia to prevent kidney injury . In the Extracorporeal therapies are possible treatment options in patients with CN and are divided into biologic and nonbiologic. Biologic therapies use living liver cells, while nonbiologic therapies use artificial membranes and adsorbents . These therapies can reduce inflammatory cytokines and bilirubin levels. Plasmapheresis is when plasma is separated from the blood, filtered, and returned to the patient. This therapy aids in the removal of excess toxins and bilirubin and replenishes albumin, coagulation factors, and hepatic regenerative stimulating substances to improve the symptoms of the patient .On the other hand, hemodialysis is a complicated process involving blood filtration and regulating fluid balance. The case report by Sens et al.  utilizesFuture implicationsThere are no systematic guidelines for diagnosing, treating, and managing a patient presenting with CN. CN is a diagnostic dilemma, and more reasonable diagnostic alternatives are crucial in approaching suspecting patients with CN. The transjugular approach for kidney biopsy may be an effective option considering the associated coagulopathic risks with traditional kidney biopsy in liver cirrhosis patients . HoweverCN is an uncommon diagnosis but a common finding in patients with liver disease. Suspicion and meaningful consideration should be given to BCN in non-respondents to HRS treatment. The kidney biopsy is an accurate diagnostic, and the transjugular approach can be a better alternative to traditional biopsy to expedite the diagnosis by simultaneously obtaining liver and kidney biopsies, also lessening the bleeding risk in high-risk patients. This review is crucial in suggesting the various mechanisms, diagnostic techniques, and treatment approaches to BCN.


Adcy1 reduced morphine-induced hypersensitivity compared to control mice. In contrast, acute morphine antinociception, along with thermal paw withdrawal latencies, motor performance, exploration in an open field test, and burrowing behaviors were not affected by intrathecal Adcy1 knockdown. Knockdown of Adcy1 by intrathecal injection also decreased inflammatory mechanical hyperalgesia and increased burrowing and nesting activity after intraplantar administration of Complete Freund’s Adjuvant (CFA) one-week post-injection.Opioid tolerance, opioid-induced hyperalgesia during repeated opioid administration, and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static  or an escalating tolerance paradigm . Systemic treatment with an AC1 inhibitor, ST03437 , reduced morphine-induced hyperalgesia in mice. Lumbar intrathecal administration of a viral vector incorporating a short-hairpin RNA targeting  On a cein vitro  and in via (DRG) .To date, nine membrane-bound AC isoforms (AC1-9) and one soluble isoform (AC 10) have been confirmed in mammalian nervous systems . AC1 is Adcy1 expression in mice. Mechanical withdrawal thresholds were measured in morphine tolerant and morphine withdrawn mice. Similarly, several evoked and spontaneous behavioral measures were used to determine if Adcy1 knockdown would also decrease hypersensitivity or improve mobility in a mouse model of inflammatory pain.Although all of the underlying mechanisms behind tolerance and opioid-induced hyperalgesia are not currently known, increased AC expression and activity have been suggested to be one of the major causative agents. To date, it is unknown if selectively inhibiting AC1 activity or reducing AC1 expression after chronic MOR stimulation alters the development of opioid tolerance and opioid-induced hypersensitivity. The purpose of this study was to better understand how the activity of AC1 in the spinal cord and dorsal root ganglia contributes to hypersensitivity seen during morphine tolerance, opioid-induced hypersensitivity, and chronic inflammatory pain. To accomplish this, systemic pharmacological inhibition of AC1 or intrathecal delivery of a short hairpin RNA (shRNA) through a viral vector was used to decrease ad libitum. Mice were kept in conventional microisolator cages with no more than five animals per cage. The cages contained irradiated corn cob bedding enriched with aspen and cotton nesting materials. After drug administration and CFA injections, mice were monitored for overall wellbeing and any adverse reactions. Mice were acclimated to individual testing apparatuses before behavioral testing. All experiments were conducted during the 14 h day cycle except for nesting behaviors. Mice were euthanized by isoflurane anesthesia (5%) followed by decapitation at the end of the study. A Table of experimental studies in provided in All experimental procedures involving animals were approved and performed under the University of Minnesota Institutional Animal Care and Use Committee guidelines. Adult male and female C57Bl6 mice were obtained via Charles River  having an average weight of ∼25 g (23–31 g). Mice were housed in a facility ranging from 20 to 26°C on a 14 h light/10 h dark cycle with water and rodent chow (Purina 5015) In behavioral studies, 5–10 male and female mice were randomly assigned to either a control or ST034307 treatment group. Viral vector studies consisted of two treatment groups, each containing 10 randomly assigned male and female mice. Use of male and female animals is consistent with the National Institute of Health’s Sex as a Biological Variable policy. For all experiments, male mice were tested before female mice and equipment cleaned in between testing of sexes.Morphine  was administered through a 100 µl subcutaneous injection in saline. For morphine tolerance experiments, baseline mechanical paw withdrawal testing was performed before and after administration of 15 mg/kg of morphine for 5 days . BaselinST034307  was dissolved in 10% β-cyclodextrin with 5% DMSO in saline and administered in a 100 µl intraperitoneal injection. ST034307 or vehicle was administered 15 min after morphine in tolerance experiments.In separate experiments, Complete Freund’s Adjuvant  was administered through an intraplantar injection  into the left hind paw.® 2450, IITC Life Science, Woodland Hills, CA, United States). The plantar surface of the hind paws was gently pressed with the probe until a nocifensive response  was elicited. Baseline measurements were collected five times from both the right and left hind paw and averaged, with an interstimulus interval of at least 1 minute.Mice were acclimated to the testing environment on at least two separate occasions for 30–60 min before formal testing. The testing environment consisted of a mesh floor, allowing access to animal hind paws, and individual clear acrylic chambers. Mechanical paw withdrawal thresholds, in grams, were determined by electronic von Frey testing equipment . Viruses were delivered by direct lumbar puncture (10 uL) in awake mice and behavioral assessments were performed 3–8 weeks post-injection . CFA was injected into a cohort of mice 7-weeks post inoculation. CFA treated mice underwent a series of behavioral tests 3–4 weeks after virus injections but before CFA administration  and after CFA administration .Four weeks post-virus injections morphine efficacy was determined using an escalating dose-response curve (5–20 mg/kg) waiting 30 min after each injection . MorphinAgility assessment was conducted using Rotamex-5 automated rotarod system . Mice were placed onto a stationary knurled PCV rod suspended in the air. The initial rotation speed of 4 rpm was gradually increased by 1 rpm in 30-s intervals until animals fell off the rod or reached a speed of 14 rpm (300 s). Two tests were administered per animal and averaged.Latencies to a radiant light beam focused on the plantar surface of each mouse hind paw were obtained using a modified Hargreaves Method  . The avehttp://ethowatcher.paginas.ufsc.br/) . The distance traveled (cm), time spent immobile (sec), average velocity (cm/s), and the change in orientation angle (degrees) were computed by using data output from the Ethowatcher computational tool software  .Adcy1 and AAV9-scramble mice were subjected to burrowing testing. Mice were acclimated to empty burrowing tubes for ∼2 h on at least two separate occasions before formal testing. The burrows were made from a 6 cm diameter plastic pipe and 5 cm machine screws were used to elevate the open end by 3 cm , AAV9- by 3 cm . During ad libitum overnight. A single 2” Nestlets™  square was weighed and added to each cage. The next morning (∼14 h) untorn pieces of each nesting square were weighed and the resulting nests were photographed and scored on a 5-point scale as described previously  and RNeasy Mini Kit  according to the manufacturer’s protocol with 30 min DNase 1 digestion. Complementary DNA synthesis was performed with 50 ng total mRNA using Omniscript RT Kit  and random nonamers  according to the manufacturer’s protocol.6 µmoles) (6.022 × 1023copies/mole). Internal controls included negative RT-PCR samples and comparative expression versus housekeeping genes, 18S and Gapdh. Amplification efficiencies were >1.8 and the targeted ΔCt between two dilutions was around -3.3. Fold expression of each gene of interest was determined by: (mean gene concentration/mean 18s concentration)/. See Quantitative PCR was performed using SYBR Green I dye with a LightCycler 480 machine . The cDNA copy number was typically quantified against a ≥5 point, 10-fold serial dilution of a gene-specific cDNA standard (∼5e1 to 5e6 copies/µL) cDNA standards were created using block PCR for one gene  and purified using Qiaquick (Qiagen). Standards were quantified using a UV-Vis spectrophotometer and DNA copies/µL calculated using the equation: (DNA µg/µl) (µmoles/DNA m. w. µg)  ELISA Kit  kit according to manufacturer instructions. Briefly, spinal cords were homogenized in RIPA lysis buffer  with added protease  and phosphatase  inhibitors. Spinal cord homogenates were centrifuged and further diluted in Sample Diluent provided by ABclonal. After incubation in Biotin Conjugate Antibody, Strepavidin-HRP, and TMB substrate, each well was read in microplate reader  at 450 nm with a wavelength correction at 570 nm. Samples were compared against an 8-point standard calibration provided by ABclonal.Histological sections were taken from spinal cord, DRG, and sciatic nerves to verify the delivery of the AAV9 virus within the lumbar intrathecal space 8-weeks post inoculation. Verification of virus inoculation was visible by the presence of green fluorescent protein (GFP). Sections  were mounted onto electrostatically charged slides and images were collected using a Nikon TiS Microscope and associated software.4, 26.2 mM NaCO3, 1.67 mM NaH2PO4, 1.5 mM CaCl2, 9.64 mM Na+ gluconate, 5.5 mM d-glucose, and 7.6 mM sucrose, pH 7.4 . Electrical stimulation was performed at a frequency of 0.3 Hz with electric pulses of 100-µs duration at 100–10,000 µA delivered by a pulse stimulator . Evoked CAPs were recorded with electrodes placed ∼5 mm from the stimulating electrodes. Dapsys software was used for data capture and analysis . The lowest stimulus producing a detectable response in the nerve was determined as the threshold stimulus and the peak amplitude determined when the response no longer increased in amplitude. The conduction velocity was calculated by dividing the latency period, the time from stimulus application to neuronal initial response, by the stimulus-to-recording electrode distance. The sciatic nerves were collected in mice previously used in the morphine escalating dose-response curve studies.Compound action potentials (CAPs) were measured from both left and right desheathed sciatic nerves from AAV9-GFP-U6-m-Adcy1-shRNA and AAV9-GFP-U6-scramble-shRNA8 weeks after intrathecal injection. Sciatic nerves were dissected from the hind limbs of mice and recordings were performed the same day. Each nerve was mounted in a chamber filled with superficial interstitial fluid composed of 107.7 mM NaCl, 3.5 mM KCl, 0.69 mM MgSOt-test, one-way, two-way, or repeated-measures ANOVA followed by either Dunnett’s or Bonferroni’s post hoc analysis was used to determine significance for mechanical thresholds, thermal latencies, gene expression, burrowing, open field testing, rotarod assessments, and CAP recordings. A Mann–Whitney U test was used for nesting behaviors. All statistical analyses were carried out using GraphPad Prism version 9 . Data presented as mean ± SEM unless otherwise indicated with p < 0.05 considered statistically significant.Data were collected by personnel blinded to the animal’s condition and treatment. The appropriate Adcy isoforms in nervous system tissues of morphine tolerant mice. Of the isoforms examined, an increased expression of Adcy1 is seen in DRG and spinal cord  mRNA were also elevated in dorsal root ganglia, while Rapgef3 (protein: Epac1) was also elevated in the spinal cord.Chronic agonist exposure of the MOR decreases inhibitory intracellular responses and increases adenylyl cyclase/cyclic-AMP activity . We attenal cord . This suTo further understand the physiological role of AC1 during tolerance and withdrawal with chronic morphine administration, pharmacological and gene knock-down strategies were implemented with behavioral assays. Previous research demonstrated ST034307 acts as an AC1 inhibitor and as an analgesic in a mouse chronic inflammatory pain model . In bothin vivo, mice were subjected to twice daily morphine injections  in combination with either an injection of vehicle or ST034307  and DRG  compared to the AAV9-scramble mice. Changes to the expression levels of Adcy5, Adcy8, and Oprm1 were also analyzed, but no significant differences were seen for any of these genes in either tissue  indicating AAV9-Adcy1 mice spent less time stationary compared to AAV9-scramble injected mice. This data indicates the AAV9-Adcy1 shRNA does not cause any major mobility changes in mice. Lastly, the downregulation of Adcy1 did not have any impact on thresholds, amplitude, or conduction velocity of C-fiber CAPs  Sin vitro . In chroin vitro , spinal in vitro , and priin vitro . Opioid in vitro . In our in vitro . This fuAdcy1. Static dosing of morphine  and escalating doses of morphine over 4 days  both resulted in enhanced baseline mechanical sensitivity. After intrathecal administration of AAV9-Adcy1, mice had higher mechanical paw withdrawal thresholds before (pre) and after (post) morphine administration compared to control mice. Our data agree with previous studies, as a global loss of either/both AC1 or AC8, appear to have a role in attenuating morphine tolerance and withdrawal , could be due the deferred hypertrophy of adenylyl cyclases after tissue injury, or the delayed role of adenylyl cyclases in enhanced transcription of pro-inflammatory molecules, taking several days to manifest , or an increase in spontaneous pain, or lowering the nociceptive threshold, the clinical effect is the same . Further


Brassica rapa var. rapa L.) (syn. B. campestris L. ssp. rapifera Sinsk) is an important crop species belonging to the Brassicaceae family. The 185 accessions belonging to this crop were collected from several areas of Toodshak region in Isfahan province, Iran, and their tubers were cultivated under homogeneous conditions in loamy clay soil. The morphological traits of different organs of those accessions were evaluated. Significant variations were detected among the accessions studied based on the traits recorded. Tuber shape showed high variation and included globose, oblong, ovate, obovate, and fusiform. Also, tuber skin color was highly variable, including white, bicolor white–violet, light violet, and dark violet. Tuber weight ranged from 1.56 to 35.70 g, while total soluble solids (TSS) of tuber flesh ranged from 7.00 to 11.80%. Principal component analysis (PCA) showed that 18 components were extracted by explaining 74.88% of total variance. The dendrogram obtained based on all the characters measured clustered the accessions into two major clusters. Sixteen accessions were placed into the first cluster, while the remaining accessions were placed into the second cluster which was divided into six subclusters. High level of morphological variabilities was observed among the accessions, which is applicable and useful for B. rapa var. rapa breeding programs. Based on the commercial and quality traits, 17 accessions could be selected for direct cultivation. Also, the promising accessions identified here can be utilized directly in breeding programs for genetic enhancement of this crop.Turnip ( Brassica rapa var. rapa L.) could be selected for direct cultivation. Also, the promising accessions identified here can be utilized directly in breeding programs for genetic enhancement of this crop. Tuber skin color was highly variable, including white, bicolor white–violet, light violet, and dark violet. Tuber weight ranged from 1.56 to 35.70 g. Tuber flesh TSS ranged from 7.00 to 11.80%. Principal component analysis (PCA) showed that 18 components were extracted by explaining 74.88% of total variance. Based on the commercial and quality traits, 17 accessions of turnip ( B. campestris L. ssp. rapifera Sinsk) is an important crop species belonging to the Brassicaceae family. It is an annual or biennial plant with wide variation in size, shape, and color. Its classification is based on morphological characteristics, leading to a division of the cultivated forms into three main subspecies: turnip, oilseed, and leafy types. Thus, it plays a vital role in agriculture, and contributes to both national economies and human health. The B. rapa var. rapa is a vital cruciferous vegetable species, with unique physiology and morphology traits. Its plant parts, including both roots and leaves, are important for human consumption and also for animal feed  was performed to evaluate the variation among accessions based on the traits measured using SAS software , followed by leaf lamina blistering (262.27%) and vivipary (228.13%). The lowest CV belonged to flower length (10.18%), total soluble solids (TSS) of tuber flesh (10.44%), petal width (11.22%), flower width (12.82%), and petal length (13.44%)  constitute only stem tissue, and carrot (Daucus carota L.) constitutes root tissue , oblong (34), ovate (33), obovate (40), and fusiform (40). Also, tuber skin color was highly variable, including white (50 accessions), bicolor white–violet (40), light violet (49), and dark violet (46). Tuber surface was smooth 52), bit wrinkled (79), and very wrinkled (54). Central tuber maximum transverse diameter position was predominant (112 accessions). Tuber flesh was not bitter in most of the accessions (167). Tuber flesh texture was firm in the majority of accessions (150)  and green (77), while the color of floral leaves was strongly variable, including light green (4 accessions), green (87), dark green (87), and green–silver (7). Leaf apex shape was rounded in the majority of accessions 102). Leaf blade shape outline (lamina) was highly variable, ranging from deltoid to oblong. Flat leaf lamina was predominant (119 accessions). Leaf division was lyrate in the majority of accessions (126). Leaf margin showed strong variability, including crenate (37 accessions), broadly crenate (13), sinuate (57), broadly sinuate (55), serrate (8), and broadly serrate (15)  regions or genes that regulate flowering and vernalization . The range of flower‐related characters was as follows: flower length: 10.75–18.62 mm, flower width: 7.80–15.21 mm, petal length: 4.95–13.14 mm, and petal width: 3.29–5.83 mm. Flowering is an important step in plant growth and defines the agriculture setting of the crop. Vernalization is the promotion of flowering after exposure to cold, where plants do not necessarily initiate flowering but acquire the competence to do so. In Silique surface outline was smooth (105 accessions), undulating (55), and constricted between seeds (65). Silique shape was cylindrical (41 accessions), spathulate (5), oblong (19), lanceolate (108), and deltoid (12). Dry silique color was highly variable, including light golden yellow (49), golden yellow (25), cream–light brown (10), light brown (86), and brown (15). Silique pedicel node color was highly variable, ranging from homochromatic to black. The range of silique number in main stem range was 2–39, while total silique number per plant was 5–820. The range of other silique‐related characters was as follows: silique length: 24.45–59.17 mm, silique width: 2.43–6.05 mm, silique thickness: 1.67–5.15 mm, silique beak length: 3.47–31.25 mm, silique pedicel length: 5.61–38.66 mm, and silique weight: 0.02–0.11 g , early June (47), and mid‐June (39) Table . The ranr = 0.73), tuber middle diameter (r = 0.63), tuber flesh texture (r = 0.51), and leaf length (r = 0.53).Pearson correlation analysis showed significant correlation between some characters (data not shown). Tuber weight showed positive correlations with tuber length , tuber middle diameter (0.91), tuber maximum transverse diameter (0.88), and tuber collar diameter (neck) (0.70) with positive correlations were found to be influential in PC1. The PC2 was correlated with four leaf‐related traits, including leaf length (0.70), petiole width (0.83), lamina length (lamina blade length) (0.68), and lamina width (lamina blade width) (0.76) with positive correlations. The PC3 was correlated with plant height until first flower (0.54), flowering branch number (0.79), leaf number until first flower (0.82), and total leaf number (0.84). The remaining characters loaded significantly in the rest components (PC4–PC18) and explained less variability.The scatter plot created based on the PC1 and PC2 Figure  showed tThe dendrogram obtained based on all the characters measured clustered the accessions into two major clusters Figure . SixteenB. rapa var. rapa breeding programs. Matthaus et al. (Brassica napus L.) cultivars from Turkey. Agro‐morphological‐based variation is important to screen best accessions in field experiment. The diverse agro‐morphological‐based accessions are useful for further biochemical and molecular evaluation. Genetic diversity study is used for efficient utilization and for development of improved cultivar/varieties (Jan et al., Here, a high level of morphological variabilities was observed among the accessions, which is applicable and useful for s et al.  reported4B. rapa var. rapa. At the present time, breeding programs, particularly with an obligate outcrossing crop such as turnip, present a challenge. Based on the commercial and quality traits, 17 accessions, including no. 40, 72, 17, 10, 7, 19, 112, 98, 83, 2, 4, 1, 5, 9, 37, 6, and 8, could be selected for direct cultivation. Also, the promising accessions identified here can be utilized directly in breeding programs for genetic enhancement of this crop.Estimation of different qualitative and quantitative traits offers a distinct means to improve varied accessions. Significant variations were recorded for various morphological traits among the accessions of The authors declare no conflict of interest.None.None.


Structured education of healthcare professionals around infection prevention practices and protocols is currently lacking. We launched a pilot program of an infection prevention interprofessional education (IPE) elective for students in their clinical years of medical, pharmacy, nursing, and physician assistant school.Both quantitative and qualitative assessments prior to initiation and at completion of the 2-week multidisciplinary interactive and practical IPE elective were performed. We assessed students’ confidence with specific infection prevention skills knowledge, and attitudes towards IPE, and obtained qualitative feedback. Wilcoxon signed rank test was used to compare assessment results before and after IPE elective.Twelve students completed the IPE elective. There was a significant increase in Lickert scale rankings of students’ comfort level with various infection prevention concepts and skills after IPE (p< 0.001). Similarly, a significant improvement in students’ assessment of their IPE attitudes was noted after completion of the IPE elective (p=0.001).Feedback comments included: “I really enjoyed learning the ‘why’ behind everything [because] it's made me comfortable passing the information to others and speaking up if needed--even still as a student”; “learned information I will use every day”; “people from different backgrounds”; “knowledgeable facilitators, excited to teach & facilitate learning.”Infection prevention education was impactful via the incorporation of an IPE elective into clinical rotations, and use of knowledgeable and adept teachers from multiple disciplines. Leaders emphasized the “why” behind protocols, and allowed students to practice the hands-on skills of infection prevention.Julie Ann Justo, PharmD, MS, FIDSA, BCPS, Gilead Sciences: Advisor/Consultant|Shionogi: Advisor/Consultant|Vaxart: Stocks/Bonds


The study aims to evaluate the neurodevelopmental outcomes of neonates with myelomeningocele (MMC) operated in the postnatal period.This is a prospective follow-up study in a tertiary neonatal intensive care unit. Neurodevelopmental outcomes of term neonates operated for MMC and healthy term newborns were compared with the Bayley Scales of Infant and Toddler Development-Third Edition (BSID III) at 12–18 months.A total of 57 cases were included in the study . Demographic data between the groups were similar. Cognitive, linguistic, and motor composite scores of the patient group were lower than those of the control group (p < 0.001). In the patient group, those who underwent ventriculoperitoneal shunt had lower cognitive, language and motor scores than those without shunt (p < 0.05). The cognitive, linguistic, and motor composite scores in the patient group who underwent surgery before 72 h were better than those who underwent surgery after 72 h.In our study, it was found that the neurodevelopmental prognosis of MMC cases requiring ventriculoperitoneal shunt in the postnatal period was significantly worse than those without shunt. It is the first study in which the neurodevelopment of patients with MMC who were operated in the postnatal period was evaluated with BSID III evaluated and delays in all areas were shown in cases with MMC compared to normal cases. Better neurodevelopmental outcomes in patients operated in the first 72 h suggest that early surgery will improve neurodevelopmental outcomes in patients with MMC. Neural tube defects (NTD) are the most common congenital malformations after congenital heart defects and occur due to the failure of the neural tube to close spontaneously, which should be closed by the third to fourth week in intrauterine life. Myelomeningocele (MMC) is the most common NTD, characterized by protrusion of the meninges and spinal cord through open vertebral arches leading to paralysis .With nearly 60 cases per 100,000 births in the United States, the prevalence of MMC varies among countries. MMCs may be part of a genetic syndrome or may occur as an isolated defect. With both environmental and genetic factors affecting the emergence of the defect, the causes remain uncertain. It has been reported that many factors may lead to the development of MMC including maternal exposure to hyperthermia during pregnancy, use of alcohol, valproic acid, carbamazepine or isotretinoin, maternal malnutrition or obesity, low folic acid levels, maternal diabetes, and genetic markers (mutations in folic acid-responsive or folic-acid-dependent enzyme pathways) ,3,4.A surgical correction should be performed as soon as possible following the diagnosis of neural tube defects. However, since other system disorders such as mental and motor retardation, bowel and bladder dysfunction, orthopedic problems can accompany NTDs in varying degrees, the treatment applied may bring limited success. Patients suffering from NTD often require long-term care, leading to a significant financial burden on healthcare costs .Today, NTD patients who lost their lives in childhood in the past can reach adulthood to a large extent. A close follow-up with a multidisciplinary approach is required from birth to preserve the neurological functions of these patients as much as possible and to overcome orthopedic and urinary complications as they reach adulthood. It is of great importance to follow the neurodevelopment of patients and to support them with appropriate methods when needed in terms of their neurological prognosis. However, unfortunately, the literature contains very few studies evaluating the neurodevelopmental outcomes of cases with MMC and investigating the factors that may positively affect these results.The current study aims to determine the demographic data of term newborns who were operated in the postnatal period with the diagnosis of MMC in the neonatal intensive care unit of our hospital and to evaluate the neurodevelopmental results with BSID III.This is a prospective follow-up study. The study protocol was approved by the local committee .The cases included in the study were divided into two groups:Patient group (group 1): The patient group includes term newborn babies who were operated in the postnatal period with the diagnosis of MMC in the neonatal intensive care unit of our hospital between January 2018 and December 2019.Control group (group 2): The control group includes healthy term newborn babies who applied to the pediatric outpatient clinics for different reasons.Criteria for exclusion from the study:Premature cases (week of gestation <37 weeks), cases with multiple organ anomalies, cases diagnosed with metabolic disease or hypoxic ischemic encephalopathy, and with low birth weight according to gestational week or with intracranial bleeding were excluded from the study.Demographic information and clinical characteristics of the patients in the patient and control groups were compiled retrospectively from their hospital records.Neurodevelopmental evaluations including cognitive, language, motor, social-sensory and adaptation behaviors of both the patients in the patient group and the control group were performed by a certified child development specialist with the BSID III at 12–18 months.In this study, all data were analyzed with the SPSS 20.0 program. Numerical data were expressed as arithmetic mean ± standard deviation (min-max) or median, and categorical data were expressed as numbers and percentages, depending on whether they showed parametric properties or not. Student-t, Mann-Whitney U and chi-square tests were used to compare two independent groups. A p value of <0.05 was considered statistically significant.A total of 57 cases, 27 in the patient group and 30 in the control group, were included in the study. Demographic information of both groups is shown in When the mothers of the cases in Group 1 were evaluated in terms of neural tube defect etiology, it was seen that there were no mothers who were exposed to the drug or another teratogen, except for two mothers who used valproic acid due to epilepsy and were learned that they did not take folic acid supplementation during their pregnancies. Mothers of the cases in group 2 did not have radiation, hyperthermia, and drug exposure during pregnancy.It was seen that 81% of the cases in group 1 had a prenatal diagnosis and three of them had NTD individuals in their families. The other cases in this group had no prenatal diagnosis.Distribution of cases according to MMC localization and accompanying anomalies is shown in Epilepsy developed in 3 (11.1%) of the patients in grup 1 during the follow-up and antiepileptic treatment was started.It was seen that 55% of the cases in group 1 were operated within the postnatal 72 h and the patients were operated on the mean postnatal 4th ± 3.54 day (1–13 days).It was determined that ventriculoperitoneal (V/P) shunt was placed in thirteen of the cases in group 1, shunt revision was required in four cases, and shunt infection developed in three of the cases that underwent shunt revision. Ventriculitis was not observed in any patient. While the cases in group 1 were followed up in the neonatal intensive care unit, clinical sepsis developed in nine, proven sepsis in four, and meningitis in one.Bayley Scales of Infant and Toddler Development-Third Edition test application age was 16.07 ± 5.53 months in group 1 and 17.4 ± 4.43 months in the control group. The two groups were found to be similar in terms of test administration time (p = 0.326).In the study, the cases in group 1 were divided into two subgroups as cases with V/P shunts (group 1a) and cases without (group 1b) to determine the factors that negatively affect their neurodevelopment. While the number of cases was 13 in group 1a, it was 14 in group 1b.The distribution of Bayley cognitive scale score, Bayley language scale score, Bayley motor scale score and Bayley composite score of the cases in groups 1a and 1b are shown in The Bayley cognitive composite score (p = 0.004) and Bayley total language composite score were found to be lower in the subjects in group 1a compared to the subjects in group 1b (p = 0.001). Bayley motor composite score was found to be lower in the cases in group 1a compared to the cases in group 1b (p < 0.001).In addition, the cases in group 1 were divided into two subgroups as those who had surgery before the postnatal 72 h and those who did not. When both groups were evaluated with BSID III, the cognitive, language and motor composite scores of the patients who had surgery before the postnatal 72 h were better than those who had surgery after 72 h, but there was no statistically significant difference between them (p > 0.05).Myelomeningocele is a common congenital malformation that occurs in the first month of embryological life and often causes permanent deformities throughout life. Despite the improvement of antenatal diagnosis possibilities and the increasing effectiveness of folic acid as a preventive factor, MMC continues to be an important health problem in our country and in the world ,7.There is not yet a consensus in the literature about how the delivery method of myelomeningocele cases should be. In some studies in the literature, it is accepted that delivery by normal spontaneous vaginal route causes spinal cord injury and poses a risk factor for a poor neurological condition, while other studies report that the mode of delivery does not affect the neurological prognosis . In the It has been reported that the management of the delivery room of babies with neural tube defects is important for the neurological prognosis of the cases. Especially, cases with MMC who do not have an intact skin tissue should be laid on their side immediately after birth, care should be taken not to tear the sac, and the defect should be covered with gauze moistened with saline . All theIt was thought that correction surgeries to be performed in the prenatal period in myelomeningocele cases would positively affect the neurodevelopmental prognosis. However, in the literature, prematurity is seen more frequently in MMC cases who were operated on prenatally, but neurodevelopmental damage is reported to be similar when compared with cases operated postnatally . All of In the literature, it has been reported that cases with MMC have a high risk of cognitive dysfunction, which becomes especially evident with increasing age. Studies show that verbal and performance IQ scores and arithmetic and reading skills of children with MMC are lower than those of children without MMC –13. HoweAlthough it has been reported in the past that the presence of hydrocephalus and V/P shunts in patients with MMC cause significantly lower scores in neurodevelopmental and cognitive tests, today, it is accepted that the presence or absence of shunt does not affect neurodevelopmental tests unless there are additional problems such as central nervous system infection or intracranial bleeding –17. In tDue to the high risk of meningitis in myelomeningocele cases, prophylactic antibiotics are recommended in patients until the defect is closed with surgery. When antibiotic prophylaxis was compared in MMC cases, it was reported that the rate of ventriculitis development was higher in those who were not given antibiotics . In the It has been reported that early and aggressive surgical intervention is associated with low morbidity and mortality in cases with myelomeningocele. In a study by Öncel et al., including 30 MMC cases, early surgical intervention (≤5 days), short hospital stay, and antibiotic therapy were associated with a low complication rate . In anotTo the best of our knowledge, there is no study in the literature comparing the effects of early or late surgery on the neurodevelopment of MMC cases in the postnatal period with the BSID III. In the current study, although the cognitive, language and motor composite scores of the patients who underwent surgery before 72 h were better than those who underwent surgery after 72 h, no statistically significant difference was found between them. Due to the small number of cases in our study, we recommend to support our outcomes by studies with a higher number of cases investigating the effect of early/late surgical intervention on neurodevelopmental outcomes.In this study, it was found that the neurodevelopmental prognosis of MMC cases requiring ventriculoperitoneal shunt in the postnatal period was significantly worse than those without shunt. It is the first study in which the neurodevelopment of patients with MMC who were operated in the postnatal period was evaluated with BSID III and delays in all areas were shown in cases with MMC compared to normal cases. Better neurodevelopmental outcomes in patients operated in the first 72 h suggest that early surgery will positively change neurodevelopmental outcomes in patients with MMC.Detection of problems at an early age with early and regular follow-up in MMC cases increases the quality of life in these babies. Close follow-up of these patients with developmental tests and after surgery, evaluation and treatment of the problems positively affect the neurodevelopmental prognosis of these patients.