Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Evolution of Fetal Growth in Symptomatic Sars-Cov-2 Pregnancies.

INTRODUCTION: SARS-CoV-2 is a viral disease with potentially devastating effects. Observational studies of pregnant women infected with SARS-CoV-2 report an increased risk for FGR. This study utilizes data from a prospective SARS-CoV-2 registry in pregnancy, investigating the progression of fetuses to fetal growth restriction (FGR) at birth following maternal SARS-CoV-2 and evaluating the hypothesis of whether the percentage of SGA at birth is increased after maternal SARS-CoV-2 taking into account the time interval between infection and birth. MATERIALS & METHODS: CRONOS is a prospective German registry enrolling pregnant women with confirmed SARS-CoV-2 infection during their pregnancy. SARS-CoV-2 symptoms, pregnancy- and delivery-specific information were recorded. The data evaluated in this study range from March 2020 until August 2021. Women with SARS-CoV-2 were divided into three groups according to the time of infection/symptoms to delivery: Group I<2 weeks, Group II 2-4 weeks, and Group III>4 weeks. FGR was defined as estimated and/or birth weight<10% ile, appropriate for gestational age (AGA) was within 10 and 90%ile, and large for gestational age (LGA) was defined as fetal or neonatal weight>90%ile. RESULTS: Data for a total of 2,650 SARS-CoV-2-positive pregnant women were available. The analysis was restricted to symptomatic cases that delivered after 24+0 weeks of gestation. Excluding those cases with missing values for estimated fetal weight at time of infection and/or birth weight centile, 900 datasets remained for analyses. Group I consisted of 551 women, Group II of 112 women, and Group III of 237 women. The percentage of changes from AGA to FGR did not differ between groups. However, there was a significantly higher rate of large for gestational age (LGA) newborns at the time of birth compared to the time of SARS-CoV-2 infection in Group III (p=0.0024), respectively. CONCLUSION: FGR rates did not differ between symptomatic COVID infections occurring within 2 weeks and>4 weeks before birth. On the contrary, it presented a significant increase in LGA pregnancies in Group III. However, in this study population, an increase in the percentage of LGA may be attributed to pandemic measures and a reduction in daily activity.

Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

Introduction: Studies have shown that pregnant women with COVID-19 have a higher risk of intensive care unit admission and invasive mechanical ventilation support than non-pregnant women. Pregnancy-associated physiological changes in respiratory function may contribute to the elevated risk. Alteration in lung volumes and capacities are attributed to the mechanical impediment caused by the growing fetus. Multiple pregnancies may therefore compromise functional lung capacity earlier than singleton pregnancies and contribute to severe respiratory symptoms of COVID-19. Materials and Methods: A total of 5514 women with a symptomatic SARS-CoV-2 infection during pregnancy registered in the COVID-19 Related Obstetric and Neonatal Outcome Study were included. The COVID-19-related adverse maternal outcomes were compared in 165 multiple versus 5349 singleton pregnancies. Combined adverse maternal outcome was defined as presence of COVID-19-related hospitalization and/or pneumonia and/or oxygen administration and/or transfer to ICU and/or death. Multivariate logistic regression was used to estimate the odds ratios and 95% confidence intervals were calculated. Results: The frequency of dyspnea, likelihood of developing dyspnea in a defined pregnancy week and duration of the symptomatic phase of the COVID-19 infection did not differ between the two groups. On average, COVID-19-related combined adverse outcome occurred earlier during pregnancy in women expecting more than one child than in singleton pregnancies. The overall incidence of singular and combined COVID-19-associated adverse maternal outcomes was not significantly different between groups. However, regression analysis revealed that multiple gestation, preconceptional BMI > 30 kg/m 2 and gestational age correlated significantly with an increased risk of combined adverse maternal outcome. Conversely, maternal age and medically assisted reproduction were not significant risk factors for combined adverse maternal outcome. Conclusion: Our data show that multiple gestation alone is a risk factor for COVID-19-associated combined adverse maternal outcome. Moreover, severe courses of COVID-19 in women expecting more than one child are observed earlier in pregnancy than in singleton pregnancies.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Correction: Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

[This corrects the article DOI: 10.1055/a-2196-6224.].

Impact of metabolic stress induced by diets, aging and fasting on tissue oxygen consumption.

OBJECTIVE: Alterations in mitochondrial function play an important role in the development of various diseases, such as obesity, insulin resistance, steatohepatitis, atherosclerosis and cancer. However, accurate assessment of mitochondrial respiration ex vivo is limited and remains highly challenging. Using our novel method, we measured mitochondrial oxygen consumption (OCR) and extracellular acidification rate (ECAR) of metabolically relevant tissues ex vivo to investigate the impact of different metabolic stressors on mitochondrial function. METHODS: Comparative analyses of OCR and ECAR were performed in tissue biopsies of young mice fed 12 weeks standard-control (STD), high-fat (HFD), high-sucrose (HSD), or western diet (WD), matured mice with HFD, and 2year-old mice aged on STD with and without fasting. RESULTS: While diets had only marginal effects on mitochondrial respiration, respiratory chain complexes II and IV were reduced in adipose tissue (AT). Moreover, matured HFD-fed mice showed a decreased hepatic metabolic flexibility and prolonged aging increased OCR in brown AT. Interestingly, fasting boosted pancreatic and hepatic OCR while decreasing weight of those organs. Furthermore, ECAR measurements in AT could indicate its lipolytic capacity. CONCLUSION: Using ex vivo tissue measurements, we could extensively analyze mitochondrial function of liver, AT, pancreas and heart revealing effects of metabolic stress, especially aging.

Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift.

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (BEM) and find that many BEM cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, BEM cells may exit the lymph node to enter distant tissues, while some BEM cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of BEM cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific BEM cells and transport of antigen back to GC may support affinity maturation to antigenic drift.

Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes.

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

Validation of reference genes for whole blood gene expression analysis in cord blood of preterm and full-term neonates and peripheral blood of healthy adults.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, but research efforts in neonatology are complicated due to the unavailability of large volume blood samples. Whole blood assays can be used to overcome this problem by performing both functional and gene expression studies using small amounts of blood. Gene expression studies using RT-qPCR estimate mRNA-levels of target genes normalized to reference genes. The goal of this study was to identify and validate stable reference genes applicable to cord blood samples obtained from developing neonates of different gestational age groups as well as to adult peripheral blood samples. Eight reference gene candidates (ACTB, B2M, GAPDH, GUSB, HPRT, PPIB, RPLP0, RPL13) were analyzed using the three published software algorithms Bestkeeper, GeNorm and NormFinder. RESULTS: A normalization factor consisting of ACTB and PPIB allows for comparative expression analyses of neonatal samples from different gestational age groups. Normalization factors consisting of GAPDH and PPIB or ACTB and GAPDH are suitable when samples from preterm and full-term neonates and adults are compared. However, all candidate reference genes except RPLP0 exhibited significant intergroup gene expression variance and a higher gene expression towards an older age which resulted in a small but statistically significant systematic bias. Systematic analysis of RNA-seq data revealed new reference gene candidates with potentially superior stability. CONCLUSIONS: The current study identified suitable normalization factors and proposed the use of the additional single gene RPLP0 to avoid systematic bias. This combination will enable comparative analyses not only between neonates of different gestational ages, but also between neonates and adults, as it facilitates more detailed investigations of developmental gene expression changes. The use of software algorithms did not prevent unintended systematic bias. This generally highlights the need for careful validation of such results to prevent false interpretation of potential age-dependent changes in gene expression. To identify the most stable reference genes in the future, RNA-seq based global approaches are recommended.

Facilitating Virtual Visitation in Critical Care Units During a Pandemic.

Presence of support persons enhances patient and family satisfaction. The introduction of the coronavirus disease-2019 (COVID-19) pandemic has impacted hospital operations and has reduced visitation. A virtual visitation program was implemented in critical care units to replicate visitation by video chat to ease stress on patients and family members to improve communication.

Critical requirement for BCR, BAFF, and BAFFR in memory B cell survival.

Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR.

Neonatal and young infant sepsis by Group B Streptococci and Escherichia coli: a single-center retrospective analysis in Germany-GBS screening implementation gaps and reduction in antibiotic resistance.

The last nationwide surveillance study on neonatal and young infant sepsis due to Group B Streptococci (GBS) and Escherichia coli in Germany was conducted between 2009 and 2010. The aim of this study is to provide longitudinal epidemiological data on neonatal and young infant sepsis caused by GBS and E. coli to reevaluate existing data and to inform clinical decision-making. Every positive blood culture for GBS and E. coli within the first 90 days of life that occurred at our center from 2008 until 2018 was identified. The epidemiological, clinical, laboratory, and microbiological data of all affected patients were analyzed through retrospective chart review, along with the pathogen's antimicrobial susceptibility results. In total, 106 episodes of neonatal sepsis were described; 31% (n = 33) being caused by GBS and 69% (n = 73) by E. coli; 87% of GBS early-onset disease (EOD) cases did not receive intrapartum antibiotic prophylaxis (IAP). Contrary to general trends, the proportion of resistant E. coli isolates decreased for all tested antibiotics over time. Coincidentally, antenatal antibiotic use beyond IAP during that period decreased significantly in our center.Conclusions: (1) Data at our center suggests at least a regional implementation gap in GBS screening and IAP. (2) The decline in the resistance rate of E. coli for all antimicrobial substances might indicate that the reduction of prenatal antibiotics use is beneficial and that neonatal antibiotic stewardship programs should include pregnant women as well. What is Known: • GBS screening and intrapartum antibiotic prophylaxis led to a 32%-reduction in GBS disease in Germany with a 0.75 (92:122) ratio of early-onset disease to late-onset disease in 2009-2010. • Prenatal antibiotic use might increase the risk of E. coli early-onset disease and antibiotic resistances. What is New: • The GBS early-onset disease rates were twice as high as those of late-onset disease, the ratio was 1.75 (21:12) in 2008-2018 at our institution. This suggests that there are at least regional implementation gaps in the antenatal GBS screening in Germany. • We found a decline in E. coli resistance rates over time for all antimicrobial substances. Reduction in use of prenatal antibiotics might be an explanation.

The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a major human pathogen, causing pneumonia and sepsis. Genetic components strongly influence host responses to pneumococcal infections, but the responsible loci are unknown. We have previously identified a locus on mouse chromosome 7 from a susceptible mouse strain, CBA/Ca, to be crucial for pneumococcal infection. Here we identify a responsible gene, Cd22, which carries a point mutation in the CBA/Ca strain, leading to loss of CD22 on B cells. CBA/Ca mice and gene-targeted CD22-deficient mice on a C57BL/6 background are both similarly susceptible to pneumococcal infection, as shown by bacterial replication in the lungs, high bacteremia and early death. After bacterial infections, CD22-deficient mice had strongly reduced B cell populations in the lung, including GM-CSF producing, IgM secreting innate response activator B cells, which are crucial for protection. This study provides striking evidence that CD22 is crucial for protection during invasive pneumococcal disease.

Collaborative & Proactive Solutions (CPS): A Review of Research Findings in Families, Schools, and Treatment Facilities.

Collaborative & Proactive Solutions (CPS) is a psychosocial treatment model for behaviorally challenging youth, which has been applied in a diverse array of settings, including families, schools, and therapeutic facilities. Numerous studies have documented its effectiveness and examined factors that mediate and moderate the effectiveness of the model. Data have thus far shown that, with regard to behavioral improvements, CPS is at least the equivalent of the standard of care for externalizing youth, Parent Management Training, and that CPS may hold additional benefits as regards parent-child interactions and children's skill enhancement.

Kind discipline: Developing a conceptual model of a promising school discipline approach.

This formative evaluation develops a novel conceptual model for a discipline approach fostering intrinsic motivation and positive relationships in schools. We used concept mapping to elicit and integrate perspectives on kind discipline from teachers, administrators, and other school staff. Three core themes describing kind discipline emerged from 11 identified clusters: (1) proactively developing a positive school climate, (2) responding to conflict with empathy, accountability, and skill, and (3) supporting staff skills in understanding and sharing expectations. We mapped the identified components of kind discipline onto a social ecological model and found that kind discipline encompasses all levels of that model including the individual, relational, environmental/structural, and even community levels. This contrasts with the dominant individual-behavioral discipline approaches that focus on fewer levels and may not lead to sustained student and staff motivation. The findings illustrate the importance of setting and communicating clear expectations and the need for them to be collaboratively developed. Products of the analysis and synthesis reported here are operationalized materials for teachers grounded in a "be kind" culture code for classrooms.

A Non-Gas-Based Cryotherapy System for the Treatment of Cervical Intraepithelial Neoplasia: A Mixed-Methods Approach for Initial Development and Testing.

BACKGROUND: Gas-based cryotherapy is the most widely used treatment strategy for cervical intraepithelial neoplasia (CIN) in low-resource settings, but reliance on gas presents challenges in low- and middle-income countries (LMICs). Our team adapted the original CryoPen Cryosurgical System, a cryotherapy device that does not require compressed gas and is powered by electricity, for use in LMICs. METHODS: A mixed-methods approach was used involving both qualitative and quantitative methods. First, we used a user-centered design approach to identify priority features of the adapted device. U.S.-based and global potential users of the adapted CryoPen participated in discussion groups and a card sorting activity to rank 7 features of the adapted CryoPen: cost, durability, efficacy and safety, maintenance, no need for electricity, patient throughput, and portability. Mean and median rankings, overall rankings, and summary rankings by discussion group were generated. In addition, results of several quantitative tests were analyzed including bench testing to determine tip temperature and heat extraction capabilities; a pathology review of CIN grade 3 cases (N=107) to determine target depth of necrosis needed to achieve high efficacy; and a pilot study (N=5) investigating depth of necrosis achieved with the adapted device to assess efficacy. RESULTS: Discussion groups revealed 4 priority themes for device development in addition to the need to ensure high efficacy and safety and low cost: improved portability, durability, ease of use, and potential for cure. Adaptions to the original CryoPen system included a single-core, single-tip model; rugged carrying case; custom circuit to allow car battery charging; and sterilization by high-level disinfection. In bench testing, there were no significant differences in tip temperature or heat extraction capability between the adapted CryoPen and the standard cryotherapy device. In 80% of the cases in the pilot study, the adapted CryoPen achieved the target depth of necrosis 3.5 mm established in the pathology review. CONCLUSION: The LMIC-adapted CryoPen overcomes barriers to standard gas-based cryotherapy by eliminating dependency on gas, increasing portability, and ensuring consistent freeze temperatures. Further testing and evaluation of the adapted CryoPen will be pursued to assess scalability and potential impact of this device in decreasing the cervical cancer burden in LMICs.

How Does Patient Radiation Exposure Compare With Low-dose O-arm Versus Fluoroscopy for Pedicle Screw Placement in Idiopathic Scoliosis?

BACKGROUND: Intraoperative C-arm fluoroscopy and low-dose O-arm are both reasonable means to assist in screw placement for idiopathic scoliosis surgery. Both using pediatric low-dose O-arm settings and minimizing the number of radiographs during C-arm fluoroscopy guidance decrease patient radiation exposure and its deleterious biological effect that may be associated with cancer risk. We hypothesized that the radiation dose for C-arm-guided fluoroscopy is no less than low-dose O-arm scanning for placement of pedicle screws. METHODS: A multicenter matched-control cohort study of 28 patients in total was conducted. Fourteen patients who underwent O-arm-guided pedicle screw insertion for spinal fusion surgery in 1 institution were matched to another 14 patients who underwent C-arm fluoroscopy guidance in the other institution in terms of the age of surgery, body weight, and number of imaged spine levels. The total effective dose was compared. A low-dose pediatric protocol was used for all O-arm scans with an effective dose of 0.65 mSv per scan. The effective dose of C-arm fluoroscopy was determined using anthropomorphic phantoms that represented the thoracic and lumbar spine in anteroposterior and lateral views, respectively. The clinical outcome and complications of all patients were documented. RESULTS: The mean total effective dose for the O-arm group was approximately 4 times higher than that of the C-arm group (P<0.0001). The effective dose for the C-arm patients had high variability based on fluoroscopy time and did not correlate with the number of imaged spine levels or body weight. The effective dose of 1 low-dose pediatric O-arm scan approximated 85 seconds of the C-arm fluoroscopy time. All patients had satisfactory clinical outcomes without major complications that required returning to the operating room. CONCLUSIONS: Radiation exposure required for O-arm scans can be higher than that required for C-arm fluoroscopy, but it depends on fluoroscopy time. Inclusion of more medical centers and surgeons will better account for the variability of C-arm dose due to distinct patient characteristics, surgeon's preference, and individual institution's protocol. LEVEL OF EVIDENCE: Level III-case-control study.

Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman.

Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225µg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined decreased at all time points and cyproheptadine doses tested. These observations indicate that cyproheptadine treatment can effectively control seizures, improve survival, reduce seizure duration and reduce the number of dying cells in the brain following soman exposure.

Switching to a Pediatric Dose O-Arm Protocol in Spine Surgery Significantly Reduced Patient Radiation Exposure.

BACKGROUND: Intraoperative computed tomography and image-guided navigation improve the accuracy of screw placement. Radiation exposure to the patient remains a primary drawback. The objective of the present study was to compare the total intraoperative radiation dose and assess the resultant image quality for O-arm-assisted pedicle screw insertion, among 3 protocols: default (manufacturer recommended), institutional (reduced dose utilized in our institution), and pediatric (new protocol with lowest dose). METHODS: Thirty-seven consecutive patients under the age of 18 years underwent posterior instrumentation of the spine and underwent an intraoperative O-arm scan. Techniques (kV and mAs) for default and institutional dose settings were manually adjusted based on spinal level and body weight. Pediatric dose techniques were 80 kV/80 mAs with no adjustment for level or weight. The number of scans repeated because of inadequate imaging was assessed, and the mean estimated effective dose between the 3 protocols was compared. RESULTS: Sixty-eight scans were performed in 37 consecutive patients with mean age of 14 years and mean weight of 55 kg. For reference, the effective radiation dose of a chest x-ray is approximately 0.10 mSv. Use of the default protocol resulted in higher mean effective dose per scan of 4.65 mSv, whereas institutional protocol resulted in 2.37 mSv. The pediatric protocol reduced the mean dose to 0.65 mSv. The total effective dose per surgery was: 1.17 mSv (pediatric), 3.83 mSv (institutional), and 12.79 mSv (default) (P<0.0001 each). All scans lead to satisfactory image quality except in 1 patient >100 kg with stainless steel implants. There were no neurological or other implant-related complications. The pediatric protocol resulted in satisfactory image quality with the lowest total radiation dose, only 1/10 of that of the default protocol. CONCLUSIONS: We successfully switched to a pediatric low-dose O-arm protocol in clinical practice, reducing the dose to <1/4 of the mean annual natural background radiation. This may allow use of intraoperative computed tomography and navigation for pedicle screw placement without excessive radiation exposure to young patients. LEVEL OF EVIDENCE: Level III-retrospective comparative study.