Search

RNA base editing relies on the introduction of adenosine-to-inosine changes into target RNAs in a highly programmable manner in order to repair disease-causing mutations. Here, we propose that RNA base editing could be broadly applied to perturb protein function by removal of regulatory phosphorylation and acetylation sites. We demonstrate the feasibility on more than 70 sites in various signaling proteins and identify key determinants for high editing efficiency and potent down-stream effects. For the JAK/STAT pathway, we demonstrate both, negative and positive regulation. To achieve high editing efficiency over a broad codon scope, we applied an improved version of the SNAP-ADAR tool. The transient nature of RNA base editing enables the comparably fast (hours to days), dose-dependent (thus partial) and reversible manipulation of regulatory sites, which is a key advantage over DNA (base) editing approaches. In summary, PTM interference might become a valuable field of application of RNA base editing., (© 2024. The Author(s).)

Objective: While there is increasing information regarding the occupational risks to pregnant physicians, there is inconsistent and limited subspecialty data. Physicians may be at increased risk for pregnancy complications due to occupational exposure, long work hours, nightshifts, and physical/mental demands. Additionally, little is known regarding the education physicians receive pertaining to pregnancy risks respective to their specialties as well as departmental/institutional support for pregnancy loss or complication. Therefore, a survey was developed and distributed across multiple academic sites to ascertain if there is an inherent occupation-associated risk of pregnancy complication(s) and/or pregnancy loss for anesthesiologists (ANES) when compared to obstetrician/gynecologists (OB/GYN)., Methods: A specialty-specific survey was distributed electronically to attending ANES and OB/GYN, via departmental listservs at six participating academic medical centers. Responses were collected from March to October 2022 and included demographic information, practice characteristics, education about pregnancy risks and details of pregnancy complications and loss. The primary comparison between specialty groups was the occurrence of at least one pregnancy complication and/or loss. Logistic regression was used to evaluate specialty outcome associations. Additionally, complication rates and types between specialties were compared using univariate and multivariable models., Results: The survey was distributed to 556 anesthesiology and 662 obstetrics-gynecology faculty members with 224 ANES and 168 OB/GYN respondents, yielding an overall 32.2% response rate. Of the survey respondents, 103 ANES and 116 OB/GYN reported at least one pregnancy. Demographics were similar between the two cohorts. ANES had higher gravidity and parity relative to OB/GYN and tended to be earlier in their career at first pregnancy ( p  = .008, <.001, and .043, respectively). The rate of any pregnancy complication, including loss, was similar between specialties (65.1% (67/103) vs. 65.5% (76/116), p  = .942). Of the respondents reporting at least one pregnancy, 56.7% of ANES and 53.9% of OB/GYN experienced a complication while at work. Obstetrician-gynecologists had higher use of reproductive assistance (28% (47/116) vs. 11% (20/103), p  < .001). There were no notable differences between cohorts for complications, prematurity, and neonatal intensive care admission. Forty-one percent (161/392) of total respondents recalled learning about occupational risks to pregnancy, and ANES were more likely than OB/GYN to have recalled learning about these risks (121/224 (54%) and 40/168 (23.8%), respectively, p  < .001)., Conclusions: ANES and OB/GYN had similar risks for pregnancy complications and loss. Anesthesiologists were more likely to recall receiving education regarding occupational risk to pregnancy, though fewer than half of all survey respondents recalled learning about these risks. Our survey results are similar to the previously identified higher rate of pregnancy complications and loss in female physicians while uncovering areas of potential knowledge gaps for which institutions and practices could strive to improve upon. More research is needed to examine the relationship between occupation and pregnancy risk pertaining to female physicians with the goal being to identify modifiable risk factors.

Background: Placenta accreta spectrum (PAS) is a disorder of abnormal placentation associated with severe postpartum hemorrhage, maternal morbidity, and mortality. Predelivery prediction of this condition is important to determine appropriate delivery location and multidisciplinary planning for operative management. This study aimed to validate a prediction model for PAS developed by Weiniger et al in 2 cohorts who delivered at 2 different United States tertiary centers., Methods: Cohort A (Brigham and Women's Hospital; N = 253) included patients with risk factors (prior cesarean delivery and placenta previa) and/or ultrasound features of PAS presenting to a tertiary-care hospital. Cohort B (Columbia University Irving Medical Center; N = 99) consisted of patients referred to a tertiary-care hospital specifically because of ultrasound features of PAS. Using the outcome variable of surgical and/or pathological diagnosis of PAS, discrimination (via c-statistic), calibration (via intercept, slope, and flexible calibration curve), and clinical usefulness (via decision curve analysis) were determined., Results: The model c-statistics in cohorts A and B were 0.728 (95% confidence interval [CI], 0.662-0.794) and 0.866 (95% CI, 0.754-0.977) signifying acceptable and excellent discrimination, respectively. The calibration intercept (0.537 [95% CI, 0.154-0.980] for cohort A and 3.001 [95% CI, 1.899- 4.335] for B), slopes (0.342 [95% CI, 0.170-0.532] for cohort A and 0.604 [95% CI, -0.166 to 1.221] for B), and flexible calibration curves in each cohort indicated that the model underestimated true PAS risks on average and that there was evidence of overfitting in both validation cohorts. The use of the model compared to a treat-all strategy by decision curve analysis showed a greater net benefit of the model at a threshold probability of >0.25 in cohort A. However, no net benefit of the model over the treat-all strategy was seen in cohort B at any threshold probability., Conclusions: The performance of the Weiniger model is variable based on the case-mix of the population with regard to PAS clinical risk factors and ultrasound features, highlighting the importance of spectrum bias when applying this PAS prediction model to distinct populations. The model showed benefit for predicting PAS in populations with substantial case-mix heterogeneity at threshold probability of >25%., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2022 International Anesthesia Research Society.)

Autoimmune gastritis is characterized by inflammation of the gastric mucosa due to autoimmune dysregulation. Upper gastrointestinal symptoms associated with autoimmune gastritis can significantly impact an individual's quality of life and require effective management strategies. This review article provides a comprehensive overview of the current understanding of upper gastrointestinal symptom management in autoimmune gastritis, aiming to consolidate existing knowledge, identify gaps, and offer insights for future research and clinical practice. The review begins by discussing the background and significance of autoimmune gastritis, highlighting its prevalence and the impact of upper gastrointestinal symptoms on affected individuals. The pathophysiology and clinical presentation of autoimmune gastritis-related upper gastrointestinal symptoms are explored, emphasizing the need for accurate diagnosis and targeted management approaches. Diagnostic approaches, including diagnostic criteria, endoscopy, histology, and biomarkers, are critically examined, along with the challenges and limitations associated with diagnosing autoimmune gastritis. The review then delves into the pharmacological approaches for symptom relief, such as proton pump inhibitors (PPIs) and H2 receptor antagonists. It explores the role of dietary modifications and lifestyle changes in symptom control. The article further discusses recent advancements in pharmacological interventions, novel therapeutic approaches, and the potential benefits of complementary and alternative medicine in symptom management. The concept of patient-centered approaches and personalized management strategies is emphasized, highlighting the importance of considering individual patient characteristics, treatment goals, and preferences. Recommendations for future research and clinical management are provided, including exploring emerging therapeutic targets, precision medicine approaches, and collaboration among researchers, clinicians, and patient advocacy groups. The review concludes by emphasizing the significance of implementing the findings and recommendations in clinical practice to enhance patient care and improve the quality of life for individuals with autoimmune gastritis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Singh et al.)

Drought stress affects growth and productivity significantly in chickpea. An integrated multi-omics analysis can provide a better molecular-level understanding of drought stress tolerance. In the present study, comparative transcriptome, proteome and metabolome analyses of two chickpea genotypes with contrasting responses to drought stress, ICC 4958 (drought-tolerant, DT) and ICC 1882 (drought-sensitive, DS), was performed to gain insights into the molecular mechanisms underlying drought stress response/tolerance. Pathway enrichment analysis of differentially abundant transcripts and proteins suggested the involvement of glycolysis/gluconeogenesis, galactose metabolism, and starch and sucrose metabolism in the DT genotype. An integrated multi-omics analysis of transcriptome, proteome and metabolome data revealed co-expressed genes, proteins and metabolites involved in phosphatidylinositol signaling, glutathione metabolism and glycolysis/gluconeogenesis pathways, specifically in the DT genotype under drought. These stress-responsive pathways were coordinately regulated by the differentially abundant transcripts, proteins and metabolites to circumvent the drought stress response/tolerance in the DT genotype. The QTL-hotspot associated genes, proteins and transcription factors may further contribute to improved drought tolerance in the DT genotype. Altogether, the multi-omics approach provided an in-depth understanding of stress-responsive pathways and candidate genes involved in drought tolerance in chickpea., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Singh, Gupta, Singh, Jain and Garg.)

Background: While flexible epidural catheters reduce the risk of paresthesia and intravascular cannulation, they may be more challenging to advance beyond the tip of a Tuohy needle. This may increase placement time, number of attempts, and possibly complications when establishing labor analgesia. This study investigated the ability to advance flexible epidural catheters through different epidural needles from 2 commonly used, commercially available, epidural kits., Methods: We hypothesized that the multiorifice wire-reinforced polyamide nylon blend epidural catheters will have a higher rate of successful first attempt insertion than the single-end hole wire-reinforced polyurethane catheters for the establishment of labor analgesia. The primary outcome was a difference in proportions of failure to advance the epidural catheter between the 2 epidural kits and was tested by a χ2 test. Two-hundred forty epidural kits were collected (n = 120/group) for 240 laboring patients requesting epidural analgesia in this open-label clinical trial from November 2018 to September 2019. Two-week time intervals were randomized for the exclusive use of 1 of the 2 kits in this study, where all patients received labor analgesia through either the flexible epidural catheter "A" or the flexible epidural catheter "B." Engineering properties of the equipment used were then determined., Results: Flexible epidural catheter "A," the single-end hole wire-reinforced polyurethane catheter, did not advance at the first attempt in 15% (n = 18 of 120) of the parturients compared to 0.8% (n = 1 of 120) of the catheter "B," the multiorifice wire-reinforced polyamide nylon blend epidural catheter (P < .0001). Twenty-five additional epidural needle manipulations were recorded in the laboring patients who received catheter "A," while 1 epidural needle manipulation was recorded in the parturients who received catheter "B" (P < .0001). Bending stiffness of the epidural catheters used from kit "B" was twice the bending stiffness of the catheters used from kit "A" (bending stiffness catheters "A" 0.64 ± 0.04 N·mm2 versus bending stiffness catheters "B" 1.28 ± 0.20 N·mm2, P = .0038), and the angle formed by the needle and the epidural catheter from kit "A" was less acute than the angle formed from kit "B" (kit "A" 14.17 ± 1.72° versus kit "B" 21.83 ± 1.33°, P = .0036), with a mean difference of 7.66° between the 2 kits' angles., Conclusions: The incidence of an inability to advance single-end hole wire-reinforced polyurethane catheter was higher compared to the use of multiorifice wire-reinforced polyamide nylon blend epidural catheter. Variation of morphological features of epidural needles and catheters may play a critical role in determining the successful establishment of labor epidural analgesia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Sugammadex, given its high affinity for amino-steroid neuromuscular blockers, offers rapid and reliable neuromuscular blockade reversal, making it a popular reversal agent. This characteristic can be very useful in pregnant women, where incomplete reversal can have poor maternal and fetal outcomes. However, its use antenatally in pregnancy is controversial given concerns for progesterone binding, a hormone that is crucial for maintenance of pregnancy. This case series presents obstetric and fetal outcomes in 25 pregnant women who received sugammadex during the antenatal period, thus highlighting the need for further research into the safety of sugammadex during pregnancy., Competing Interests: Conflicts of Interest: None., (Copyright © 2021 International Anesthesia Research Society.)

Background: The risk for transient tachypnea of newborns, a common cause of respiratory distress in the neonatal period, is 2- to 6-fold higher during elective cesarean delivery compared to vaginal delivery. Here, we evaluated the association between transient tachypnea of newborns and the degree and duration of predelivery maternal hypotension during spinal anesthesia for elective cesarean delivery., Methods: Demographic data, details of anesthetic management, blood pressure measurements, and vasopressor requirement preceding delivery were compared between transient tachypnea newborns (n = 30) and healthy neonates (n = 151) with normal respiratory function born via elective cesarean delivery between July 2015 and February 2016. The degree and duration of hypotension were assessed using area under the curve for systolic blood pressure (SBP) ≤90 mm Hg and area under the curve for mean arterial pressure ≤65 mm Hg. After adjusting for confounders, multivariable logistic regression was used to evaluate the association between area under the curve for SBP and transient tachypnea of newborns., Results: The median area under the curve for SBP was higher in cases of transient tachypnea of newborns (0.94; interquartile range, 0-28.7 mm Hg*min) compared to healthy controls (0; interquartile range, 0-3.30 mm Hg*min; P = .001). Similarly, median area under the curve for mean arterial pressure was also higher in cases of transient tachypnea of newborns (0; interquartile range, 0-18.6 mm Hg*min) compared to controls (0; interquartile range, 0-1.1 mm Hg*min; P = .01). Mothers of transient tachypnea newborns received significantly higher amounts of phenylephrine and ephedrine compared to controls (P = .001 and 0.01, respectively). Hence, the total vasopressor dose given to mothers in the transient tachypnea of newborn group was much higher than for the control group (P = .001). In the multivariable logistic regression, area under the curve for SBP was significantly associated with transient tachypnea of newborns (odds ratio, 1.02; 95% CI, 1.01-1.04, P = .005) after adjusting for gravidity and the type of anesthetic (spinal versus combined spinal epidural)., Conclusions: Our results suggest that the degree and duration of maternal SBP <90 mm Hg after neuraxial anesthesia during elective cesarean delivery are associated with transient tachypnea of newborns. Future prospective studies should further explore the effects of maternal hypotension, its prevention, and treatment for transient tachypnea of newborns.