The Management of Posttraumatic Stress Disorder and Acute Stress Disorder: Synopsis of the 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

DESCRIPTION: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article summarizes the 2023 clinical practice guideline (CPG) and its development process, focusing on assessments and treatments for which evidence was sufficient to support a recommendation for or against. METHODS: Subject experts from both departments developed 12 key questions and reviewed the published literature after a systematic search using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) method. The evidence was then evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Recommendations were made after consensus was reached; they were based on quality and strength of evidence and informed by other factors, including feasibility and patient perspectives. Once the draft was peer reviewed by an external group of experts and their inputs were incorporated, the final document was completed. RECOMMENDATIONS: The revised CPG includes 34 recommendations in the following 5 topic areas: assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of posttraumatic stress disorder (PTSD) with co-occurring conditions. Six recommendations on PTSD treatment were rated as strong. The CPG recommends use of specific manualized psychotherapies over pharmacotherapy; prolonged exposure, cognitive processing therapy, or eye movement desensitization and reprocessing psychotherapy; paroxetine, sertraline, or venlafaxine; and secure video teleconferencing to deliver recommended psychotherapy when that therapy has been validated for use with video teleconferencing or when other options are unavailable. The CPG also recommends against use of benzodiazepines, cannabis, or cannabis-derived products. Providers are encouraged to use this guideline to support evidence-based, patient-centered care and shared decision making to optimize individuals' health outcomes and quality of life.

Maternal Morbidity According to Mode of Delivery Among Pregnant Patients With Pulmonary Hypertension.

BACKGROUND: Patients with pulmonary hypertension have a high risk of maternal morbidity and mortality. It is unknown if a trial of labor carries a lower risk of morbidity in these patients compared to a planned cesarean delivery. The objective of this study was to examine the association of delivery mode with severe maternal morbidity events during delivery hospitalization among patients with pulmonary hypertension. METHODS: This retrospective cohort study used the Premier inpatient administrative database. Patients delivering ≥25 weeks gestation from January 1, 2016, to September 30, 2020, and with pulmonary hypertension were included. The primary analysis compared intended vaginal delivery (ie, trial of labor) to intended cesarean delivery (intention to treat analysis). A sensitivity analysis was conducted comparing vaginal delivery to cesarean delivery (as treated analysis). The primary outcome was nontransfusion severe maternal morbidity during the delivery hospitalization. Secondary outcomes included blood transfusion (4 or more units) and readmission to the delivery hospital within 90 days from discharge from delivery hospitalization. RESULTS: The cohort consisted of 727 deliveries. In the primary analysis, there was no difference in nontransfusion morbidity between intended vaginal delivery and intended cesarean delivery groups (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], 0.49-1.15). In secondary analyses, intended cesarean delivery was not associated with blood transfusion (aOR, 0.71; 95% CI, 0.34-1.50) or readmission within 90 days (aOR, 0.60; 95% CI, 0.32-1.14). In the sensitivity analysis, cesarean delivery was associated with a 3-fold higher risk of nontransfusion morbidity compared to vaginal delivery (aOR, 2.64; 95% CI, 1.54-3.93), a 3-fold higher risk of blood transfusion (aOR, 3.06; 95% CI, 1.17-7.99), and a 2-fold higher risk of readmission within 90 days (aOR, 2.20; 95% CI, 1.09-4.46) compared to vaginal delivery. CONCLUSIONS: Among pregnant patients with pulmonary hypertension, a trial of labor was not associated with a higher risk of morbidity compared to an intended cesarean delivery. One-third of patients who required an intrapartum cesarean delivery had a morbidity event, demonstrating the increased risk of adverse events in this group.

Postoperative analgesic consumption for primary versus first repeat Cesarean delivery: a historical cohort study.

PURPOSE: It is unclear if postoperative pain experience and opioid consumption differ in patients undergoing primary vs repeat Cesarean delivery (CD) as prior studies have yielded conflicting results and none used the same patients as their own controls. We sought to compare opioid consumption and pain scores in patients undergoing both a primary and a first repeat CD, using the same patients as their own controls. METHODS: We conducted a single-centre historical cohort study of patients who underwent both a primary and a first repeat CD under neuraxial anesthesia between 1 January 2016 and 30 November 2022. The same standardized multimodal analgesic regimen was used for all patients. The primary outcome was opioid consumption in oral morphine equivalents (OME) at 48 hr after surgery. Secondary outcomes included area under the curve for pain scores at 24 and 48 hr, and opioid consumption at 24 hr. RESULTS: We included 409 patients. In unadjusted analysis, there were no significant differences between primary and repeat CD in median [interquartile range] opioid consumption at 48 hr (45 [15-89] mg vs 45 [15-83] mg OME) or in any of the secondary outcomes. In the multivariable model adjusting for age, body mass index, anxiety, depression, priority, surgery duration, gestational age, receipt of postoperative ketorolac, and neuraxial type, repeat CD was still not associated with increased opioid consumption compared with primary CD (adjusted rate ratio, 1.20; 95% confidence interval, 0.95 to 1.51). CONCLUSION: In this retrospective study, we found no differences in postoperative opioid consumption or reported pain scores in patients who underwent both a primary and a first repeat CD.

RéSUMé: OBJECTIF: Nous ne savons pas si l'expérience de la douleur postopératoire et la consommation d'opioïdes diffèrent chez la patientèle accouchant par césarienne pour la première fois ou pour la seconde fois. En effet, les études antérieures ont donné des résultats contradictoires et aucune n'a utilisé la même patientèle comme témoins. Nous avons cherché à comparer la consommation d'opioïdes et les scores de douleur chez les personnes parturientes exposées à la fois à un premier puis un deuxième accouchement par césarienne en recrutant les mêmes personnes en tant que leurs propres témoins. MéTHODE: Nous avons mené une étude de cohorte historique monocentrique auprès de personnes parturientes ayant subi à la fois une première et une seconde césarienne sous anesthésie neuraxiale entre le 1er janvier 2016 et le 30 novembre 2022. Le même régime analgésique multimodal standardisé a été utilisé pour toutes les personnes dans l'étude. Le critère d'évaluation principal était la consommation d'opioïdes en équivalents morphine oraux (EMO) 48 heures après la chirurgie. Les critères d'évaluation secondaires comprenaient la surface sous la courbe pour les scores de douleur à 24 et 48 heures, et la consommation d'opioïdes à 24 heures. RéSULTATS: Nous avons inclus 409 personnes. Dans l'analyse non ajustée, il n'y avait pas de différence significative entre le premier et le deuxième accouchement par césarienne en ce qui concerne la consommation médiane d'opioïdes [écart interquartile] à 48 heures (45 [15 à 89] mg vs 45 [15­83] mg EMO) ou dans l'un des critères d'évaluation secondaires. Dans le modèle multivarié ajusté en fonction de l'âge, l'indice de masse corporelle, l'anxiété, la dépression, la priorité, la durée de la chirurgie, l'âge gestationnel, l'administration de kétorolac postopératoire et le type d'anesthésie neuraxiale, une deuxième césarienne n'était toujours pas associée à une consommation accrue d'opioïdes par rapport à une première césarienne (rapport de taux ajusté, 1,20; intervalle de confiance à 95 %, 0,95 à 1,51). CONCLUSION: Dans cette étude rétrospective, nous n'avons trouvé aucune différence dans la consommation d'opioïdes postopératoires ou les scores de douleur rapportés chez la patientèle ayant accouché par césarienne pour la première ou pour la deuxième fois.

The 90% effective dose of intrathecal hyperbaric bupivacaine for Cesarean delivery under combined spinal-epidural anesthesia in parturients with super obesity: an up-down sequential allocation study.

PURPOSE: To determine the 90% effective dose (ED90) of intrathecal hyperbaric bupivacaine for Cesarean delivery under combined spinal-epidural anesthesia (CSE) in parturients with super obesity (body mass index [BMI] ≥ 50 kg·m-2). METHODS: We enrolled parturients with BMI ≥ 50 kg·m-2 with term, singleton vertex pregnancies undergoing elective Cesarean delivery under CSE. An independent statistician generated the 0.75% hyperbaric bupivacaine dosing regimen in increments of 0.75 mg using a biased-coin up-down sequential allocation technique. This was combined with 15 µg fentanyl, 150 µg morphine, and normal saline to a volume of 2.05 mL. The initial and maximum doses were 9.75 mg and 12 mg, respectively. Participants, clinical team, and outcome assessors were blinded to the dose. The primary outcome was block success, defined as T6 block to pinprick within ten minutes and no intraoperative analgesic supplementation within 90 min of spinal injection. We determined the ED90 using logistic regression. RESULTS: We enrolled 45 parturients and included 42 in the analysis. All doses achieved a T6 level within ten minutes, and the primary outcome occurred in 0/1 (0%) of the 9.75-mg doses, 2/3 (67%) of the 10.5-mg doses, 21/27 (78%) of the 11.25-mg doses, and 11/11 (100%) of the 12-mg doses. The ED90 of hyperbaric bupivacaine was 11.56 mg (95% confidence interval, 11.16 to 11.99). Four parturients (9.5%) had sensory level higher than T2, but none was symptomatic or required general anesthesia. CONCLUSION: The estimated ED90 of hyperbaric bupivacaine with fentanyl and morphine in parturients with super obesity undergoing Cesarean delivery under CSE was approximately 11.5 mg. STUDY REGISTRATION: ClinicalTrials.gov (NCT03781388); first submitted 18 December 2018.

RéSUMé: OBJECTIF: Notre objectif était de déterminer la dose efficace à 90 % (DE90) de bupivacaïne hyperbare intrathécale pour l'accouchement par césarienne sous péri-rachianesthésie combinée (PRC) chez les personnes parturientes atteintes de super obésité (indice de masse corporelle [IMC] ≥ 50 kg·m−2). MéTHODE: Nous avons recruté des personnes parturientes ayant un IMC ≥ 50 kg·m−2 présentant des grossesses uniques à terme, en présentation céphalique et bénéficiant d'un accouchement par césarienne programmée sous PRC. Un·e statisticien·ne indépendant·e a généré le schéma posologique de bupivacaïne hyperbare à 0,75 % par incréments de 0,75 mg à l'aide d'une technique d'allocation séquentielle en escalier. La bupivacaïne a été combinée à 15 µg de fentanyl, 150 µg de morphine et à une solution physiologique salée jusqu'à un volume de 2,05 mL. Les doses initiale et maximale étaient respectivement de 9,75 mg et 12 mg. Les participant·es, l'équipe clinique et les personnes évaluant les résultats n'avaient pas connaissance de la dose. Le critère d'évaluation principal était la réussite du bloc, définie comme un bloc à T6 à la piqûre dans les dix minutes et aucune supplémentation analgésique peropératoire dans les 90 minutes suivant l'injection rachidienne. Nous avons déterminé la DE90 à l'aide d'une méthode de régression logistique. RéSULTATS: Nous avons recruté 45 personnes parturientes et en avons inclus 42 dans l'analyse. Toutes les doses ont atteint le niveau T6 en dix minutes, et le critère d'évaluation principal a été obtenu pour 0/1 (0 %) des doses de 9,75 mg, 2/3 (67 %) des doses de 10,5 mg, 21/27 (78 %) des doses de 11,25 mg et 11/11 (100 %) des doses de 12 mg. La DE90 de bupivacaïne hyperbare était de 11,56 mg (intervalle de confiance à 95 %, 11,16 à 11,99). Quatre personnes parturientes (9,5 %) ont affiché un niveau sensoriel supérieur à T2, mais aucune n'était symptomatique ni n'a nécessité d'anesthésie générale. CONCLUSION: La DE90 estimée de bupivacaïne hyperbare avec fentanyl et morphine chez les personnes parturientes hyperobèses bénéficiant d'une césarienne sous PRC était d'environ 11,5 mg. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03781388); soumis pour la première fois le 18 décembre 2018.

Trends in the Utilization of Multiorgan Support Among Adults Undergoing High-risk Cardiac Surgery in the United States.

OBJECTIVES: To examine trends in the prevalence of multiorgan dysfunction (MODS), utilization of multi-organ support (MOS), and mortality among patients undergoing cardiac surgery with MODS who received MOS in the United States. DESIGN: Retrospective cohort study. SETTING: 183 hospitals in the Premier Healthcare Database. PARTICIPANTS: Adults ≥18 years old undergoing high-risk elective or non-elective cardiac surgery. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: The exposure was time (consecutive calendar quarters) January 2008 and June 2018. We analyzed hospital data using day-stamped hospital billing codes and diagnosis and procedure codes to assess MODS prevalence, MOS utilization, and mortality. Among 129,102 elective and 136,190 non-elective high-risk cardiac surgical cases across 183 hospitals, 10,001 (7.7%) and 21,556 (15.8%) of patients developed MODS, respectively. Among patients who experienced MODS, 2,181 (22%) of elective and 5,425 (25%) of non-elective cardiac surgical cases utilized MOS. From 2008-2018, MODS increased in both high-risk elective and non-elective cardiac surgical cases. Similarly, MOS increased in both high-risk elective and non-elective cardiac surgical cases. As a component of MOS, mechanical circulatory support (MCS) increased over time. Over the study period, risk-adjusted mortality, in patients who developed MODS receiving MOS, increased in high-risk non-elective cardiac surgery and decreased in high-risk elective cardiac surgery, despite increasing MODS prevalence and MOS utilization (p<0.001). CONCLUSIONS: Among patients undergoing high-risk cardiac surgery in the United States, MODS prevalence and MOS utilization (including MCS) increased over time. Risk-adjusted mortality trends differed in elective and non-elective cardiac surgery. Further research is necessary to optimize outcomes among patients undergoing high-risk cardiac surgery.

Spatial and Temporal Variability in Stream Thermal Regime Drivers for Three River Networks During the Summer Growing Season.

Many cold-water dependent aquatic organisms are experiencing habitat and population declines from increasing water temperatures. Identifying mechanisms which drive local and regional stream thermal regimes facilitates restoration at ecologically relevant scales. Stream temperatures vary spatially and temporally both within and among river basins. We developed a modeling process to identify statistical relationships between drivers of stream temperature and covariates representing landscape, climate, and management-related processes. The modeling process was tested in 3 study areas of the Pacific Northwest USA during the growing season (May [start], August [warmest], September [end]). Across all months and study systems, covariates with the highest relative importance represented the physical landscape (elevation [1st], catchment area [3rd], main channel slope [5th]) and climate covariates (mean monthly air temperature [2nd] and discharge [4th]). Two management covariates (ground water use [6th] and riparian shade [7th]) also had high relative importance. Across the growing season (for all basins) local reach slope had high relative importance in May, but transitioned to a regional main channel slope covariate in August and September. This modeling process identified regionally similar and locally unique relationships among drivers of stream temperature. High relative importance of management-related covariates suggested potential restoration actions for each system.

Postoperative Acute Kidney Injury by Age and Sex: A Retrospective Cohort Association Study.

BACKGROUND: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. METHODS: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. RESULTS: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). CONCLUSIONS: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery.

Opioid-Sparing Multimodal Analgesia Use After Cesarean Delivery Under General Anesthesia: A Retrospective Cohort Study in 729 US Hospitals.

BACKGROUND: Optimizing analgesia after cesarean delivery is essential to quality of patient recovery. The American Society of Anesthesiologists and the Society for Obstetric Anesthesia and Perinatology recommend multimodal analgesia (MMA). However, little is known about clinical implementation of these guidelines after cesarean delivery under general anesthesia (GA). We performed this study to describe the use of MMA after cesarean delivery under GA in the United States and determine factors associated with use of MMA, variation in analgesia practice across hospitals, and trends in MMA use over time. METHODS: A retrospective cohort study of women over 18 years who had a cesarean delivery under GA between 2008 and 2018 was conducted using the Premier Healthcare database (Premier Inc). The primary outcome was utilization of opioid-sparing MMA (osMMA), defined as receipt of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen with or without opioids and without the use of an opioid-combination drug. Any use of either agent within a combination preparation was not considered osMMA. The secondary outcome was use of optimal opioid-sparing MMA (OosMMA), defined as use of a local anesthetic technique such as truncal block or local anesthetic infiltration in addition to osMMA. Mixed-effects logistic regression models were used to examine factors associated with use of osMMA, as well as variation across hospitals. RESULTS: A total of 130,946 patients were included in analysis. osMMA regimens were used in 11,133 patients (8.5%). Use of osMMA increased from 2.0% in 2008 to 18.8% in 2018. Black race (7.9% vs 9.3%; odds ratio [OR] [95% confidence interval {CI}] 0.87 [0.81-0.94]) and Hispanic ethnicity (8.6% vs 10.0%; OR, 0.86 [0.79-0.950]) were associated with less receipt of osMMA compared to White and non-Hispanic counterparts. Medical comorbidities were generally not associated with receipt of osMMA, although patients with preeclampsia were less likely to receive osMMA (9.0%; OR, 0.91 [0.85-0.98]), while those with a history of drug abuse (12.5%; OR, 1.42 [1.27-1.58]) were more likely to receive osMMA. There was moderate interhospital variability in the use of osMMA (intraclass correlation coefficient = 38%). OosMMA was used in 2122 (1.6%) patients, and utilization increased from 0.8% in 2008 to 4.1% in 2018. CONCLUSIONS: Variation in osMMA utilization was observed after cesarean delivery under GA in this cohort of US hospitals. While increasing trends in utilization of osMMA and OosMMA are encouraging, there is need for increased attention to postoperative analgesia practices after GA for cesarean delivery given low percentage of patients receiving osMMA and OosMMA.

Incidence of Postreperfusion Hyperfibrinolysis in Liver Transplantation by Donor Type and Observed Treatment Strategies.

BACKGROUND: Hyperfibrinolysis is a possible complication during liver transplantation, particularly immediately after reperfusion. METHODS: We performed a retrospective study to examine the incidence, treatment, and resolution of postreperfusion hyperfibrinolysis in patients undergoing liver transplantation at Duke University Hospital from 2015 to 2020. RESULTS: Out of 535 patients undergoing liver transplantation, 21 or 3.9%, 95% CI (2.5-5.9), had hyperfibrinolysis after reperfusion. Hyperfibrinolysis occurred in 16 of 511 (3.1%) patients receiving livers from DBD donors, 5 of 18 (27.8%) patients receiving livers from donation after circulatory death (DCD) donors, and 0 of 6 (0.0%) patients receiving livers from living donors. Fibrinolysis was treated with cryoprecipitate (12/21), a combination of cryoprecipitate and tranexamic acid (3/21), or neither (6/21) and resolved within several hours in all cases. CONCLUSIONS: Anesthesiologists should be aware of the possibility of postreperfusion hyperfibrinolysis in liver transplantation, particularly with DCD donors, and may consider treatment with cryoprecipitate or tranexamic acid. Further work is needed to identify any potential differences, such as faster resolution of fibrinolysis, between different treatment modalities.

Maternal Cardiovascular Morbidity Events Following Preeclampsia: A Retrospective Cohort Study.

BACKGROUND: Patients with preeclampsia are at high risk for long-term cardiovascular events, yet the short-term, acute cardiovascular complications that follow preeclampsia are understudied. The objective of this study was to compare the short-term, acute maternal cardiovascular morbidity events after delivery among patients with a diagnosis of preeclampsia versus those without this diagnosis. METHODS: In this retrospective cohort study, the Premier inpatient database was used to examine a cohort of obstetric patients older than 18 years, who delivered from January 1, 2016, to September 30, 2020. A diagnosis of preeclampsia and preeclampsia with severe features during delivery hospitalization were the exposures of interest. The primary outcome was a composite of maternal cardiovascular morbidity events during delivery hospital admission. The secondary outcome was the occurrence of maternal cardiovascular morbidity events during a readmission within 90 days of delivery hospitalization. RESULTS: In total, 4,488,759 patients met inclusion criteria, of which 158,114 (3.5%) were diagnosed with preeclampsia without severe features, and 117,940 (2.6%) with preeclampsia with severe features. Adjusted odds of maternal cardiovascular morbidity events were higher in patients with preeclampsia and in those with preeclampsia with severe features compared with those without preeclampsia during delivery hospitalization (adjusted odds ratio [OR] [95% confidence interval {CI}] 1.87 [1.78-1.97] and 4.74 [4.44-5.05], respectively) and within 90 days (adjusted OR [95% CI] 2.01 [1.83-2.21] and 2.32 [2.10-2.57], respectively). CONCLUSIONS: Patients with both preeclampsia and preeclampsia with severe features have higher rates of maternal cardiovascular morbidity events than those without preeclampsia. Future studies are necessary to examine which patients with preeclampsia are at highest risk for cardiovascular complications.

The Management of Major Depressive Disorder: Synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

DESCRIPTION: In February 2022, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline (CPG) for the management of major depressive disorder (MDD). This synopsis summarizes key recommendations. METHODS: Senior leaders within the VA and the DoD assembled a team to update the 2016 CPG for the management of MDD that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy CPGs. The guideline panel developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and distilled 36 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Select recommendations that were identified by the authors to represent key changes from the prior CPG are presented in this synopsis. RECOMMENDATIONS: The scope of the CPG is diverse; however, this synopsis focuses on key recommendations that the authors identified as important new evidence and changes to prior recommendations on pharmacologic management, pharmacogenomics, psychotherapy, complementary and alternative therapies, and the use of telemedicine.

The NS1 protein of the parvovirus MVM Aids in the localization of the viral genome to cellular sites of DNA damage.

The autonomous parvovirus Minute Virus of Mice (MVM) localizes to cellular DNA damage sites to establish and sustain viral replication centers, which can be visualized by focal deposition of the essential MVM non-structural phosphoprotein NS1. How such foci are established remains unknown. Here, we show that NS1 localized to cellular sites of DNA damage independently of its ability to covalently bind the 5' end of the viral genome, or its consensus DNA binding sequence. Many of these sites were identical to those occupied by virus during infection. However, localization of the MVM genome to DNA damage sites occurred only when wild-type NS1, but not its DNA-binding mutant was expressed. Additionally, wild-type NS1, but not its DNA binding mutant, could localize a heterologous DNA molecule containing the NS1 binding sequence to DNA damage sites. These findings suggest that NS1 may function as a bridging molecule, helping the MVM genome localize to cellular DNA damage sites to facilitate ongoing virus replication.

ED 90 of Intrathecal Chloroprocaine With Fentanyl for Prophylactic Cervical Cerclage: A Sequential Allocation Biased-Coin Design.

BACKGROUND: Chloroprocaine is a short-acting local anesthetic that has been used for spinal anesthesia in outpatient surgery. There is limited experience with spinal chloroprocaine for prophylactic cervical cerclage placement. We sought to determine the effective dose of intrathecal chloroprocaine for 90% of patients (ED90) undergoing prophylactic cervical cerclage placement. We hypothesized that the ED90 of intrathecal chloroprocaine when combined with 10-ug fentanyl would be between 33 and 54 mg. METHODS: In this prospective 2-center double-blinded study, we enrolled women undergoing prophylactic cervical cerclage placement under combined spinal-epidural anesthesia. A predetermined dose of intrathecal 3% chloroprocaine with fentanyl 10 ug was administered. The initial dose was 45-mg intrathecal chloroprocaine. Subsequent dose adjustments were determined based on the response of the previous subject using an up-down sequential allocation with a biased-coin design. A dose was considered effective if at least a T12 block was achieved, and there was no requirement for epidural activation or intraoperative analgesic supplementation during the procedure. The primary outcome was the ED90 of intrathecal chloroprocaine with fentanyl 10 ug. Secondary outcomes included duration of surgery, anesthetic side effects, time to resolution of motor and sensory block, time to achieve recovery room discharge criteria, and patient satisfaction with anesthetic care. Isotonic regression was used to estimate the ED90. RESULTS: Forty-seven patients were enrolled into the study. Two patients were excluded (1 protocol violation and 1 failed block). In total, 45 patients completed the study. The estimated ED90 (95% confidence interval) for intrathecal chloroprocaine combined with fentanyl 10 ug was 49.5 mg (45.0-50.1 mg). The median (interquartile range [IQR]) duration of surgery was 15 (10-24) minutes. Resolution of the motor (Bromage 0) and sensory block took a median time of 60 (45-90) minutes and 90 (75-105) minutes, respectively. The median time to achieve recovery room discharge criteria was 150 (139-186) minutes. Satisfaction with anesthetic management was high in all patients. There were no reports of postdural puncture headache or transient neurological symptoms postoperatively. CONCLUSIONS: The ED90 of intrathecal chloroprocaine combined with fentanyl 10 ug was 49.5 mg. Intrathecal chloroprocaine was associated with rapid block recovery and high patient satisfaction, which makes it well suited for outpatient obstetric procedures.

Andexanet alfa and four-factor prothrombin complex concentrate for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage.

Limited data exists regarding the clinical outcomes of andexanet alfa and four factor prothrombin complex concentrate (4F-PCC) for reversal of apixaban or rivaroxaban in the setting of intracranial hemorrhage (ICH). The objective of this study was to evaluate clinical outcomes of 4F-PCC and andexanet alfa for reversal of ICH associated with oral factor Xa inhibitors. This was a retrospective, single-center, case series evaluating hemostatic efficacy of patients receiving andexanet alfa) or 4F-PCC for reversal of apixaban or rivaroxaban after ICH. Secondary endpoints included in-hospital mortality, thrombotic complications, timing of reversal agents, intensive care unit and hospital length of stay, patient disposition, and 30-day readmission rate. During the study period, 21 patients received andexanet alfa and 35 received 4F-PCC. Hemostatic efficacy occurred in 64.7% of patients receiving andexanet alfa and 54.8% of receiving 4F-PCC. Thirty-day all-cause mortality was 45.2% for 4F-PCC and 30% for andexanet alfa. Thrombotic events were higher with 4F-PCC (31.4%) compared to andexanet alfa (14.3%). Median time from presentation to administration of reversal agent was 2.67 [1.75-4.13] hours with andexanet alfa and 1.73 [1.21-3.55] hours with 4F-PCC. Discharge to skilled nursing facilities and 30-day readmission were similar between groups. In this cohort, reversal with andexanet alfa and 4F-PCC differed in terms ofhemostatic efficacy and thrombotic events after ICH in patients anticoagulated with apixaban or rivaroxaban.

The impact of race on utilization of durable left ventricular assist device therapy in patients with advanced heart failure.

BACKGROUND: Heart failure affects >6 million people in the United States alone and is most prevalent in Black patients who suffer the highest mortality risk. Yet prior studies have suggested that Black patients are less likely to receive advanced heart failure therapy. We hypothesized that Black patients would have decreased rates of durable left ventricular assist device (LVAD) implantation within our expansive heart failure program. METHODS: A retrospective single-center cohort study was conducted at a single high-volume academic medical center. Patients between 18 and 85 years admitted with a diagnosis of cardiogenic shock or congestive heart failure between 1, 2013 and 12, 2017 with a left ventricular ejection fraction < 30% and inotropic dependence or need for mechanical circulatory support were included. Patients with contraindications to durable LVAD were excluded. An adjusted logistic regression model for durable LVAD implantation within 90 days of the index admission was used to determine the effect of race on durable LVAD implantation. RESULTS: Among the 702 study patients (60.9% White, 34.1% Black), durable LVAD implantation was performed within 90 days of the index admission in 183 (26%) of the cohort. After multivariate analysis, Black patients were not found to have a statistically significant difference in durable LVAD implantation rates compared to White patients in our study (OR: 0.68 [95% confidence interval: 0.45-1.04; p: .074]). CONCLUSIONS: Black patients in our study did not have a statistically significant difference in the rate of durable LVAD implantation compared with White patients after adjustments were made for age, sex, socioeconomic, and clinical covariates. Larger prospective studies are needed to validate these findings.

The association between intravenous iron for antenatal anemia and postnatal depression: a retrospective cohort study.

PURPOSE: Determine if intravenous iron for antenatal anemia is associated with reduced incidence of postnatal depression (PND) within 12 months. METHODS: This retrospective cohort study included adult women with antenatal anemia (hemoglobin value of < 11.0 g/dL within 3 months before delivery). PND was defined as Edinburgh Postnatal Depression Scale (EPDS) or Patient Health Questionnaire-9 (PHQ-9) ≥ 10. Data on intravenous iron, lowest hemoglobin concentration, EPDS and PHQ-9 scores, insurance status, history of anxiety, depression, chronic pain, and substance use, obstetric complications, labor analgesia, and mode of delivery were obtained. Standardized mean difference (SMD) was estimated and multivariable logistic regression models were constructed with adjustment for potential confounders with absolute SMD of ≥ 0.1. RESULTS: Data from 3988 women were analyzed. The 368 (9.2%) women who received intravenous iron therapy had lower antenatal hemoglobin levels, were more likely to be African American or single/widowed women, and more commonly had  Medicaid coverage, repeat cesarean delivery, and history of depression compared to those who did not receive intravenous iron therapy. Unadjusted analysis showed women who received intravenous iron had higher incidence of PND (18.5%) than those who did not (13.4%) (p = 0.008). Multivariable analysis showed no significant association between intravenous iron and PND incidence (aOR 1.21, 95%CI 0.89-1.63, p = 0.232), although history of depression (aOR 2.42, 95%CI 1.91-3.08, p < 0.001), higher gravidity (aOR 1.09, 95%CI 1.02-1.17, p = 0.016), and Medicaid insurance (aOR 1.44, 95%CI 1.16-1.80, p = 0.001) were independently associated with PND. CONCLUSION: Intravenous iron for antenatal anemia was not associated with significant change in the incidence of PND.

Riparian vegetation shade restoration and loss effects on recent and future stream temperatures.

River temperatures are expected to increase this century harming species requiring cold-water habitat unless restoration activities protect or improve habitat availability. Local shading by riparian vegetation can cool water temperatures, but uncertainty exists over the scaling of this local effect to larger spatial extents. We evaluate this issue using a regional spatial stream network temperature model with covariates representing shade effects to predict mean August stream temperatures across 78,195 km of tributaries flowing into the Columbia River in the northwestern US. We evaluate nine scenarios predicting stream temperatures for three riparian shade conditions (current, restored, and no riparian vegetation) within three different climate periods (2000s, 2040s, and 2080s). Results suggest riparian shade restoration (2000s climate) could decrease mean August stream temperatures by 0.62°C across the study network. Under the same restored shade conditions, temperature predictions for tributaries at their confluence with the Columbia River range from 0.02-2.08°C cooler than under current shade conditions. The climate warming effect predicted for the 2040s and 2080s, however, is greater than the cooling effect from restoring riparian shade. Streams less than 10m bankfull width cooled more frequently with riparian shade restoration. In Oregon, the proportion of fish habitat for salmon and trout rearing and migration that meet temperature numeric water quality criteria could be increased by 20% under restored shade conditions although net habitat declines may still occur in the future. We conclude riparian vegetation restoration could partially mitigate future warming and help maintain cold-water habitats that function as thermal refuges if implemented strategically.

Revisiting racial disparities in ED CT utilization during the Affordable Care Act era: 2009-2018 data from the NHAMCS.

OBJECTIVE: To examine the trends in CT utilization in the emergency department (ED) for different racial and ethnic groups, factors that may affect utilization, and the effects of increased insurance coverage since passage of the Affordable Care Act in 2010. MATERIALS AND METHODS: Data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) for the years 2009-2018 were used for the analysis. The NHAMCS is a cross-sectional survey which has random and systematical samples of more than 200,000 visits to over 250 hospital EDs in the USA. Patient demographic characteristics, source of payment/insurance, clinical presentation, and disposition from the ED were recorded. Descriptive statistics and multivariate logistic regression were performed. RESULTS: Between 2009 and 2018, the rate of uninsured patients in the ED decreased from 18.1% to as low as 9.9%, but this was not associated with a decrease in the disparity in CT utilization between non-Hispanic Black and non-Hispanic White patients. CT use rate increased 38% over the study period. Factors strongly associated with CT utilization include age, source of payment, triage category, disposition from the ED, and residence. After controlling for these factors, non-Hispanic White patients were 21% more likely to undergo CT than non-Hispanic Black patients, though no disparity was seen for Hispanic or Asian/other groups. CONCLUSION: Despite increased insurance coverage over the sample period, racial disparities between non-Hispanic Black and non-Hispanic White patients persist in CT utilization, though no disparity was seen for Hispanic or Asian/other patients. The source of this disparity remains unclear and is likely multifactorial.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Modulation of red blood cell oxygen affinity with a novel allosteric modifier of hemoglobin is additive to the Bohr effect.

PURPOSE: The Bohr effect describes hemoglobin's affinity for oxygen dependent on solution pH. Within pH range 6.0-8.5, hemoglobin's oxygen affinity decreases with decreasing pH. This results in increased oxygen delivery to metabolically active, acidic tissues and improved oxygen uptake in basic regions including lung tissue. Myo-Inositol tripyrophosphate (ITPP) translocates the erythrocyte membrane and allosterically modifies hemoglobin (Hb). We tested the hypothesis that ITPP does not abrogate the Bohr effect. METHODS: Experiments were conducted to determine the effect of increasing concentrations of ITPP on P50 with varying pH. We incubated 10 mL red blood cells at 37 °C for 1 h with ITPP concentrations from 0 to 240 mM. The Clark oxygen electrode (Hemox-Analyzer; TCS Scientific, New Hope, PA) determined oxygen affinity of each sample, in triplicate, using buffers pH 6.8, 7.4, and 7.6. A mixed linear regression model with fixed effects for ITPP concentration and pH was used. RESULTS: Increasing ITPP concentration and decreasing pH increased P50 (p < 0.0001 for ITPP concentration, p < 0.0001 for pH). ITPP modulated increased P50 in normal pH (7.4) and acidic condition pH (6.8); with no effect at alkaline pH (7.6). CONCLUSION: The Bohr effect is conserved, with ITPP augmenting the decreased oxygen affinity seen with tissue acidosis, while not affecting oxygen affinity in conditions similar to a pulmonary microenvironment.