Search

Background: Stress exposure is a key risk factor for the development of major depressive disorder and posttraumatic stress disorder. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced disorders. The administration of ketamine one week prior to an acute stressor prevents the development of stress-induced depressive-like behavior in rodents. This study aimed to test if the prophylactic effect of ketamine against stress also applies to humans., Methods: We conducted a double-blind, placebo-controlled study wherein 24 healthy subjects (n = 11 males) were randomized to receive either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) intravenously one week prior to an acute stress [Trier Social Stress Test (TSST)]. The primary endpoint was the anxious-composed subscale of the Profile of Mood States Bipolar Scale (POMS-Bi) administered immediately after the TSST. Salivary and plasma cortisol and salivary alpha amylase were also measured at 15-min intervals for 60 min following the stressor, as proxies of hypothalamic pituitary adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axis activity, respectively., Results: Compared to the midazolam group (n = 12), the ketamine group (n = 12) showed a moderate to large (Cohen's d = 0.7) reduction in levels of anxiety immediately following stress, although this was not significant (p = 0.06). There was no effect of group on change in salivary cortisol or salivary alpha amylase following stress. We conducted a secondary analysis excluding one participant who did not show an expected correlation between plasma and salivary cortisol (n = 23, ketamine n = 11). In this subgroup, we observed a significant reduction in the level of salivary alpha amylase in the ketamine group compared to midazolam (Cohen's d = 0.7, p = 0.03). No formal adjustment for multiple testing was made as this is a pilot study and all secondary analyses are considered hypothesis-generating., Conclusions: Ketamine was associated with a numeric reduction in TSST-induced anxiety, equivalent to a medium-to-large effect size. However, this did not reach statistical significance . In a subset of subjects, ketamine appeared to blunt SAM reactivity following an acute stressor. Future studies with larger sample size are required to further investigate the pro-resilient effect of ketamine., Competing Interests: Dr. Dennis Charney (Dean of Icahn School of Medicine at Mount Sinai) is a named co-inventor on several issued U.S. patents, and several pending U.S. patent applications filed by the Icahn School of Medicine at Mount Sinai (ISMMS) related to pharmacologic therapy for treatment-resistant depression, suicidal ideation and other disorders. ISMMS has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. and it has and will receive payments from Janssen under the license agreement related to these patents. As a co-inventor, Dr. Charney is entitled to a portion of the payments received by the ISMMS. Since SPRAVATO (esketamine) has received regulatory approval for treatment-resistant depression, ISMMS and Dr. Charney as its employee and a co-inventor, will be entitled to additional payments, under the license agreement. Drs. Charney and Feder are named co-inventors on an issued patent in the United States and several issued patents outside of the United States, filed by the Icahn School of Medicine at Mount Sinai for the use of ketamine as therapy for posttraumatic stress disorder; this intellectual property has not been licensed. Dr. Costi has provided consultation services for Guidepoint and TCG Crossover. Dr. Jha has received contract research grants from 10.13039/100014387Acadia Pharmaceuticals, 10.13039/100014593Neurocrine Bioscience, Navitor/Supernus and 10.13039/100005205Janssen Research & Development, educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network, consultant fees from Eleusis Therapeutics US, Inc, Janssen Global Services, Janssen Scientific Affairs, Worldwide Clinical Trials/Eliem, and Guidepoint Global, and honoraria from North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, and Global Medical Education. Dr. Matthew Klein is currently a full-time employee of Janssen Research & Development. Dr. Klein conducted all work related to this manuscript during his previous position as a full-time employee of the ISMMS. In the past 5 years, Dr. Murrough has provided consultation services and/or served on advisory boards for Boehreinger Ingelheim, Clexio Biosciences, FSV7, Global Medical Education (GME), Otsuka, and Sage Therapeutics. Dr. Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions. All the other authors report no conflict of interest., (© 2022 Published by Elsevier Inc.)

The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study ( n  = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249., Competing Interests: The authors report no related conflicts of interest., (© 2022 Published by Elsevier Inc.)

Background: Multifetal pregnancy reduction is a technique used to reduce the fetal number to mitigate the risks of adverse outcomes associated with multiple gestations. Monochorionic diamniotic twin pregnancies are subject to unique complications, contributing to adverse pregnancy outcomes. Thus, patients have an option to electively reduce 1 fetus to improve outcomes., Objective: This study aimed to compare outcomes of elective reduction of monochorionic diamniotic twins by radiofrequency ablation to planned ongoing monochorionic diamniotic twins., Study Design: We performed a retrospective review of 315 monochorionic diamniotic twin gestations that underwent first-trimester ultrasound within 1 institution. Planned electively reduced twins were compared with ongoing monochorionic diamniotic twins. All reductions were performed via radiofrequency ablation of the cord insertion site into the fetal abdomen. The primary outcome was preterm birth at <36 weeks' gestation. Secondary outcomes included gestational age at delivery; preterm birth at less than 37-, 34-, 32-, and 28-weeks' gestation; unintended loss; and adverse perinatal outcomes., Results: Among 315 monochorionic diamniotic pregnancies, 14 (4.4%) underwent elective multifetal pregnancy reduction, and 301 (95.6%) were planned ongoing twins. The mean gestational age of radiofrequency ablation in the elective multifetal pregnancy reduction group was 15.1±0.68 weeks. Patients who underwent elective multifetal pregnancy reduction had significantly higher maternal age (P<.01) and were more likely to be Asian (P<.01). Moreover, they were more likely to have undergone in vitro fertilization (P=.03) and chorionic villus sampling (P<.01). There was a significantly higher rate of term deliveries in the elective radiofrequency ablation group compared with ongoing twins (gestational age, 38 weeks [interquartile range, 36.1-39.1] vs 35.9 weeks [interquartile range, 34.0-36.9]; P<.01). Patients with ongoing pregnancies had a trend of increased rate of preterm birth at <36 weeks' gestation (odds ratio, 3.4; 95% confidence interval, 1.0-12.0; P=.06), a significantly increased risk of preterm birth at <37 weeks' gestation (odds ratio, 8.0; 95% confidence interval, 2.4-26.4; P<.01), and no difference at less than 34-, 32-, or 28- weeks' gestation. All patients who underwent elective radiofrequency ablation had successful pregnancies with no pregnancy losses or terminations. Of ongoing gestations, 36 required procedures, including 16 (5.3%) medically indicated radiofrequency ablation, 14 (4.6%) laser ablation, and 6 (1.9%) amnioreductions. Furthermore, 22 patients (7.3%) with planned ongoing twins had total pregnancy loss at <24 weeks' gestation. Notably, 12 patients (4.0%) had unintended loss of 1 fetus before 24 weeks' gestation in the ongoing pregnancy cohort, and 12 patients (4.0%) had unintended loss of both fetuses before 24 weeks' gestation. Moreover, 5 patients (1.7%) in the ongoing pregnancy group had intrauterine fetal demise at >24 weeks' gestation and 10 patients (3.3%) electively terminated both fetuses. There was no significant difference in loss rates between the 2 groups., Conclusion: In this study of monochorionic diamniotic twins, patients who elected to undergo multifetal pregnancy reduction had significantly lower rates of preterm birth at <37 weeks and a lower trend of preterm birth at <36 weeks' gestation without an increased risk of pregnancy loss. Median gestational age at delivery was significantly higher in the elective multifetal pregnancy reduction group (38 weeks) than in the ongoing pregnancy group (35.9 weeks). Further research is needed to clarify if multifetal pregnancy reduction improves long-term outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Propranolol hydrochloride is a nonselective beta-adrenergic antagonist that has a known activity in the myometrium. Small trials have shown that propranolol decreases the duration of induced labor, although those studies are limited by methodological variability., Objective: Our objective was to determine whether the addition of a single dose of propranolol to induce labor in nulliparous women would decrease total time to vaginal delivery., Study Design: This study was a double-blind, randomized, placebo-controlled trial of nulliparous patients undergoing term induction of labor with a singleton, nonanomalous gestation. Subjects were randomized to 2 mg of intravenous propranolol hydrochloride or an identical-appearing saline placebo, administered 30 minutes after starting the induction of labor. Investigators, labor floor staff, and patients were blinded to the study drug allocation. The primary outcome was time to vaginal delivery. Secondary outcomes included mode of delivery, duration of the phases of labor, time to full dilation, composite maternal morbidity, and composite neonatal morbidity. Data were analyzed by intention-to-treat analysis with a P value of ≤.05 considered significant., Results: In this study, 240 patients were enrolled from December 2017 to December 2018, with 121 patients randomized to the propranolol group and 119 to the placebo group. The 2 groups had similar baseline characteristics. Of the patients randomized, 154 (64.2%) delivered vaginally. There was no significant difference in time from the start of the induction of labor to vaginal delivery (13.8±5.4 hours for propranolol vs 14.3±5.3 hours for placebo; P=.58). There was also no difference in the rate of cesarean delivery (38% vs 33.6%; P=.48), time to active labor (11.0±5.0 vs 11.2±4.5 hours; P=.77), or time to full dilation (12.4±5.1 vs 12.8±5.2 hours; P=.60) in patients receiving propranolol compared with those receiving placebo. Subjects randomized to the propranolol group had a significantly lower rate of composite maternal morbidity (28.9% vs 41.2%; risk ratio, 0.70; 95% confidence interval, 0.49-1.00; P=.047). Rates of postpartum hemorrhage (12.4% vs 21.8%; P=.05) and transfusion (0% vs 4.2%; P=.03) were also lower in the treated group. There was no significant difference in neonatal outcomes or composite morbidity (risk ratio, 0.74; 95% confidence interval, 0.44-1.22)., Conclusion: In this study, there is no evidence that the addition of a 1-time dose of propranolol to induce labor in nulliparous women decreases time to delivery or the rate of cesarean delivery. However, propranolol significantly reduced composite maternal morbidity without adverse neonatal effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Common variable immunodeficiency may be complicated by interstitial lung disease, which leads to worsened morbidity and mortality in some. Although immunomodulatory treatment has efficacy, choice of patient, duration of treatment, and long-term follow-up are not available. Interstitial lung disease appears stable in certain instances, so it is not known whether all patients will develop progressive disease or require immunomodulatory therapy., Objective: This study aims to determine if all common variable immunodeficiency patients with interstitial lung disease have physiological worsening, and if clinical and/or laboratory parameters may correlate with disease progression., Methods: A retrospective review of medical records at Mount Sinai Medical Center in New York was conducted for referred patients with common variable immunodeficiency, CT scan-confirmed interstitial lung disease, and periodic pulmonary function testing covering 20 or more months before immunomodulatory therapy. Fifteen patients were identified from the retrospective review and included in this study., Results: Of the 15 patients with common variable immunodeficiency, 9 had physiological worsening of interstitial lung disease adapted from consensus guidelines, associated with significant reductions in forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of the lung for carbon monoxide. Those with progressive lung disease also had significantly lower mean immunoglobulin G levels, greater increases and highest levels of serum immunoglobulin M (IgM), and more significant thrombocytopenia., Conclusion: Interstitial lung disease resulted in physiological worsening in many, but not all subjects, and was associated with suboptimal immunoglobulin G replacement. Those with worsening pulmonary function tests, elevated IgM, and severe thrombocytopenic episodes appear to be at highest risk for progressive disease. Such patients may benefit from immunomodulatory treatment., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)