Search

The advances in treatment of HIV and the introduction of polymerase chain reaction assay for the virus now make it acceptable for HIV discordant couples where the male partner is seropositive to attempt to conceive through artificial insemination by husband (AIH) or via in vitro fertilisation. With undetectable viral load and washed sperm, there is minimal risk of transmission of HIV to the female partner, children, other patients, or staff. We describe the development of a programme of AIH for HIV discordant couples and the reasoning behind offering such a programme. [ABSTRACT FROM AUTHOR]

Introduction: Community stroke education has shown promising results with sustained stroke knowledge and behavioral changes; however less is known about the effects of targeted education towards youth. We developed an interactive educational program for high school students, Stroke Busters, that focuses on stroke prevention, recognizing warning signs, and the importance of seeking prompt care., Methods: This is a prospective cohort study where students are offered a stroke education program, 'Stroke Busters', through the Yale Pathways to Science Program, a Science, Technology, Engineering and Math (STEM) pipeline program for high school students living near New Haven, Connecticut. Students filled out a stroke knowledge survey before, after, and 8-months-post program. Data from four separate sessions were collected (two 5-day programs and two 1-day programs) and scores were compared. Students who returned to help teach were also evaluated with an additional post-test., Results: The average pre-program score was 36.9% and post-program was 62.5% (N=67, p<0.001) across all sessions. Between sessions, scores were not significantly different. 8-month post-program scores (n=5) were not significantly different from immediate post-program scores. Students in the role of teaching-assistant had post-program scores of 85.7%., Discussion: High school students who participated in Stroke Busters retained stroke knowledge for up to 8 months. The 1-day program showed similar results to the 5-day program, which suggests providing shorter programs to high school students may represent a more feasible opportunity for community stroke prevention. Additionally, including students in a teaching role is a promising way to increase enthusiasm and stroke knowledge for youth., Conclusion: Stroke Busters was successfully able to educate high school youth about stroke and programs of both 1 and 5-day are equally effective., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Inc.)

Background: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants., Methods: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality symptoms, associated comorbidities, treatment history, services used, and social determinants of health. Subsequent assessments occur every two months for 24 months., Results: Among 1000 participants, 68.7 % were 12-17 years, 24.6 % were ≥ 18 years, and 6.7 % were < 12. Overall, 36.8 % were non-Hispanic Caucasian, 73.4 % were female, and 79.9 % had a primary depressive disorder. Nearly half of the sample reported ≥1 suicide attempt, with rates similar in youth 12-17 years old (49.9 %) and those 18 years and older (45.5 %); 29.9 % of children <12 reported at least one suicide attempt. Depression and anxiety scores were in the moderate-severe range for all age groups (Patient Health Questionnaire for Adolescents [PHQ-A]: 12.9 ± 6.4; Generalized Anxiety Disorder [GAD-7]: 11.3 ± 5.9)., Limitations: The sample includes youth who are receiving depression care at enrollment and may not be representative of non-diagnosed, non-treatment seeking youth., Conclusions: The TX-YDSRN is one of the largest prospective longitudinal cohort registries designed to develop predictive models for outcome trajectories based on disorder heterogeneity, social determinants of health, and treatment availability., Competing Interests: Declaration of competing interest Dr. Trivedi has provided consulting services to Alkermes Inc., Axsome Therapeutics, Biogen MA Inc., Cerebral Inc., Circular Genomics Inc., Compass Pathfinder Limited, GH Research Limited, Heading Health Inc., Janssen, Legion Health Inc., Merck Sharp & Dohme Corp., Mind Medicine (MindMed) Inc., Merck Sharp & Dhome LLC, Naki Health, Ltd., Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka American Pharmaceutical Inc., Otsuka Canada Pharmaceutical Inc., Otsuka Pharmaceutical Development & Commercialization Inc., Praxis Precision Medicines Inc., SAGE Therapeutics, Sparian Biosciences Inc., Takeda Pharmaceutical Company Ltd., WebMD. He sits on the Scientific Advisory Board of Alto Neuroscience Inc., Cerebral Inc., Compass Pathfinder Limited, Heading Health, GreenLight VitalSign6 Inc., Legion Health Inc., Merck Sharp & Dohme Corp, Orexo US Inc., Signant Health. He holds stock in Alto Neuroscience Inc., Cerebral Inc., Circular Genomics Inc., GreenLight VitalSign6 Inc., Legion Health Inc. Additionally, he has received editorial compensation from American Psychiatric Association, and Oxford University Press. Dr. Blader reports having received consultant and speakers' honoraria from Supernus Pharmaceuticals. Dr. Brown has received consulting fees from Sage and Biogen Pharmaceuticals. Dr. Hughes reports receiving research funding to her institution from NIH and the American Foundation for Suicide Prevention (AFSP). She reports receiving support from the Society of Clinical Child and Adolescent Psychology, the Jed Foundation, and Mental Health in Mind, International AB, and consulting on quality improvement interventions for depression and suicidal/self-harm behavior. She receives book royalties from Guilford Press. Dr. Kennard receives royalties from Guilford, Press, Inc.; and serves on the board of trustees for the Jerry M. Lewis, III, MD Research Foundation. Dr. Soares has served as an advisor or consultant for Asofarma, Boehringer Ingelheim, Johnson & Johnson, Livanova, Pfizer, Pulvinar Neuro LLC, Relmada, Sanofi, and Sunovian. He has received research grants from Alkermes, Allergan, and Compass and holds less than U.S. $5000 in Atai Life Sciences stock. Dr. Soutullo reports for the period 2018–2022 non-personal research funds from Lundbeck and Janssen; is a consultant/advisory board member of Editorial Médica Panamericana, EUNETHYDIS (European Network on Hyperkinetic Disorder), NeuroTech Solutions Ltd. (Israel), Limbix Health DSMB (United States), MEDEA (Spain), Tech Innosphere Engineering LTD (Germany), and Shire/now part of Takeda (Spain); received speaker's bureau fees from Bial (Portugal), Cuquerella Medical Consulting (Spain), Medice (Germany), Rubio (Spain), Tecnofarma (Peru), and Shire/now part of Takeda (Spain), and royalties from Editorial Médica Panamericana (Spain). Dr. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He is a consultant for Brainsway and Biohaven Pharmaceuticals. He owns stock less than $5000 in NView. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, and Jessica Kingsley. Dr. Wakefield serves as an Executive Committee Member of the Texas Child Mental Health Care Consortium. Drs. Minhajuddin, Slater, Baronia, DeFelippis, Farmer, Garza, Liberzon, Martin, and Mrs. Mayes have no declarations to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Contemporary perioperative practice seeks to use less intraoperative opioid, diminish postoperative pain and opioid use, and enable less postdischarge opioid prescribing. For inpatient surgery, anesthesia with intraoperative methadone, compared with short-duration opioids, results in less pain, less postoperative opioid use, and greater patient satisfaction. This pilot investigation aimed to determine single-dose intraoperative methadone feasibility for next-day discharge outpatient surgery, determine an optimally analgesic and well-tolerated dose, and explore whether methadone would result in less postoperative opioid use compared with conventional short-duration opioids., Methods: This double-blind, randomized, dose-escalation feasibility and pilot study in next-day discharge surgery compared intraoperative single-dose IV methadone (0.1 then 0.2, 0.25 and 0.3 mg/kg ideal body weight) versus as-needed short-duration opioid (fentanyl, hydromorphone) controls. Perioperative opioid use, pain, and side effects were assessed before discharge. Patients recorded pain, opioid use, and side effects for 30 days postoperatively using take-home diaries. Primary clinical outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30-day opioid consumption, pain, opioid side effects, and leftover opioid counts., Results: Median (interquartile range) intraoperative methadone doses were 6 (5 to 7), 11 (10 to 12), 14 (13 to 16), and 18 (15 to 19) mg in 0.1, 0.2, 0.25, and 0.3 mg/kg ideal body weight groups, respectively. Anesthesia with single-dose methadone and propofol or volatile anesthetic was effective. Total in-hospital opioid use (IV milligram morphine equivalents [MME]) was 25 (20 to 37), 20 (13 to 30), 27 (18 to 32), and 25 (20 to 36) mg, respectively, in patients receiving 0.1, 0.2, 0.25 and 0.3 mg/kg methadone, compared to 46 (33 to 59) mg in short-duration opioid controls. Opioid-related side effects were not numerically different. Home pain and opioid use were numerically lower in patients receiving methadone., Conclusions: The most effective and well-tolerated single intraoperative induction dose of methadone for next-day discharge surgery was 0.25 mg/kg ideal body weight (median, 14 mg). Single-dose intraoperative methadone was analgesic and opioid-sparing in next-day discharge outpatient surgery., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects., Methods: The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing., Results: For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids., Conclusions: For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Profound lymphopenia is an independent predictor of adverse clinical outcomes in sepsis. Interleukin-7 (IL-7) is essential for lymphocyte proliferation and survival. A previous phase II study showed that CYT107, a glycosylated recombinant human IL-7, administered intramuscularly reversed sepsis-induced lymphopenia and improved lymphocyte function. Thepresent study evaluated intravenous administration of CYT107. This prospective, double-blinded, placebo-controlled trial was designed to enroll 40 sepsis patients, randomized 3:1 to CYT107 (10 µg/kg) or placebo, for up to 90 days., Results: Twenty-one patients were enrolled (fifteen CYT107 group, six placebo group) at eight French and two US sites. The study was halted early because three of fifteen patients receiving intravenous CYT107 developed fever and respiratory distress approximately 5-8 h after drug administration. Intravenous administration of CYT107 resulted in a two-threefold increase in absolute lymphocyte counts (including in both CD4 + and CD8 + T cells (all p < 0.05)) compared to placebo. This increase was similar to that seen with intramuscular administration of CYT107, was maintained throughout follow-up, reversed severe lymphopenia and was associated with increase in organ support free days (OSFD). However, intravenous CYT107 produced an approximately 100-fold increase in CYT107 blood concentration compared with intramuscular CYT107. No cytokine storm and no formation of antibodies to CYT107 were observed., Conclusion: Intravenous CYT107 reversed sepsis-induced lymphopenia. However, compared to intramuscular CYT107 administration, it was associated with transient respiratory distress without long-term sequelae. Because of equivalent positive laboratory and clinical responses, more favorable pharmacokinetics, and better patient tolerability, intramuscular administration of CYT107 is preferable., Trial Registration: Clinicaltrials.gov, NCT03821038. Registered 29 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821038?term=NCT03821038&draw=2&rank=1 ., (© 2023. The Author(s).)

Aims: Methadone metabolism and clearance are determined principally by polymorphic cytochrome P4502B6 (CYP2B6). Some CYP2B6 allelic variants affect methadone metabolism in vitro and disposition in vivo. We assessed methadone metabolism by CYP2B6 minor variants in vitro. We also assessed the influence of CYP2B6 variants, and P450 oxidoreductase (POR) and CYP2C19 variants, on methadone clearance in surgical patients in vivo., Methods: CYP2B6 and P450 oxidoreductase variants were coexpressed with cytochrome b 5 . The metabolism of methadone racemate and enantiomers was measured at therapeutic concentrations and intrinsic clearances were determined. Adolescents receiving methadone for surgery were genotyped for CYP2B6, CYP2C19 and POR, and methadone clearance and metabolite formation clearance were determined., Results: In vitro, CYP2B6.4 was more active than wild-type CYP2B6.1. CYPs 2B6.5, 2B6.6, 2B6.7, 2B6.9, 2B6.17, 2B6.19 and 2B6.26 were less active. CYPs 2B6.16 and 2B6.18 were inactive. CYP2B6.1 expressed with POR variants POR.28, POR.5 and P228L had lower rates of methadone metabolism than wild-type reductase. In vivo, methadone clinical clearance decreased linearly with the number of CYP2B6 slow metabolizer alleles, but was not different in CYP2C19 slow or rapid metabolizer phenotypes, or in carriers of the POR*28 allele., Conclusions: Several CYP2B6 and POR variants were slow metabolizers of methadone in vitro. Polymorphisms in CYP2B6, but not CYP2C19 or P450 reductase, affected methadone clearance in vivo. CYP2B6 polymorphisms 516G>T and 983T>C code for canonical loss of function variants and should be assessed when considering genetic influences on clinical methadone disposition. These complementary translational in vitro and in vivo results inform on pharmacogenetic variability affecting methadone disposition in patients., (© 2022 British Pharmacological Society.)

A nonimmunocompromised patient developed life-threatening soft tissue infection with Trichosporon asahii , Fusarium , and Saksenaea that progressed despite maximum antifungal therapies and aggressive debridement. Interleukin-7 immunotherapy resulted in clinical improvement, fungal clearance, reversal of lymphopenia, and improved T-cell function. Immunoadjuvant therapies to boost host immunity may be efficacious in life-threatening fungal infections., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aims: Changes in serotonergic sensory modulation associated with overexpression of 5-HT 3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT 3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT 3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration., Methods: Fifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS., Results: The individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26., Conclusions: After intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration-time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain., (© 2020 The British Pharmacological Society.)

The antidepressant bupropion is stereoselectively metabolized and metabolite enantiomers have differential pharmacologic effects, but steady-state enantiomeric disposition is unknown. Controversy persists about bupropion XL 300 mg generic equivalence to brand product, and whether generics might have different stereoselective disposition leading to enantiomeric non-bioequivalence and, thus, clinical nonequivalence. This preplanned follow-on analysis of a prospective, randomized, double-blinded, crossover study of brand and 3 generic bupropion XL 300 mg products measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations and evaluated bioequivalence and pharmacokinetics. Steady-state plasma and urine bupropion disposition was markedly stereoselective, with up to 40-fold differences in plasma concentrations of the active metabolite S,S-hydroxybupropion vs. R,R,-hydroxybupropion. Urine metabolite glucuronides were prominent, but glucuronidation was metabolite-specific and enantioselective. There were no differences between any generic and brand, or between generics, in plasma enantiomer concentrations of bupropion or the major metabolites. All generic products satisfied formal bioequivalence criteria (peak plasma concentration (C max ) and area under the plasma concentration-time curve over 24 hours (AUC 0-24 )) using enantiomers for bupropion as well as for metabolites, and generics were comparable to each other, and were considered bioequivalent, based on enantiomeric analysis. Enantiomeric bioequivalence explains the previously observed therapeutic equivalence of bupropion generics and brand in treating major depression. These results have important implications for understanding the clinical therapeutic effects of bupropion based on complex and stereoselective metabolism., (© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-ɣ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-ɣ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-ɣ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.

Controversy persists about bupropion XL 300 mg generic equivalence to brand product. A prospective, randomized, double-blinded crossover in 70 adults with major depression in stable remission taking any bupropion XL 300 mg tested bioequivalence and therapeutic equivalence of available XL 300 mg products. After a 4-week lead-in on patients' existing bupropion, four 6-week phases evaluated brand and three generics. Patients were uninformed of switching. Drug overencapsulation ensured blinding. There were no differences between any generic and brand, or between generics, in peak plasma concentration (C max ) and area under the plasma concentration-time curve over the 24-hour dosing interval (AUC 0-24 ) for racemic bupropion or major metabolites. All generics met formal bioequivalence criteria for bupropion and metabolites. There were no differences between generics and brand, or between generics, in depression symptoms or side effects, assessed by every 3-week in-person interview and daily smartphone-based self-report. There were no differences in patients' perceptions of bupropion products. Results show three bupropion XL 300 mg generic products are both bioequivalent and not therapeutically different from brand drug and each other., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Background: Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery., Methods: A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects., Results: Median (interquartile range) methadone doses were 6 (5-6) and 9 (8-9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3-11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1-3.3; P < .001) but not 0.1 mg/kg methadone (5.0 mg, 3.3-8.1; P = .60). Dose-escalation ended at 0.15 mg/kg methadone. Total in-hospital nonmethadone opioid use after short-duration opioid, 0.1 mg/kg methadone, and 0.15 mg/kg methadone was 35.3 (25.0-44.0), 7.1 (3.7-10.0), and 3.3 (0.1-5.8) mg morphine equivalents, respectively (P < .001 for both versus control). In-hospital pain scores and side effects were not different between groups. In the 30 days after discharge, patients who received methadone 0.15 mg/kg had less pain at rest (P = .02) and used fewer opioid pills than controls (P < .0001), whereas patients who received 0.1 mg/kg had no difference in pain at rest (P = .69) and opioid use compared to controls (P = .08)., Conclusions: In same-day discharge surgery, this pilot study identified a single intraoperative dose of methadone (0.15 mg/kg ideal body weight), which decreased intraoperative and postoperative opioid requirements and postoperative pain, compared with conventional intermittent short-duration opioids, with similar side effects.

Background: A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common γ-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity., Methods: We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia. Twenty-seven patients at academic sites in France and the United States received CYT107 or placebo for 4 weeks. Primary aims were to determine the safety of CYT107 in sepsis and its ability to reverse lymphopenia., Results: CYT107 was well tolerated without evidence of inducing cytokine storm or worsening inflammation or organ dysfunction. CYT107 caused a 3- to 4-fold increase in absolute lymphocyte counts and in circulating CD4+ and CD8+ T cells that persisted for weeks after drug administration. CYT107 also increased T cell proliferation and activation., Conclusions: This is the first trial of an immunoadjuvant therapy targeting defects in adaptive immunity in patients with sepsis. CYT107 reversed the marked loss of CD4+ and CD8+ immune effector cells, a hallmark of sepsis and a likely key mechanism in its morbidity and mortality. CYT107 represents a potential new way forward in the treatment of patients with sepsis by restoring adaptive immunity. Such immune-based therapy should be broadly protective against diverse pathogens including multidrug resistant bacteria that preferentially target patients with impaired immunity., Trial Registration: Trials registered at clinicaltrials.gov: NCT02640807 and NCT02797431., Funding: Revimmune, NIH National Institute of General Medical Sciences GM44118.

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status., Methods: The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics., Results: Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at <3 years (both), 73% and 100% at 3-<7 years (P < .05), and 77% and 97% at ≥ 7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥ 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated ≥ 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02)., Conclusions: Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥ 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism., Methods: Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry., Results: Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism., Conclusions: CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.

Background: Prolonged administration of nitrous oxide causes an increase in plasma homocysteine in children via vitamin B12 inactivation. However, it is unclear whether nitrous oxide doses used in clinical practice cause adverse hematological effects in pediatric patients., Methods: This retrospective study included 54 pediatric patients undergoing elective spinal surgery: 41 received nitrous oxide throughout anesthesia (maintenance group), 9 received nitrous oxide for induction and/or emergence (induction/emergence group), and 4 did not receive nitrous oxide (nitrous oxide-free group). Complete blood counts obtained before and up to 4 days after surgery were assessed for anemia, macrocytosis/microcytosis, anisocytosis, hyperchromatosis/hypochromatosis, thrombocytopenia, and leukopenia. The change (Δ) from preoperative to the highest postoperative value was calculated for mean corpuscular volume (MCV) and red cell distribution width (RDW)., Results: No pancytopenia was present in any patient after surgery. All patients had postoperative anemia, and none had macrocytosis. Postoperative MCV (mean [99% confidence interval]) peaked at 86 fL (85-88 fL), 85 fL (81-89 fL), and 88 fL (80-96 fL) and postoperative RDW at 13.2% (12.8-13.5%), 13.3% (12.7-13.8%), and 13.0% (11.4-14.6%) for the maintenance group, the induction/emergence group, and the nitrous oxide-free group. Two patients in the maintenance group (5%) developed anisocytosis (RDW >14.6%), but none in the induction/emergence group or in the nitrous oxide-free group (P = 0.43). Both ΔMCV (P = 0.52) and ΔRDW (P = 0.16) were similar across all groups., Conclusions: Nitrous oxide exposure for up to 8 hours is not associated with megaloblastic anemia in pediatric patients undergoing major spinal surgery.

Background: Interindividual variability and drug interaction studies suggest that blood-brain barrier drug transporters mediate human methadone brain biodistribution. In vitro and animal studies suggest that methadone is a substrate for the efflux transporter P-glycoprotein, and that P-glycoprotein-mediated transport influences brain access and pharmacologic effect. This investigation tested whether methadone is a transporter substrate in humans [corrected]., Methods: Healthy volunteers received oral (N=16) or IV (N=12) methadone in different crossover protocols after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (4.5 mg/kg orally twice daily for 4 days, or 5 mg/kg IV over 2 h). Plasma and urine methadone and metabolite concentrations were measured by mass spectrometry. Methadone effects were measured by miosis and thermal analgesia (maximally tolerated temperature and verbal analog scale rating of discreet temperatures)., Results: Cyclosporine marginally but significantly decreased methadone plasma concentrations and apparent oral clearance, but had no effect on methadone renal clearance or on hepatic N-demethylation. Cyclosporine had no effect on miosis or on R-methadone concentration-miosis relationships after either oral or IV methadone. Peak miosis was similar in controls and cyclosporine-treated subjects after oral methadone (1.4±0.4 and 1.3±0.5 mm/mg, respectively) and IV methadone (3.1±1.0 and 3.2±0.8 mm, respectively). Methadone increased maximally tolerated temperature, but analgesia testing was confounded by cyclosporine-related pain., Conclusions: Cyclosporine did not affect methadone pharmacodynamics. This result does not support a role for cyclosporine-inhibitable transporters mediating methadone brain access and biodistribution.

Background: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS., Methods: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria., Results: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom., Conclusion: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Background: The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans., Methods: Fourteen healthy volunteers received morphine (0.1 mg/kg, 1-h IV infusion) in a crossover study without (control) or with the infusion of validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2-h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia., Results: Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml·h (P < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm·h), plasma effect-site transfer rate constant (k(e0), median 0.27 vs. 0.17 h(-1)), and maximum calculated effect-site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml; all P < 0.05). Analgesia testing was confounded by cyclosporine-related pain., Conclusions: Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects.

Background: Nitrous oxide inactivates vitamin B(12), inhibits methionine synthase, and consequently increases plasma total homocysteine (tHcy). Prolonged exposure to nitrous oxide can lead to neuropathy, spinal cord degeneration, and even death in children. We tested the hypothesis that nitrous oxide anesthesia causes a significant increase in plasma tHcy in children., Methods: Twenty-seven children (aged 10-18 years) undergoing elective major spine surgery were enrolled, and serial plasma samples from 0 to 96 hours after induction were obtained. The anesthetic regimen, including the use of nitrous oxide, was at the discretion of the anesthesiologist. Plasma tHcy was measured using standard enzymatic assays., Results: The median baseline plasma tHcy concentration was 5.1 μmol/L (3.9-8.0 μmol/L, interquartile range) and increased in all patients exposed to nitrous oxide (n = 26) by an average of +9.4 μmol/L (geometric mean; 95% confidence interval, 7.1-12.5 μmol/L) or +228% (mean; 95% confidence interval, 178%-279%). Plasma tHcy peaked between 6 and 8 hours after induction of anesthesia. One patient who did not receive nitrous oxide had no increase in plasma tHcy. Several patients experienced a severalfold increase in plasma tHcy (maximum +567%). The increase in plasma tHcy was strongly correlated with the duration and average concentration of nitrous oxide anesthesia (r = 0.80; P < 0.001)., Conclusions: Pediatric patients undergoing nitrous oxide anesthesia develop significantly increased plasma tHcy concentrations. The magnitude of this effect seems to be greater compared with adults; however, the clinical relevance is unknown.

Hyperresponsiveness to norepinephrine contributes to post-traumatic stress disorder (PTSD). Prazosin, a brain-active blocker of α(1)-adrenoceptors, originally used for the treatment of hypertension, has been reported to alleviate trauma nightmares, sleep disturbance and improve global clinical status in war veterans with PTSD. Thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) may play a role in the pathophysiology and treatment of neuropsychiatric disorders such as major depression, and PTSD (an anxiety disorder). To investigate whether TRH or TRH-like peptides (pGlu-X-Pro-NH(2), where "X" can be any amino acid residue) participate in the therapeutic effects of prazosin, male rats were injected with prazosin and these peptides then measured in brain and endocrine tissues. Prazosin stimulated TRH and TRH-like peptide release in those tissues with high α(1)-adrenoceptor levels suggesting that these peptides may play a role in the therapeutic effects of prazosin., (Published by Elsevier Inc.)

Leptin is not only a feedback modulator of feeding and energy expenditure but also regulates reproductive functions, CNS development and mood. Obesity and major depression are growing public health concerns which may derive, in part, from disregulation of leptin feedback at the level of the hypothalamic feeding centers and mood regulators within the limbic system. Identifying downstream mediators of leptin action may provide therapeutic opportunities. We and others have previously reported that thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) and TRH-like peptides (pGlu-X-Pro-NH(2), where "X" can be any amino acid residue) have neuroprotective, antidepressant, anti-epileptic, analeptic, anti-ataxic, and anorectic properties. For this reason, young, adult male Sprague-Dawley rats were injected ip with 1mg/kg rat leptin and peptide and protein levels were measured in brain and peripheral tissues at 0, 0.5, 1 and 2h later. Eleven brain regions: pyriform cortex (PYR), entorhinal cortex (ENT), cerebellum (CBL), nucleus accumbens (NA), frontal cortex (FCX), amygdala (AY), posterior cingulate (PCNG), striatum (STR), hippocampus (HC), medulla oblongata (MED) and anterior cingulate (ACNG) and five peripheral tissues (adrenals, testes, epididymis, pancreas and prostate) were analyzed. TRH and six TRH-like peptide levels in STR fell by 0.5h consistent with leptin-induced release of these peptides: STR (7 downward arrow). Significant changes in TRH and TRH-like peptide levels for other brain regions were: CBL (5 downward arrow), ENT (5 downward arrow), HC (4 downward arrow), AY (4 downward arrow), FCX (3 downward arrow), and ACNG (1 downward arrow). The rapid modulation of TRH and TRH-like peptide release combined with their similarity in behavioral, neuroendocrine, immunomodulatory, metabolic and steroidogenic effects to that of leptin is consistent with these peptides participating in downstream signaling., (Published by Elsevier B.V.)

Sustained abnormalities of glucocorticoid levels have been associated with neuropsychiatric illnesses such as major depression, posttraumatic stress disorder (PTSD), panic disorder, and obsessive compulsive disorder. The pathophysiological effects of glucocorticoids may depend not only on the amount of glucocorticoid exposure but also on its temporal pattern, since it is well established that hormone receptors are down-regulated by continuously elevated cognate hormones. We have previously reported that TRH (pGlu-His-Pro-NH2) and TRH-like peptides (pGlu-X-Pro-NH2) have endogenous antidepressant-like properties and mediate or modulate the acute effects of a single i.p. injection of high dose corticosterone (CORT) in rats. For these reasons, two accepted methods for inducing chronic hyperglucocorticoidemia have been compared for their effects on brain and peripheral tissue levels of TRH and TRH-like peptides in male, 250 g, Sprague-Dawley rats: (1) the dosing effect of CORT hemisuccinate in drinking water, and (2) s.c. slow-release pellets. Overall, there were 93% more significant changes in TRH and TRH-like peptide levels in brain and 111% more in peripheral tissues of those rats ingesting various doses of CORT in drinking water compared to those with 1-3 s.c. pellets. We conclude that providing rats with CORT in drinking water is a convenient model for the pathophysiological effects of hyperglucocorticoidemia in rodents.

Background: Escitalopram (eCIT) is a highly selective serotonin reuptake inhibitor (SSRI) that can be an effective treatment for a number of neuropsychiatric disorders including major depression. We, and others, have previously reported that thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) and TRH-like peptides with the general structure pGlu-X-Pro-NH(2), where 'X' can be any amino acid residue, have neuroprotective, antidepressant, analeptic, arousal, and anti-epileptic effects that could mediate the neuropsychiatric and therapeutic effects of a variety of neurotropic agents. The present work explores the possible mediation of the therapeutic effects of eCIT by TRH and TRH-like peptides., Methods: In order to extend our understanding of the range of neurotransmitter systems that are modulated by and, in turn, influence the expression of TRH and TRH-like peptides, 16 male Sprague-Dawley rats were injected i.p. with eCIT (24 mg/kg BW) and the brain levels of TRH and TRH-like peptides in various brain regions involved in mood regulation and peripheral tissues with serotonergic innervation were measured 0, 2, 4, and 6 h later by combined HPLC and RIA., Results and Conclusion: Remarkable 3- to 25-fold increases in TRH and TRH-like peptide levels were observed 2 h after i.p. eCIT in the epididymis. This reproductive tissue has the highest level of serotonin found in most mammals. The acute (2 h) effect of eCIT in brain regions involved in mood regulation, particularly the nucleus accumbens and medulla oblongata, cerebellum, and striatum was to increase the levels of TRH-like peptides, most consistently Phe-TRH. An important exception was a decrease in the level of TRH in the nucleus accumbens. These responses, in general, were the opposite of those we have previously observed after acute restraint stress in this same rat strain. We conclude that some of the therapeutic effects of inhibition of serotonin reuptake are mediated by altered release of TRH and TRH-like peptides., ((c) 2008 S. Karger AG, Basel.)