Enrollment of Neonates in More Than One Clinical Trial

Because the highest rates of morbidity and mortality in neonates are seen in those born at 1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies

Measurements of ψ(2S) and X(3872) → J/ψπ+π− production in pp collisions at √s=8 TeV with the ATLAS detector

Differential cross sections are presented for the prompt and non-prompt production of the hidden-charm states X(3872) and ψ(2S), in the decay mode J/ψπ+π−, measured using 11.4 fb−1 of pp collisions at √s=8 TeV by the ATLAS detector at the LHC. The ratio of cross-sections X(3872)/ψ(2S) is also given, separately for prompt and non-prompt components, as well as the non-prompt fractions of X(3872) and ψ(2S). Assuming independent single effective lifetimes for non-prompt X(3872) and ψ(2S) production gives RB=B(B→X(3872)+any)B(X(3872)→J/ψπ+π−)B(B→ψ(2S)+any)B(ψ(2S)→J/ψπ+π−)=(3.95±0.32(stat)±0.08(sys))×10−2RB=B(B→X(3872)+any)B(X(3872)→J/ψπ+π−)B(B→ψ(2S)+any)B(ψ(2S)→J/ψπ+π−)=(3.95±0.32(stat)±0.08(sys))×10−2 separating short- and long-lived contributions, assuming that the short-lived component is due to Bc decays, gives RB = (3.57 ± 0.33(stat) ± 0.11(sys)) × 10−2, with the fraction of non-prompt X(3872) produced via Bc decays for pT(X(3872)) > 10 GeV being (25 ± 13(stat) ± 2(sys) ± 5(spin))%. The distributions of the dipion invariant mass in the X(3872) and ψ(2S) decays are also measured and compared to theoretical predictions

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Thyroxin and development of hepatic microsomal drug oxidation and electron transport in man and rats.

The neonatal phase of the ontogenetic pattern of hepatic microsomal mixed function oxidases (HMMFQ) in man and the influence of thyroid hormone on this ontogenetic pattern in rats were studied. In the neonatal period in man, there is a significant deficiency in the activity of hepatic microsomal aminopyrine N-demethylase, aniline p-hydroxylase, NADPH oxidase, NADPH cytochrome c reductase and in the amount of cytochrome P-450 and no measurable activity of NADPH cytochrome P-450 reductase. All of these enzymes except aminopyrine N-demethylase significantly correlated with postconceptional age indicating that significantly developmental events occur during the newborn period. [...]Nous avons étudie l'ontogénèse des oxidases hépatiques à function mixte chèz l'homme, et l'influence des hormones thyroidiennes sur l'ontogénèse de ces enzymes chez le rat. Durant la période néonatale chez l'homme, on observe une déficience significative de l'aminopyrine-N-danethylase, de l'aniline-p-hydroxylase, de l'NADPH oxidase, NADPH cytochrane c reductase et du cytochrome P-450, tandis que l'NADPH cytochrome P-450 reductase n'est pas mesurable

Yaffe and Aranda's neonatal and pediatric pharmacology: therapeutic principles in practice/ Jacob (Jack) Aranda, MD, PhD, FRCPC, FAAP, Johannes (John) van den Ankerr, MD, PhD, FCP, FAAP.

Revision of: Neonatal and pediatric pharmacology / [edited by] Sumner J. Yaffe, Jacob V. Aranda. c2010. 4th ed.Includes bibliographical references and index."Textbook in pediatric pharmacology and provides evidence-based guidelines for safe, effective, and rational drug therapy in newborns, children, and adolescents"--Section I: Section II: Section III: Section IV: Section V: Section VI: Section VII: Section VIII: Section IX: Section X: Section XI: Appendix A1: Appendix A2: General principles. Clinical trials involving children: history, rationale, regulatory framework, and technical considerations ; Clinical pharmacokinetics in infants and children ; Developmental pharmacodynamics, receptor function, and drug actions in newborns and children ; Drug absorption, distribution, metabolsim, excretion, and transporters in newborns and children ; Pharmacogenetics, pharmacogenomics, and pharmacoproteomics in newborns and children ; Ethics of drug research in newborns and children ; Precision medicie and therapeutic drug monitoring ; Drug formulations for children -- Pharmacology in special settings and population: the newborn. Role of placenta in drug metabolism and drug transfer ; Maternal medications during pregnancy and lactation ; Principles of neonatal pharmacology ; Renal function and excretion of drugs in the newborn ; Neuroprotective drugs and perinatal brain injury ; Pharmacologic agents for neonatal hyperbilirubinemia ; Pharmacologic treatment of neonatal apnea -- Pharmacology in special settings and population. Therapeutic applications in pediatric intensive care ; Drug therapy in the pediatric emergency department ; Topical medications ; Ophthalmologic drugs in infants and children -- Antimicrobial pharmacology. Penicillins, cephalosporins, and other [beta]-lactams ; Glycopeptides, lipoglycopeptides, and lipopeptides ; Aminoglycosides ; Macrolides, clindamycin, and oxazolidinones ; Fluoroquinolones ; Sulfonamides, dihydrofolate reductase inhibitors, and dapsone ; Tetracyclines, chloramphenicol, and metronidazole ; Antimalarials ; Anthelminthics drugs in children ; Antimycobacterial drugs (mycobacterium tuberculosis and atypical mycobacteria) ; Antifungal agents ; Antivirals in newborns and children ; Pharmacology of antiretroviral drugs in pregnant and breastfeeding women and their newborns -- Neuropharmacology. Anticonvulsants ; Antidepressants and mood stabilizers ; Stimulants, ADHD treatments, and antipsychotics ; Analgesics and sedatives ; Pharmacologic management of neonatal abstinence syndrome ; Local anesthetic agents for regional and superficial anesthesia in infants, children and adolescents -- Immunopharmacology, allergy, and inflammation. Nonsteroida anti-inflammatory drugs ; Antihistamine drugs ; Antiasthmatics ; Immunosuppressive and immunomodulatory drugs -- Pharmacology of biologic drugs. Microbial therapeutics: beyond probiotics ; Monoclonal antibiotics ; Stem cells ; Drugs, lung development, and pulmonary surfactant ; Childhood vaccines -- Cardiorenal drugs. Neonatal cardiovascular pharmacology ; Antiarrhythmic drugs: disorders of cardiac rhythm and pharmacologic management ; Antihypertensive drugs ; Diuretics -- Gastrointestinal pharmacology. Gastrointestinal drugs ; Drugs in inflammatory bowel disease -- Endocrine and hematologic pharmacology. Glucocorticoids ; Insulin and diabetes ; Growth hormone ; Thyroid hormones ; Hematologic agents ; Clinical pharmacology of antineoplastic drugs -- Nutritional pharmacology, pharmacotoxidromes, adverse drug reactions, and interactions. Nutrient supplements ; Herbal drugs in children ; Pediatric poisonings and antidotes ; Adverse drug reactions in newborns and children ; Medication errors in children ; Drug interactions in newborns and children -- Neonatal drug formulary -- Pediatric drug formulary.1 online resource

Chorioamnionitis and Ontogeny of Circulating Prostaglandin and Thromboxane in Preterm Infants

Our objective was to determine the effect of chorioamnionitis on plasma prostaglandin E2 (PGE2) and thromboxane 132 (TxB2) during the first week in preterm infants. Plasma PGE2 and TxB2 were measured at 1, 3, and 7 days of age in preterm infants (birth weights 501 to 1500 g), with (n = 26) and without (n = 22) chorioamnionitis. Infants with maternal chorioamnionitis had significantly lower mean gestational age (p = 0.0001) and birth weight (p = 0.03) and a marginally higher rate of bronchopulmonary dysplasia (37% versus 12.5, p = 0.05), a result that may be related to the lower mean gestational age. Plasma PGE2 and TxB2 varied widely, more so on the first day but did not significantly differ between the two groups. TxB2 was lower among infants who died or developed morbidities. Circulating PGE2 and TxB2 concentrations in preterm infants in the first week vary considerably, are relatively unaltered by chorioamnionitis, and are lower in association with mortality and clinical morbidities. Further research on their role in the causation of adverse neonatal outcomes is necessary

Dose Response of Bumetanide on Aquaporins and Angiogenesis Biomarkers in Human Retinal Endothelial Cells Exposed to Intermittent Hypoxia

Aquaporins (AQPs) are important for regulating cellular water, solute transport, and balance. Recently, AQPs have also been recognized as playing a key role in cell migration and angiogenesis. In the retina, hypoxia induces vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, resulting in retinal edema, which is facilitated by AQPs. Bumetanide is a diuretic agent and AQP 1–4 blocker. We tested the hypothesis that bumetanide suppression of AQPs ameliorates intermittent hypoxia (IH)-induced angiogenesis and oxidative stress in human microvascular retinal endothelial cells (HMRECs). HMRECs were treated with a low-dose (0.05 µg/mL) or high-dose (0.2 µg/mL) of bumetanide and were exposed to normoxia (Nx), hyperoxia (50% O2), or IH (50% O2 with brief hypoxia 5% O2) for 24, 48, and 72 h. Angiogenesis and oxidative stress biomarkers were determined in the culture media, and the cells were assessed for tube formation capacity and AQP-1 and -4 expression. Both doses of bumetanide significantly decreased oxidative stress and angiogenesis biomarkers. This response was reflected by reductions in tube formation capacity and AQP expression. These findings confirm the role of AQPs in retinal angiogenesis. Therapeutic targeting of AQPs with bumetanide may be advantageous for IH-induced aberrant retinal development