United States (US) and European Union (EU) laws attempt to counterbalance the presumed discrimination of children in drug treatment and drug development. The US Food and Drug Administration ...(FDA)-rewarded pediatric studies with antidepressants triggered in 2004 an FDA black-box warning of suicidality in young patients. Fewer antidepressants were prescribed, and the number of completed suicides of young persons increased. The dilemma between this warning and the need to adequately treat young depressed patients remains unsolved. We analyzed the history of drug development, the evolving view of diseases in young patients, US/EU pediatric laws, and pediatric studies triggered by FDA/European Medicines Agency (EMA) in depression and other diseases on the background of developmental pharmacology; financial, institutional, and other interests; and the literature. The FDA/EMA define children administratively, not physiologically, as <17 (FDA)/<18 years old (EMA). But young persons mature physiologically well before their 17th/18th birthday. Depression occurs in young persons, has special characteristics, but is not fundamentally different from adult depression. Young persons are not another species. Regulatory requirements for “pediatric” studies focus on “pediatric” labels. Many “pediatric” studies, including those in depression, lacked and lack medical sense and harm patients by placebo treatment although effective drugs exist. The FDA has partially abandoned separate “pediatric” efficacy studies, but not in psychiatry. Clinicians, parents, institutional review boards, and ethics committees should become aware of questionable “pediatric” studies, should re-evaluate ongoing ones, consider to suspend them, and to reject new ones. The concept of separate “pediatric” drug approval needs to be abandoned.
Almorexant (ACT-078573) is an orally active dual orexin receptor antagonist that is being developed by Actelion Ltd, in collaboration with GlaxoSmithKline plc, for the treatment of primary insomnia. ...Almorexant is a first-in-class compound that targets the orexin system, which plays a key role in wake promotion and stabilization, in addition to having other regulatory functions. Decreasing orexin activity was hypothesized to have a sleep-promoting effect. Preclinical studies and phase I clinical trials have demonstrated that almorexant decreases alertness and increases sleep in healthy rats, dogs and humans when administered during the active phase of the circadian cycle, at peak endogenous orexin tone. No significant toxicological or safety concerns have been identified in studies in animals and humans, including no evidence of cataplexy, a sudden postural muscle tone weakening that is triggered by emotional stimuli and is considered unique to narcolepsy. The reported efficacy and safety data for almorexant support the continued development of the compound. At the time of publication, phase III clinical trials were underway, but no results had been reported; Actelion and GlaxoSmithKline were also investigating almorexant for other orexin-related neurological disorders. The use of an orexin receptor antagonist for the treatment of sleep disorders appears to be an approach that may provide unique benefits.
In children requiring electroencephalography (EEG), sleep recording can provide crucial information. As EEG recordings during spontaneous sleep are not always possible, pharmacological sleep-inducing ...agents are sometimes required. The aim of the study was to evaluate safety and efficacy of melatonin (Mel) and dexmedetomidine (Dex; intranasal and sublingual application) for sleep induction prior to EEG.
In this prospective randomized study, 156 consecutive patients aged 1-19 years were enrolled and randomized by draw into melatonin group (Mel;
= 54; dose: 0.1 mg/kg), dexmedetomidine (Dex) sublingual group (DexL;
= 51; dose: 3 mcg/kg) or dexmedetomidine intranasal group (DexN;
= 51; dose: 3 mcg/kg). We compared the groups in several parameters regarding efficacy and safety and also carried out a separate analysis for a subgroup of patients with complex behavioral problems.
Sleep was achieved in 93.6% of participants after the first application of the drug and in 99.4% after the application of another if needed. Mel was effective as the first drug in 83.3% and Dex in 99.0% (
< 0.001); in the subgroup of patients with complex developmental problems Mel was effective in 73.4% and Dex in 100% (
< 0.001). The patients fell asleep faster after intranasal application of Dex than after sublingual application (
= 0.006). None of the patients had respiratory depression, bradycardia, desaturation, or hypotension.
Mel and Dex are both safe for sleep induction prior to EEG recording in children. Dex is more effective compared to Mel in inducing sleep, also in the subgroup of children with complex behavioral problems.
Dexmedetomidine and Melatonin for Sleep Induction for EEG in Children, NCT04665453.
Abstract Background Neonatal seizures may cause irreversible changes to the immature brain and. A scoring system for early prognostic information could be a useful clinical tool. The aim of the study ...was to analyze risk factors for epilepsy after neonatal seizures, to validate Garfinkle's scoring system, and to analyze whether a new scoring system is feasible. Methods A retrospective study of 176 newborns (59.1% boys, 40.9% girls, 70.5% term, 29.5% preterm; mean birth weight 2820 g), admitted to the Department of Neonatology, Division of Pediatrics, University Medical Centre, Ljubljana, because of neonatal seizures (clinical and/or neurophysiological), was performed. Epilepsy rate between 2 and 12 years of follow-up was 18.1%. Five independent predictors from Garfinkle's study and other known predictors were entered into hierarchical binary logistic regression models and analyzed through four steps to identify independent predictors of epilepsy. We tested whether any of the predictors was an effect modifier. Results Of five potential predictors from Garfinkle's score, electroencephalograph background findings and etiology were predictive. Etiologies, gestation, mode of delivery, duration of seizures, and other risk factors at birth were found to be independent predictors. Duration of seizures has a different effect on prognosis depending on the gestational age. Conclusion Gestational age determines the association between duration of seizures and epilepsy. Scoring systems to predict development of epilepsy after neonatal seizures need to limit interaction between important predictor variables.
Children are infected with coronavirus disease 2019 (COVID-19) as often as adults, but with fewer symptoms. During the first wave of the COVID-19 pandemic, multisystem inflammatory syndrome (MIS) in ...children (MIS-C), with symptoms similar to Kawasaki syndrome, was described in young minors testing positive for COVID-19. The United States (US) Centers for Disease Control and Prevention (CDC) defined MIS-C as occurring in <21-year-olds, triggering hundreds of PubMed-listed papers. However, postpubertal adolescents are no longer children biologically; the term MIS-C is misleading. Furthermore, MIS also occurs in adults, termed MIS-A by the CDC. Acute and delayed inflammations can be triggered by COVID-19. The 18th birthday is an administrative not a biological age limit, whereas the body matures slowly during puberty. This blur in defining children leads to confusion regarding MIS-C/MIS-A. United States and European Union (EU) drug approval is handled separately for children, defined as <18-year-olds, ascribing non-existent physical characteristics up to the 18th birthday. This blur between the administrative and the physiological meanings for the term child is causing flawed demands for pediatric studies in all drugs and vaccines, including those against COVID-19. Effective treatment of all conditions, including COVID-19, should be based on actual physiological need. Now, the flawed definition for children in the development of drugs and vaccines and their approval is negatively impacting prevention and treatment of COVID-19 in minors. This review reveals the necessity for redefining pediatric age groups to rapidly establish recommendations for optimal prevention and treatment in minors.
Phosphoribosylpyrophosphate synthetase 1 (PRSI) is an enzyme involved in nucleotide metabolism. Pathogenic variants in the PRPS1 are rare and PRS-I deficiency can manifest as three clinical ...syndromes: X-linked non-syndromic sensorineural deafness (DFN2), X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5) and Arts syndrome. We present a Slovenian patient with PRS-I enzyme deficiency due to a novel pathogenic variant – c.424G > A (p.Val142Ile) in the PRPS1 gene, who presented with gross motor impairment, severe sensorineural deafness, balance issues, ataxia, and frequent respiratory infections. In addition, we report the findings of a systemic literature review of all described male cases of Arts syndrome and CMTX5 as well as intermediate phenotypes. As already proposed by other authors, our results confirm PRS-I deficiency should be viewed as a phenotypic continuum rather than three separate syndromes because there are multiple reports of patients with an intermediary clinical presentation.
Biases in aerosol optical depths (AOD) and land surface albedos in the AeroCom models are manifested in the top‐of‐atmosphere (TOA) clear‐sky reflected shortwave (SW) fluxes. Biases in the SW fluxes ...from AeroCom models are quantitatively related to biases in AOD and land surface albedo by using their radiative kernels. Over ocean, AOD contributes about 25% to the 60°S–60°N mean SW flux bias for the multi‐model mean (MMM) result. Over land, AOD and land surface albedo contribute about 40% and 30%, respectively, to the 60°S–60°N mean SW flux bias for the MMM result. Furthermore, the spatial patterns of the SW flux biases derived from the radiative kernels are very similar to those between models and CERES observation, with the correlation coefficient of 0.6 over ocean and 0.76 over land for MMM using data of 2010. Satellite data used in this evaluation are derived independently from each other, consistencies in their bias patterns when compared with model simulations suggest that these patterns are robust. This highlights the importance of evaluating related variables in a synergistic manner to provide an unambiguous assessment of the models, as results from single parameter assessments are often confounded by measurement uncertainty. Model biases in land surface albedos can and must be corrected to accurately calculate TOA flux. We also compare the AOD trend from three models with the observation‐based counterpart. These models reproduce all notable trends in AOD except the decreasing trend over eastern China and the adjacent oceanic regions due to limitations in the emission data set.
Plain Language Summary
Aerosol optical depths (AOD) from satellite retrievals have been used to evaluate the AeroCom models. However, these evaluations are often non‐conclusive due to uncertainties in the retrievals and the differences among many products. In this study, biases in top‐of‐atmosphere (TOA) reflected SW fluxes are linked to biases in AOD and surface albedo by using their respective radiative kernels. We found that biases in AOD and land surface albedo can explain significant amount of the SW flux biases on both global and regional scales. This study highlights the importance of evaluating related variables in a synergistic manner to provide an unambiguous assessment of the models, as results from single parameter assessments are often confounded by measurement uncertainty. This study clearly demonstrates the deficiency of land surface albedo used by the AeroCom models and usage of observation‐based land surface albedo should be required for all models participating in AeroCom experiments.
Key Points
Over ocean, aerosol optical depth (AOD) bias contributes about 25% to the 60°S–60°N mean shortwave (SW) flux bias for the multi‐model mean (MMM) result
Over land, AOD and land surface albedo biases contribute about 40% and 30% to the 60°S–60°N mean SW flux bias for the MMM result
Observation‐based land surface albedo should be used by all models to accurately calculate the top‐of‐atmosphere (TOA) SW fluxes
We report optical transmission measurements through a single crystal of the Weyl semimetal TaAs at terahertz frequencies. The measurements were performed at T=1.6 K using intense coherent light from ...a free-electron laser in high magnetic fields. We detected small but measurable changes in the sample’s transparency upon applying dc voltage (current) to the sample. In a constant magnetic field, the sign of the transmission change depends on the current direction. The effect disappears in zero magnetic field. These observations are qualitatively consistent with theory predictions for optical signatures of the chiral anomaly in a Weyl semimetal.
Abstract Background Abrupt discontinuation of heavy marijuana (MJ) use is associated with self-reports of sleep difficulty. Disturbed sleep is clinically important because MJ users experiencing sleep ...problems may relapse to MJ use to improve their sleep quality. Few studies have used polysomnography (PSG) to characterize changes in sleep architecture during abrupt abstinence from heavy MJ use. Methods We recorded PSG measures on nights 1, 2, 7, 8, and 13 after abrupt MJ discontinuation in 18 heavy MJ users residing in an inpatient unit. Results Across abstinence, Total Sleep Time (TST), Sleep Efficiency (SEff), and amount of REM sleep declined, while Wake after Sleep Onset (WASO) and Periodic Limb Movements (PLM) increased. Furthermore, quantity (joints/week) and duration (years) of MJ use were positively associated with more PLMs. Conclusion The treatment of sleep disturbance is a potential target for the management of cannabis use disorders since poor sleep could contribute to treatment failure in heavy MJ users.
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