A very-high-energy component deep in the γ-ray burst afterglow.

Gamma-ray bursts (GRBs) are brief flashes of γ-rays and are considered to be the most energetic explosive phenomena in the Universe1. The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow-produced by the interaction between the ejected matter and the circumburst medium-slows down, and a gradual decrease in brightness is observed2. GRBs typically emit most of their energy via γ-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments3. However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive4. Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow-ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and γ-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.

Search for Dark Matter Annihilation Signals in the H.E.S.S. Inner Galaxy Survey.

The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented γ-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100 GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant γ-ray excess is found in the search region of the 2014-2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section ⟨σv⟩. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach ⟨σv⟩ values of 3.7×10^{-26} cm^{3} s^{-1} for 1.5 TeV DM mass in the W^{+}W^{-} annihilation channel, and 1.2×10^{-26} cm^{3} s^{-1} for 0.7 TeV DM mass in the τ^{+}τ^{-} annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based γ-ray observations thus probe ⟨σv⟩ values expected from thermal-relic annihilating TeV DM particles.

Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone.

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose-concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20-60 ng/ml) is applicable for minors. In the 64 patients (aged 11-18 years) included, a positive correlation between daily dose and the active moiety (RISam) concentration was found (rs = 0.49, p = 0.001) with variation in dose explaining 24% (rs2 = 0.240) of the variability in serum concentrations. While the RISam concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RISam was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.

Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride.

PURPOSE: Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. METHODS: Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. RESULTS: In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97-19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. CONCLUSIONS: This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa.

OBJECTIVE: Patients with anorexia nervosa (AN) exhibit high rates of psychiatric comorbidity. To disentangle the effects of duration of illness on comorbid psychiatric symptoms, we investigated the rates of comorbid psychiatric disorders, suicidality and self-harm behaviour in adolescent patients with a first onset of AN. METHODS: In adolescent females (n = 148) with a first onset of AN, body mass index, psychiatric comorbidity (according to DSM-IV), depressive symptoms, suicidality and self-injurious behaviour were assessed. RESULTS: Seventy patients (47.3%) met the criteria for at least one comorbid psychiatric disorder. The binge-purging subtype was associated with increased rates of psychiatric comorbidity, suicidality and self-injurious behaviour. The severity of eating disorder-specific psychopathology influenced current psychiatric comorbidity and suicidal ideation. CONCLUSION: Prevalence rates of comorbid psychiatric disorders and suicidal ideation are considerably lower among adolescents with AN compared with adults. An early and careful assessment, along with adequate treatment of the eating disorder, might prevent the development of severe psychiatric comorbidities.

Acceleration and transport of relativistic electrons in the jets of the microquasar SS 433.

SS 433 is a microquasar, a stellar binary system that launches collimated relativistic jets. We observed SS 433 in gamma rays using the High Energy Stereoscopic System (H.E.S.S.) and found an energy-dependent shift in the apparent position of the gamma-ray emission from the parsec-scale jets. These observations trace the energetic electron population and indicate that inverse Compton scattering is the emission mechanism of the gamma rays. Our modeling of the energy-dependent gamma-ray morphology constrains the location of particle acceleration and requires an abrupt deceleration of the jet flow. We infer the presence of shocks on either side of the binary system, at distances of 25 to 30 parsecs, and that self-collimation of the precessing jets forms the shocks, which then efficiently accelerate electrons.

Search for photon-linelike signatures from dark matter annihilations with H.E.S.S.

Gamma-ray line signatures can be expected in the very-high-energy (E(γ)>100 GeV) domain due to self-annihilation or decay of dark matter (DM) particles in space. Such a signal would be readily distinguishable from astrophysical γ-ray sources that in most cases produce continuous spectra that span over several orders of magnitude in energy. Using data collected with the H.E.S.S. γ-ray instrument, upper limits on linelike emission are obtained in the energy range between ∼ 500 GeV and ∼ 25 TeV for the central part of the Milky Way halo and for extragalactic observations, complementing recent limits obtained with the Fermi-LAT instrument at lower energies. No statistically significant signal could be found. For monochromatic γ-ray line emission, flux limits of (2 × 10(-7) -2 × 10(-5)) m(-2) s(-1) sr(-1) and (1 × 10(-8) -2 × 10(-6)) m(-2) s(-1)sr(-1) are obtained for the central part of the Milky Way halo and extragalactic observations, respectively. For a DM particle mass of 1 TeV, limits on the velocity-averaged DM annihilation cross section ⟨σv⟩(χχ → γγ) reach ∼ 10(-27) cm(3)s(-1), based on the Einasto parametrization of the Galactic DM halo density profile.

Therapeutic drug monitoring of children and adolescents treated with fluoxetine.

INTRODUCTION: Information about therapeutic serum levels of fluoxetine (FLX) and its major metabolite norfluoxetine (NORFLX) in children and adolescents is scarce. METHODS: Therapeutic drug monitoring (TDM) of FLX was routinely performed in 71 subjects treated for a major depressive disorder (MDD) (10-60 mg/d FLX, median: 20 mg/d). Correlations between serum concentration and dosage, age, gender, smoking habits and adverse events were analysed. RESULTS: Serum concentrations of the active moiety (FLX + NORFLX) ranged from 21 to 613 ng/mL (mean concentration of 213 ± 118 ng/mL, median: 185 ng/mL). High inter-individual variability in serum concentrations of the active moiety of FLX at each dosage level was observed and no relationship between serum concentration and clinical outcome was found. Apart from smoking, none of the factors tested had a significant eff ect on the serum concentration. DISCUSSION: It was shown that serum concentrations of the active moiety of FLX in children and adolescents seem to be similar to those in adults, with a high level of inter-individual variation. The proportion of patients who showed benefits from treatment with a dose of 20 mg/d FLX was high.

Time-resolved hadronic particle acceleration in the recurrent nova RS Ophiuchi.

Recurrent novae are repeating thermonuclear explosions in the outer layers of white dwarfs, due to the accretion of fresh material from a binary companion. The shock generated when ejected material slams into the companion star's wind can accelerate particles. We report very-high-energy (VHE; [Formula: see text]) gamma rays from the recurrent nova RS Ophiuchi, up to 1 month after its 2021 outburst, observed using the High Energy Stereoscopic System (H.E.S.S.). The temporal profile of VHE emission is similar to that of lower-energy giga-electron volt emission, indicating a common origin, with a 2-day delay in peak flux. These observations constrain models of time-dependent particle energization, favoring a hadronic emission scenario over the leptonic alternative. Shocks in dense winds provide favorable environments for efficient acceleration of cosmic rays to very high energies.

Search for a dark matter annihilation signal from the galactic center halo with H.E.S.S.

A search for a very-high-energy (VHE; ≥100 GeV) γ-ray signal from self-annihilating particle dark matter (DM) is performed towards a region of projected distance r∼45-150 pc from the Galactic center. The background-subtracted γ-ray spectrum measured with the High Energy Stereoscopic System (H.E.S.S.) γ-ray instrument in the energy range between 300 GeV and 30 TeV shows no hint of a residual γ-ray flux. Assuming conventional Navarro-Frenk-White and Einasto density profiles, limits are derived on the velocity-weighted annihilation cross section (σv) as a function of the DM particle mass. These are among the best reported so far for this energy range and in particular differ only little between the chosen density profile parametrizations. In particular, for the DM particle mass of ∼1 TeV, values for (σv) above 3×10(-25) cm(3) s(-1) are excluded for the Einasto density profile.

Screening for anorexia nervosa via measurement of serum leptin levels.

Due to their sub-normally low fat mass, leptin levels in patients with acute anorexia nervosa (AN) are well below reference levels for age and sex-matched controls. This hypoleptinemia entails endocrinological and behavioral characteristics observed in AN patients during starvation. We aimed to study the appropriateness of hypoleptinemia as a diagnostic marker for AN by assessing sensitivity, specificity and likelihood ratios for different referral serum leptin levels for predicting anorexia nervosa and healthy leanness. For prediction, we additionally generated a score based on a multivariate logistic model including body mass index (BMI; kg/m²) and leptin level. For this purpose, we measured leptin levels in 74 female patients with acute AN upon admission for inpatient or outpatient treatment. Adolescent and adult patients were recruited according to DSM-IV criteria from two multi-center studies. Additionally, leptin levels were measured in 65 female healthy, lean students. Mean serum leptin level was significantly decreased in patients with AN compared to underweight controls (0.87 ± 0.90 vs. 6.43 ± 3.55 µg/L, p < 0.001). Leptin predicted AN independently of BMI; we confirmed a cutoff value in the range of 2 µg/L as having both high specificity and sensitivity. Hypoleptinemia represents a state marker of acute AN and is useful for a laboratory-based diagnostic screening.

Therapeutic drug monitoring in child and adolescent psychiatry.

Psychopharmacotherapy in children and adolescents is characterized by an increased susceptibility for adverse events and an increased risk of ineffective treatment due to specific age-dependent and developmental characteristics in comparison to adults. Dosing in paediatric psychiatric patients requires careful handling, since the dose recommendations for adults can not simply be extrapolated to minors because of pharmacokinetic and pharmacodynamic differences. In addition, psychopharmacotherapy in children and adolescents is hampered by lack of high quality evidence on efficacy and safety in many indications and subsequently a high degree of off-label use. Therapeutic Drug Monitoring (TDM) is an established and useful tool in psychiatry to individualize and optimize the outcomes (efficacy/safety balance) of psychopharmacological drug treatment in the individual patient by dose adjustments based upon measured serum concentrations. In children and adolescents the administration of psychotropic drugs is a general indication for performing TDM. However, TDM studies specific in these age groups are necessary to identify age and indication specific therapeutic ranges of serum concentrations. Systematic collection of data on drug exposure, serum concentrations and clinical characteristics as well as outcomes can generate such practice-based evidence. A German-Swiss-Austrian competence network for TDM in child and adolescent psychiatry using a multi-centre internet-based data infrastructure was founded to document and collect demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents (further information: www.tdm-kjp.com).

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

Comparison of metabolic profiles of acutely ill and short-term weight recovered patients with anorexia nervosa reveals alterations of 33 out of 163 metabolites.

Starvation represents an extreme physiological state and entails numerous endocrine and metabolic adaptations. The large-scale application of metabolomics to patients with acute anorexia nervosa (AN) should lead to the identification of state markers characteristic of starvation in general and of the starvation specifically associated with this eating disorder. Novel metabolomics technology has not yet been applied to this disorder. Using a targeted metabolomics approach, we analysed 163 metabolite concentrations in 29 patients with AN in the acute stage of starvation (T0) and after short-term weight recovery (T1). Of the 163 metabolites of the respective kit, 112 metabolites were quantified within restrictive quality control limits. We hypothesized that concentrations are different in patients in the acute stage of starvation (T0) and after weight gain (T1). Furthermore, we compared all 112 metabolite concentrations of patients at the two time points (T0, T1) with those of 16 age and gender matched healthy controls. Thirty-three of the metabolite serum levels were found significantly different between T0 and T1. At the acute stage of starvation (T0) serum concentrations of 90 metabolites differed significantly from those of healthy controls. Concentrations of controls mostly differed even more strongly from those of AN patients after short-term weight recovery than at the acute stage of starvation. We conclude that AN entails profound and longer lasting alterations of a large number of serum metabolites. Further studies are warranted to distinguish between state and trait related alterations and to establish diagnostic sensitivity and specificity of the thus altered metabolites.