Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial.

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.

Model-Based Condition Monitoring of the Sensors and Actuators of an Electric and Automated Vehicle.

Constant monitoring of driving conditions and observation of the surrounding area are essential for achieving reliable, high-quality autonomous driving. This requires more reliable sensors and actuators, as there is always the potential that sensors and actuators will fail under real-world conditions. The sensitive condition-monitoring methods of sensors and actuators should be used to improve the reliability of the sensors and actuators. They should be able to detect and isolate the abnormal situations of faulty sensors and actuators. In this paper, a developed model-based method for condition monitoring of the sensors and actuators in an electric vehicle is presented that can determine whether a sensor has a fault and further reconfigure the sensor signal, as well as detect the abnormal behavior of the actuators with the reconfigured sensor signals. Through the simulation data obtained by the vehicle model in complex road conditions, it is proved that the method is effective for the state detection of sensors and actuators.

The effect of duration of antimicrobial treatment for bacteremia in critically ill patients on in-hospital mortality - Retrospective double center analysis.

PURPOSE: Excessive duration of antibiotic treatment is a major factor for inappropriate antibiotic consumption. Although in some instances shorter antibiotic courses are as efficient as longer ones, no specific recommendations as to the duration of antimicrobial treatment for bloodstream infections currently exist. In the present study, we investigated the effect of antibiotic treatment duration on in-hospital mortality using retrospective data from two cohorts that included patients with bacteremia at two Swiss tertiary Intensive Care Units (ICUs). MATERIALS AND METHODS: Overall 8227 consecutive patients requiring ICU admission were screened for bacteremia between 01/2012-12/2013 in Lausanne and between 07/2016-05/2017 in Bern. Patients with an infection known to require prolonged treatment or having single positive blood culture with common contaminant pathogens were excluded. The primary outcome of interest was the time from start of antimicrobial treatment to in-hospital death or hospital discharge, whichever comes first. The predictor of interest was adequate antimicrobial treatment duration, further divided into shorter (≤10 days) and longer (>10 days) durations. A time-dependent Cox model and a cloning approach were used to address immortality bias. The secondary outcomes were the median duration of antimicrobial treatment for patients with bacteremia overall and stratified by underlying infectious syndrome and pathogens in the case of secondary bacteremia. RESULTS: Out of the 707 patients with positive blood cultures, 382 were included into the primary analysis. Median duration of antibiotic therapy was 14 days (IQR, 7-20). Most bacteremia (84%) were monomicrobial; 18% of all episodes were primary bacteremia. Respiratory (28%), intra-abdominal (23%) and catheter infections (17%) were the most common sources of secondary bacteremia. Using methods to mitigate the risk of confounding associated with antibiotic treatment durations, shorter versus longer treatment groups showed no differences in in-hospital survival (time-dependent Cox-model: HR 1.5, 95% CI (0.8, 2.7), p = 0.20; Cloning approach: HR 1.0, 95% CI (0.7,1.5) p = 0.83). Sensitivity analyses showed that the interpretation did not change when using a 7 days cut-off. CONCLUSIONS: In this restrospective study, we found no evidence for a survival benefit of longer (>10 days) versus shorter treatment course in ICU patients with bacteremia. TRIAL REGISTRATION: The study was retrospectively registered on clinicatrials.gov (NCT05236283), 11 February 2022. The respective cantonal ethics commission (KEK Bern # 2021-02302) has approved the study.

J-modulated 19 F- and 1 H-detected dual-optimized inverted 1 JCC 1,n-ADEQUATE: A universal ADEQUATE experiment.

The recently reported 19 F-detected dual-optimized inverted 1 JCC 1,n-ADEQUATE experiment and the previously reported 1 H-detected version have been modified to incorporate J-modulation, making it feasible to acquire all 1,1- and 1,n-ADEQUATE correlations as well as 1 JCC and n JCC homonuclear scalar couplings in a single experiment. The experiments are demonstrated using N,N-dimethylamino-2,5,6-trifluoro-3,4-phthalonitrile and N,N-dimethylamino-3,4-phthalonitrile.

19 F-detected dual-optimized inverted 1 JCC 1,n-ADEQUATE.

Modification of the recently reported 19 F-detected 1,1-ADEQUATE experiment that incorporates dual-optimization to selectively invert a wide range of 1 JCC correlations in a 1,n-ADEQUATE experiment is reported. Parameters for the dual-optimization segment of the pulse sequence were modified to accommodate the increased size of 1 JCC homonuclear coupling constants of poly- and perfluorinated molecules relative to protonated molecules to allow broadband inversion of the 1 JCC correlations. The observation and utility of isotope shifts are reported for the first time for 1,1- and 1,n-ADEQUATE correlations.

Development of 19 F-detected 1,1-ADEQUATE for the characterization of polyfluorinated and perfluorinated compounds.

Polyfluorinated and perfluorinated compounds in the environment are a growing health concern. 19 F-detected variants of commonly employed heteronuclear shift correlation experiments such as heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) are available; 19 F-detected experiments that employ carbon-carbon homonuclear coupling, in contrast, have never been reported. Herein, we report the measurement of the 1 JCC and n JCC coupling constants of a simple perfluorinated phthalonitrile and the first demonstration of a 19 F-detected 1,1-ADEQUATE experiment.

Neoadjuvant Chemotherapy in Pancreatic Cancer: An Appraisal of the Current High-Level Evidence.

At the time of diagnosis, only about 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have resectable disease. PDAC treatment necessitates a multidisciplinary approach, and adjuvant chemotherapy after upfront resection is an established means of preventing recurrence. Neoadjuvant chemotherapy (NAT), originally introduced to downstage tumor size, is nowadays more frequently used for selection of patients with favorable tumor biology and to control potential micrometastases. While NAT is routinely applied in locally advanced (LA) PDAC, there is increasing evidence demonstrating benefits of NAT in borderline resectable (BR) PDAC. The concept of NAT has recently been tested in resectable PDAC, but to date NAT has been restricted to clinical trials, as the data are limited and no clear benefits have yet been shown in this patient group. This review summarizes the current evidence for NAT in resectable, BR, and LA PDAC, with a focus on high-level evidence and randomized controlled trials.

Modular Approach for Odometry Localization Method for Vehicles with Increased Maneuverability.

Localization and navigation not only serve to provide positioning and route guidance information for users, but also are important inputs for vehicle control. This paper investigates the possibility of using odometry to estimate the position and orientation of a vehicle with a wheel individual steering system in omnidirectional parking maneuvers. Vehicle models and sensors have been identified for this application. Several odometry versions are designed using a modular approach, which was developed in this paper to help users to design state estimators. Different odometry versions have been implemented and validated both in the simulation environment and in real driving tests. The evaluated results show that the versions using more models and using state variables in models provide both more accurate and more robust estimation.

Age and sex specific incidence for depression from early childhood to adolescence: A 13-year longitudinal analysis of German health insurance data.

BACKGROUND: Epidemiological studies indicate a disproportionate increase of depression incidence among adolescent girls, compared with boys. Since results regarding the age of onset of this sex difference are heterogeneous, this study aimed to investigate this difference on a large and representative sample. A second investigation sought to clarify whether there is a relevant sex difference in prepubertal onset of depression regarding the further course. METHODS: Health insurance data of 6-18-year-old Barmer insured patients, representing a 7.9% sample of the German population born in 1999 (N = 61.199), were analyzed. The incidence of depression episodes (ICD-10 F32.x) was evaluated. Subsequently, the absolute and relative risk of a depression diagnosis (F32.x/F33.x) in early/late adolescence was analyzed based on the diagnosis of depression in primary school age in unstratified and stratified univariate analyses performed in SAS. RESULTS: From 13 years of age, we found a significantly higher incidence of depressive disorders in girls than in boys. More than a fifth of the children with a depression diagnoses in primary school age had a depression relapse in early or late adolescence (early: 23.2%; 95% CI 19.6-26.9/late: 22.9%; 95% CI 19.3-26.5). Boys with depression in primary school age have a significantly higher relative risk for a depression relapse in late adolescence than girls (boys RR 4.2, 95% CI 3.3-5.2, girls RR: 2.1, 95% CI 1.7-2.7). LIMITATIONS: The analysis is based on administrative data. Low sensitivity for depression in primary care setting and low service utilization leads to an underestimation of the incidence. CONCLUSIONS: During puberty the risk for a first depressive episode increases more steeply in girls than in boys. Childhood depression has a high risk of relapse for both sexes, but is much more pronounced for boys.

The adaptation and evaluation of a CBT-based manual for the inpatient treatment of youth depression: a pilot study.

BACKGROUND: Although there is good evidence to support the effectiveness of cognitive behavioral therapy (CBT) for the outpatient treatment of adolescent major depressive disorder (MDD), evidence-based manuals for the inpatient setting are lacking. This pilot study sought to (i) adapt an existing CBT manual (treatment of adolescent depression; TADS) to an inpatient setting (TADS-in), (ii) test its effectiveness at symptom reduction and remission of MDD in a pre-post design, and (iii) assess the strengths and limitations of the manual via a focus-group with clinicians. METHODS: Twenty nine adolescents aged 12-17 years with a primary ICD-10 diagnosis of MDD being treated as inpatients at a psychiatric clinic were included. Embedded in the regular inpatient treatment course (8 weeks), patients received 12 sessions of the TADS-in manual. Quantitative assessment of symptom reduction and remission of MDD was conducted using a non-controlled pre-post design. The quantitative results were supplemented by a focus group with participating psychotherapists. RESULTS: Of the 29 patients included in the study at the beginning, 19 (65.5%) remained in the study at week 8. Symptoms of depression were statistically significantly lower at the end of treatment than at baseline according to self- (d = 1.38; mean change = 19.88; 95% CI = 12.48-27.28) and other reports (d = 0.64, mean change = 0.35; 95% CI = 0.08-0.62). Clinicians ratings of improvement (CGI-I) suggested that at the end of treatment, 15.8% were very much improved, 68.4% much improved, and 15.8% were minimally improved. According to diagnostic interviews with patients conducted at the end of treatment, 73.3% were in remission. The qualitative analysis showed that on the whole, the TADS-in manual is suitable for the inpatient setting. However, clinicians believed the effectiveness of TADS-in was limited by patient comorbidity and the fact that the inpatients were unable to practice incorporating techniques learnt into everyday life. CONCLUSIONS: This study is the first to adapt the TADS manual to the inpatient setting. The sample of depressed adolescents showed reduced symptomology following treatment, although these findings require replicating in a randomized controlled trial before effects can be attributed to the TADS-in manual specifically. This pilot study informs further development of the manual as well as representing an important first step in the evaluation of the inpatient treatment of adolescent depression.The study was retrospectively registered (DRKS00017308) and received no external funding.

13C-13C spin-coupling constants in crystalline 13C-labeled saccharides: conformational effects interrogated by solid-state 13C NMR spectroscopy.

Solid-state 13C NMR spectroscopy has been used in conjunction with selectively 13C-labeled mono- and disaccharides to measure 13C-13C spin-couplings (JCC) in crystalline samples. This experimental approach allows direct correlation of JCC values with specific molecular conformations since, in crystalline samples, molecular conformation is essentially static and can be determined by X-ray crystallography. JCC values measured in the solid-state in known molecular conformations can then be compared to corresponding JCC values calculated in the same conformations using density functional theory (DFT). The latter comparisons provide important validation of DFT-calculated J-couplings, which is not easily obtained by other approaches and is fundamental to obtaining reliable experiment-based conformational models from redundant J-couplings by MA'AT analysis. In this study, representative 1JCC, 2JCCC and 3JCOCC values were studied as either intra-residue couplings in the aldohexopyranosyl rings of monosaccharides or inter-residue (trans-glycoside) couplings in disaccharides. The results demonstrate that (a) accurate JCC values can be measured in crystalline saccharides that have been suitably labeled with 13C, and (b) DFT-calculated JCC values compare favorably with those determined by solid-state 13C NMR when molecular conformation is a constant in both determinations.

Interactions between FKBP5 variation and environmental stressors in adolescent Major Depression.

OBJECTIVE: Major Depression (MD) results from a complex interplay between environmental stressors and biological factors. Previous studies in adults have shown that adverse life events interact with genetic variation in FKBP5, a gene implicated in the stress-response system, to predict depressive symptoms and MD. This is the first study to investigate interactions between FKBP5 variants and a range of environmental stressors in adolescents with a clinical diagnosis of MD. METHOD: 148 male and female adolescents with MD and 143 typically developing (TD) controls (13-18 years) were included in the present study. For self-reported environmental stressors, subjective severity was assessed to allow a classification of these factors as mild, moderate and severe. Sociodemographic stressors were assessed via parental-report. RESULTS: With a heightened number of sociodemographic, moderate and total number of stressors, participants carrying at least one copy of the FKBP5 CATT haplotype or at least one minor allele of various FKBP5 SNPs had the highest risk for being in the MD group. No genetic main effects were found. Sociodemographic stressors as well as self-reported mild, moderate, and severe stressors were more common in depressed than in TD adolescents. CONCLUSION: This is the first study to show interactions between genetic variation in FKBP5 and environmental stressors in a sample of clinically depressed adolescents. The current study provides important starting-points for preventive efforts and highlights the need for a fine-grained analysis of different forms and severities of environmental stressors and their interplay with genetic variation for understanding the complex etiology of (youth) MD.

Resting frontal EEG asymmetry in adolescents with major depression: Impact of disease state and comorbid anxiety disorder.

OBJECTIVE: Greater relative right- than left-frontal cortical activity has been frequently found in adults with major depression (MD). As the few studies in adolescents with MD have been inconclusive, the aim of this study was to assess frontal alpha asymmetry (FAA) in an adolescent sample with MD whilst taking into account possible confounding variables such as disease state and comorbid anxiety disorder. METHODS: An 8-minute resting frontal EEG was assessed in 34 healthy controls (HCs), 16 adolescents with MD in remission without comorbid anxiety disorder (rMDa-), 22 adolescents with acute depression without comorbid anxiety disorder (MDa-), and 23 adolescents with acute depression and comorbid anxiety disorder (MDa+). Alpha power was analyzed over corresponding frontal Regions of Interests. RESULTS: Compared to HCs, MDa+ adolescents demonstrated more left- than right-sided EEG alpha power, indicating greater right-than left-frontal cortical activity. No other group differences emerged. CONCLUSIONS: The results suggest that greater relative right-frontal cortical activity in adolescent MD is not a result of disease state but can be attributed to comorbid anxiety disorder. SIGNIFICANCE: Results suggest that FAA is not linked to adolescent depression per se and highlight the importance of considering comorbid disorders when examining asymmetry patterns in adolescent MD.

The prevalence and volumetry of pituitary cysts in children with growth hormone deficiency and idiopathic short stature.

Background Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented. Results Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm3 vs. 29.4 mm3, p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%±12.8 vs. 7.1%±8.0). Observers were blinded to patient groups. Conclusions GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure.

Dual-Bayes Localization Filter Extension for Safeguarding in the Case of Uncertain Direction Signals.

In order to run a localization filter for parking systems in real time, the directional information must be directly available when a distance measurement of the wheel speed sensor is detected. When the vehicle is launching, the wheel speed sensors may already detect distance measurement in the form of Delta-Wheel-Pulse-Counts (DWPCs) without having defined a rolling direction. This phenomenon is particularly problematic during parking maneuvers, where many small correction strokes are made. If a localization filter is used for positioning, the restrained DWPCs cannot process in real time. Without directional information in the form of a rolling direction signal, the filter has to ignore the DWPCs or artificially stop until a rolling direction signal is present. For this reason, methods for earlier estimation of the rolling direction based on the pattern of the incoming DWPCs and based on the force equilibrium have been presented. Since the new methods still have their weaknesses and a wrong estimation of the rolling direction can occur, an extension of a so-called Dual-Localization filter approach is presented. The Dual-Localization filter uses two localization filters and an intelligent initialization logic that ensures that both filters move in opposite directions at launching. The primary localization filter uses the estimated and the secondary one the opposite direction. As soon as a valid rolling direction signal is present, an initialization logic is used to decide which localization filter has previously moved in the true direction. The localization filter that has moved in the wrong direction is initialized with the states and covariances of the other localization filter. This extension allows for a fast and real-time capability to be achieved, and the accumulated velocity error can be dramatically reduced.

Sacroplasty: A Ten-Year Analysis of Prospective Patients Treated with Percutaneous Sacroplasty: Literature Review and Technical Considerations.

BACKGROUND: The treatment of sacral fractures has evolved since its first description in 1982. Several techniques for sacral augmentation have been developed since 2001, and the rate of improvement is rapid with over 50% reduction in pain achieved prior to post-procedure discharge of the patient. Pain reduction occurs primarily within the first 3 months and is sustained at 12 months; however, the long-term outcomes have not previously been studied. OBJECTIVES: We aim to evaluate the long-term efficacy of sacroplasty versus non-surgical management (NSM) in treating sacral insufficiency fractures (SIFs), including the effect on pain relief, opioid and other analgesic use, patient satisfaction, and complication rates. Additionally, we aim to review the most current sacroplasty literature. STUDY DESIGN: A 10-year prospective, observational cohort study of patients with SIFs treated with sacral augmentation. SETTING: A single-center interventional pain management private practice. METHODS: Two-hundred and forty-four patients with SIFs were treated with sacroplasty (210 patients) or NSM (34 patients) beginning in January 2004 and then followed for 10 years. The patients' gender, age, pre-procedure pain duration, analgesic use, pain level, and satisfaction were recorded at baseline and at post-procedure follow-up intervals of 2, 4, 12, 24, 52 weeks, and 2 years. The experimental group was then contacted at 10 years. Post-procedure complications before discharge and at each follow-up were also evaluated. RESULTS: Both NSM and sacroplasty resulted in statistically significant drops in visual analog scale (VAS) scores from pre-treatment to 2-year follow-up (P < 0.001). When measured from follow-up to follow-up, the NSM group's only significant decrease in the mean VAS score was between pre-treatment and 2 weeks (P = 0.002). The experimental group had significant decreases over the periods pre-op through post-op (P < 0.001), post-op through 2 weeks (P < 0.001), 12 weeks through 24 weeks (P = 0.014), and 24 weeks through one year (P = 0.002). The experimental cohort experienced statistically significant drops in the mean VAS scores between follow-ups for a longer period of time. Opioid and non-opioid analgesic use was markedly decreased preoperatively to postoperatively and was sustained at the 10-year follow-up. LIMITATIONS: Patients were placed into the control group, NSM, if they did not meet inclusion criteria for sacroplasty. However, the baseline characteristics of the sacroplasty versus NSM group were not statistically different. Additionally, the control group was only followed through 2 years and was not contacted at the 10-year follow-up. CONCLUSIONS: Our results and those reported in previous studies establish that sacroplasty allows for decreased use of medications and results in pain relief, greater patient mobility, and improved patient satisfaction. In addition to the published body of literature, our results show strong evidence in support of sacroplasty as a safe and efficacious treatment of SIFs. KEY WORDS: Sacroplasty, sacral fracture, fracture, osteoporosis, insufficiency, radiology.

Pavement type and wear condition classification from tire cavity acoustic measurements with artificial neural networks.

Tire road noise is the major contributor to traffic noise, which leads to general annoyance, speech interference, and sleep disturbances. Standardized methods to measure tire road noise are expensive, sophisticated to use, and they cannot be applied comprehensively. This paper presents a method to automatically classify different types of pavement and the wear condition to identify noisy road surfaces. The methods are based on spectra of time series data of the tire cavity sound, acquired under normal vehicle operation. The classifier, an artificial neural network, correctly predicts three pavement types, whereas there are few bidirectional mis-classifications for two pavements, which have similar physical characteristics. The performance measures of the classifier to predict a new or worn out condition are over 94.6%. One could create a digital map with the output of the presented method. On the basis of these digital maps, road segments with a strong impact on tire road noise could be automatically identified. Furthermore, the method can estimate the road macro-texture, which has an impact on the tire road friction especially on wet conditions. Overall, this digital map would have a great benefit for civil engineering departments, road infrastructure operators, and for advanced driver assistance systems.

Pituitary volume in children with growth hormone deficiency, idiopathic short stature and controls.

BACKGROUND: The objective of the study was to describe the pituitary volume (PV) in pediatric patients with isolated growth hormone deficiency (IGHD), idiopathic short stature (ISS) and normal controls. METHODS: Sixty-nine patients (57 male, 12 female), with a mean age of 11.9 (±2.0), were determined to have IGHD. ISS was identified in 29 patients (20 male, 9 female), with a mean age of 12.7 (±3.7). Sixty-six controls (28 female, 38 male), mean age 9.8 (±4.7) were also included. Three-dimensional (3D) magnetic resonance images with contrast were obtained to accurately measure PV. RESULTS: There was a significant difference in the mean PV among the three groups. The IGHD patients had a mean PV 230.8 (±89.6), for ISS patients it was 286.8 (±108.2) and for controls it was 343.7 (±145.9) (p<0.001). There was a normal increase in PV with age in the ISS patients and controls, but a minimal increase in the IGHD patients. CONCLUSIONS: Those patients with isolated GHD have the greatest reduction in PV compared to controls and the patients with ISS fall in between. We speculate that a possible cause for the slowed growth in some ISS patients might be related to diminished chronic secretion of growth hormone over time, albeit having adequate pituitary reserves to respond acutely to GH stimulation. Thus, what was called neurosecretory GHD in the past, might, in some patients, be relative pituitary hypoplasia and resultant diminished growth hormone secretion. Thus, PV determinations by magnetic resonance imaging (MRI) could assist in the diagnostic evaluation of the slowly growing child.