Feasibility, satisfaction, and goal attainment in routine telemedicine consultation in child and adolescent psychiatry and psychotherapy.

Telehealth services were rapidly adopted during the COVID-19 pandemic, but evidence regarding the effectiveness and feasibility of telehealth services in child and adolescent mental healthcare is sparse. This study aims to investigate feasibility, satisfaction, and goal attainment in video-delivered consultations in routine care child and adolescent psychiatry and psychotherapy. A total of 1046 patients from four university child and adolescent outpatient psychiatric clinics and one university outpatient unit for child and adolescent psychotherapy were screened for study participation. We examined a) the percentage of patients considered eligible for video-delivered consultation, b) clinicians', parents' and patients' satisfaction with video consultation, c) clinicians' ratings of goal attainment in video consultation, and d) factors associated with satisfaction and goal attainment. 59% of the screening sample (n = 621) fulfilled eligibility criteria and were considered eligible for video consultation. A total of 267 patients consented to participate in the study and received a video consultation. Clinicians reported high levels of satisfaction with video consultation and high levels of goal attainment in video consultations, especially for patients scheduled for initial patient assessments. Parents and patients were also highly satisfied with the video consultations, especially if patients had less severe emotional and behavioral problems. The present findings suggest that video consultations are a feasible and well-accepted alternative to in-person consultations in child and adolescent mental health care, especially for children with less severe symptoms and for children in early phases of assessment and treatment. Limitations include the lack of a control group. The study was registered at the German Clinical Trials Registry (DRKS00023525).

Webcam-Based Online Coaching with Children and Adolescents with Obsessive-Compulsive Disorders - A Single-Case Study.

Objective: Although there is clear evidence-based knowledge regarding state-of-the-art treatment for pediatric obsessive-compulsive disorder (OCD), two main issues remain in clinical practice: (1) Exposure-based cognitive behavioral therapy (CBT) is limited in terms of availability and accessibility or is not adequately provided, and (2) despite large effect sizes of exposure-based CBT, the achieved recovery rates of 50-60 % still show room for improvement. These issues have prompted an increasing focus on delivering exposure-based CBT in new and innovative ways. This study aims to evaluate an intensive therapist-administered online coaching program consisting of exposure with response prevention via video teleconferencing (VTC) as an add-on to weekly outpatient CBT (blended therapy). Method: The blended therapy is examined in n = 5 children and adolescents with OCD using an AB design and multi-informant ratings. Results: This single-case study shows promising results, indicating that a decrease in OCD severity and related functional impairment can be attributed to blended therapy. Moreover, satisfaction with online coaching was high. Conclusions: Despite some principal limitations, the results support the effectiveness and feasibility of blended therapy.

Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases.

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.

Progress feedback in children and adolescents with internalizing and externalizing symptoms in routine care (OPTIE study): study protocol of a randomized parallel-group trial.

BACKGROUND: Progress feedback provides therapists with progress notes on a regular basis through the continuous assessment of participants throughout their treatment (e.g., symptoms, therapeutic alliance). While for adults the evidence base has increased over the years, progress feedback in the therapy of children and adolescents has not been sufficiently investigated. This manuscript describes the trial protocol of the OPTIE study: a randomized trial that tests the efficacy of a progress feedback system in children and adolescents under conditions of routine care. METHODS: The study is based on a randomized parallel-group trial with two treatment groups (routine, feedback) at an outpatient unit of a university hospital. The target sample size is 439 families consisting of children and adolescents aged 6 to17 years old with internalizing and/or externalizing symptoms. Both the patients and the therapists are independently assigned to the treatment groups by stratified block randomization. In both treatment groups patients receive routine care behavioral therapy for a study-related 12 months; additionally, in the feedback group, a progress feedback system with three components is applied (monitoring, report, and supervision). For three informants (caregiver, child [≥ 11 years], therapist) surveys are conducted every 6 weeks (e.g., symptoms, goals, motivation). For both treatment groups, comparison data is collected at baseline and at six and 12 months after the beginning of the intervention (pre, inter, post), and includes five informants (blinded clinician, therapist, caregiver, child [≥ 11 years], teacher). DISCUSSION: The OPTIE study will contribute to the evidence base of progress feedback in children and adolescents and has the potential to uncover treatments' effects in the small to medium range. Noteworthy features are the inclusion of children younger than 10 years old and the consideration of a blinded clinician rating. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00016737 ( https://www.drks.de/DRKS00016737 ). Registered 17 September, 2019.

Incidence of concomitant chondral/osteochondral lesions in acute ankle fractures and their effect on clinical outcome: a systematic review and meta-analysis.

INTRODUCTION: Despite successful osteosynthesis, some patients report residual symptoms after ankle fractures. One of the reasons behind the postoperative complaints might be traumatic concomitant chondral lesions (CL) and/or osteochondral lesions (OCL) within the ankle joint. The study aims to systematically review the incidence of CL and/or OCL in ankle fractures and to assess their effect on the clinical outcome. MATERIALS AND METHODS: This work was conducted according to PRISMA checklists. A systematic literature search was performed using following keywords: "Ankle Fractures" OR "Trimalleolar Fracture" OR "Bimalleolar Fracture" OR "Maisonneuve fracture" OR "Malleolus Fracture" AND "Cartilage" OR "Cartilage Diseases" OR "Cartilage, Articular" OR "chondral" up to March 2020. The identified articles were analysed to determine the incidence of CL and/or OCL. Included studies in the meta-analysis assessed possible cartilage damage through arthroscopy or MRI immediately after traumatic ankle fractures and described the postoperative clinical outcome. RESULTS: The search identified a total of 111 publications; 19 described the incidence of CL and/or OCL after ankle fractures; six met the criteria to be included in the meta-analysis: five (n = 293) diagnosed CL and/or OCL through arthroscopy during ORIF and one study (n = 153) used preoperative MRI. The clinical outcome was evaluated in four studies (n = 177) using AOFAS score and in two (n = 269) using FAOS score. The mean incidence of arthroscopically detected CL and/or OCL was 65 ± 21% [95% CI 53.9 to 76.72]. The cumulative meta-analysis sample size comprised a total of 400 Patients (170 with and 230 without CL and/or OCL) available for a mean follow-up of 23.9 ± 11.5 months [95% CI 11.79 to 36.07]. The average age was 44.3 ± 5.5 years [95% CI 38.57 to 50.13]. The meta-analysis revealed a mean AOFAS score of 91.2 ± 4.8 [95% CI 83.53 to 98.93] with versus 94.4 ± 4.7 [95% CI 86.81 to 102.07] without CL and/or OCL (p = 0.15) and a mean FAOS score of 73.2 ± 11.31 [95% CI - 28.44 to 174.85] with versus 79.0 ± 18.4 [95% CI - 86.77 to 244.87] without CL and/or OCL (p = 0.18). CONCLUSIONS: CL and/or OCL appear very frequently after ankle fractures. A tendency towards a favourable short- to mid-term clinical outcome was noticed in ankle fractures without CL and/or OCL, however without reaching statistical significance. LEVEL OF EVIDENCE: Level I.

[The mental burden of children, adolescents, and their families during the COVID-19 pandemic and associations with emotional and behavioral problems]. / Die psychische Belastung von Kindern, Jugendlichen und ihren Familien während der COVID-19-Pandemie und der Zusammenhang mit emotionalen und Verhaltensauffälligkeiten.

BACKGROUND AND OBJECTIVE: The infection protection measures adopted as part of the COVID-19 pandemic led to profound restrictions and changes in the social, (pre-) school, family, and leisure areas. The objective of the current study was to examine the mental burden of children and adolescents and their families during the COVID-19 pandemic. Furthermore, this study aimed to identify possible factors that influence the mental burden. MATERIALS AND METHODS: The examinations were carried out between autumn 2020 and spring 2021 in a clinical sample (n = 280 patients aged 4-17 years) and a community sample (n = 1958 children and adolescents aged 4-19 years recruited via schools and preschools). Ratings of parents as well as children and adolescents via questionnaires were assessed. RESULTS: Mental burden due to the corona pandemic was assessed as slightly to moderately increased across both rating perspectives and both samples. Overall, around 60 to 70% of the parents, children, and adolescents describe an increase in mental burden; in contrast, up to 12% of parents as well as children and adolescents describe relief. When comparing both samples, a slightly higher burden on children and adolescents can only be seen in the self-assessment of the clinical sample. None of the socio-demographic factors analyzed influences the mental burden statistically significant. However, low to moderate correlations between the subjectively experienced deterioration in the family and social situation and an increased level of stress is found. DISCUSSION: Targeted interventions for exposed subgroups should be offered during a pandemic. Universal interventions are not indicated.

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats.

Charcot-Marie-Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low-dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co-culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant ("translational") study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003-treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003-treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003-treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

MuB is an AAA+ ATPase that forms helical filaments to control target selection for DNA transposition.

MuB is an ATP-dependent nonspecific DNA-binding protein that regulates the activity of the MuA transposase and captures target DNA for transposition. Mechanistic understanding of MuB function has previously been hindered by MuB's poor solubility. Here we combine bioinformatic, mutagenic, biochemical, and electron microscopic analyses to unmask the structure and function of MuB. We demonstrate that MuB is an ATPase associated with diverse cellular activities (AAA+ ATPase) and forms ATP-dependent filaments with or without DNA. We also identify critical residues for MuB's ATPase, DNA binding, protein polymerization, and MuA interaction activities. Using single-particle electron microscopy, we show that MuB assembles into a helical filament, which binds the DNA in the axial channel. The helical parameters of the MuB filament do not match those of the coated DNA. Despite this protein-DNA symmetry mismatch, MuB does not deform the DNA duplex. These findings, together with the influence of MuB filament size on strand-transfer efficiency, lead to a model in which MuB-imposed symmetry transiently deforms the DNA at the boundary of the MuB filament and results in a bent DNA favored by MuA for transposition.

Higher Accuracy of Arthroscopy Compared to MRI in the Diagnosis of Chondral Lesions in Acute Ankle Fractures: A Prospective Study.

Even after successful surgery for acute ankle fractures, many patients continue having complaints. A possible explanation is the presence of concomitant chondral lesions. The aim of this study is to investigate the accuracy of MRI compared to that of arthroscopy in the assessment of chondral lesions in acute ankle fractures. In this prospective single-center study, patients presenting with acute ankle fractures over a period of three years were identified. A preoperative MRI was performed within a maximum of 10 days after trauma. During surgery, ankle arthroscopy was also performed. The International Cartilage Repair Society (ICRS) cartilage lesion classification was used to grade the detected chondral lesions. To localize the chondral lesions, the talar dome was divided into eight zones and the tibial/fibular articular surfaces into three zones. In total, 65 patients (28 females) with a mean age of 41.1 ± 15 years were included. In the MRI scans, 70 chondral lesions were detected (69.2% of patients) affecting mostly the tibial plafond (30%) and mostly graded as ICRS 3. The mean lesion area measured was 20.8 mm2. In the arthroscopy, 85 chondral lesions were detected (70.8% of patients) affecting mostly the medial surface of the talar dome (25.9%) and mostly graded ICRS 3. The mean lesion area measured was 43.4 mm2. The highest agreement between the two methods was observed in the size estimation of the chondral lesions. The present study shows the reduced accuracy of MRI when compared to arthroscopy in the assessment of traumatic chondral lesions in the setting of acute ankle fractures especially regarding lesion size. MRI remains an essential instrument in the evaluation of such lesions; however, surgeons should take this discrepancy into consideration, particularly the underestimation of chondral lesions' size in the preoperative planning of surgical treatment and operative technique.

A Multi-Disciplinary MRI Assessment May Optimize the Evaluation of Chondral Lesions in Acute Ankle Fractures: A Prospective Study.

Chondral lesions (CL) in the ankle following acute fractures are frequently overlooked immediately after the injury or diagnosed at a later stage, leading to persistent symptoms despite successful surgery. The literature presents a wide range of discrepancies in the reported incidence of CLs in acute ankle fractures. The objective of this prospective study is to provide a precise assessment of the occurrence of chondral lesions (CLs) in acute ankle fractures through MRI scans conducted immediately after the trauma and prior to scheduled surgery. Furthermore, the study aims to highlight the disparities in the interpretation of these MRI scans, particularly concerning the size and extent of chondral damage, between radiologists and orthopedic surgeons. Over the period of three years, all patients presenting with an unstable ankle fracture that underwent operative treatment were consecutively included in this single-center prospective study. Preoperative MRIs were obtained for all included patients within 10 days of the trauma and were evaluated by a trauma surgeon and a radiologist specialized in musculoskeletal MRI blinded to each other's results. The location of the lesions was documented, as well as their size and ICRS classification. Correlations and kappa coefficients as well as the p-values were calculated. A total of 65 patients were included, with a mean age of 41 years. The evaluation of the orthopedic surgeon showed CLs in 52.3% of patients. CLs occurred mainly on the tibial articular surface (70.6%). Most talar lesions were located laterally (11.2%). The observed CLs were mainly ICRS grade 4. According to the radiologist, 69.2% of the patients presented with CLs. The most common location was the talar dome (48.9%), especially laterally. Most detected CLs were graded ICRS 3a. The correlation between the two observers was weak/fair regarding the detection and classification of CLs and moderate regarding the size of the detected CLs. To enhance the planning of surgical treatment for ankle chondral lesions (CLs), it may be beneficial to conduct an interdisciplinary preoperative assessment of the performed scans. This collaborative approach can optimize the evaluation of ankle CLs and improve overall treatment strategies.

Satisfaction with videoconference-delivered CBT provided as part of a blended treatment approach for children and adolescents with mental disorders and their families during the COVID-19 pandemic: A follow-up survey among caregivers and therapists.

INTRODUCTION: Psychotherapy delivered via videoconferencing (teletherapy) was a well-accepted treatment option for children and adolescents during the early phases of the COVID-19 pandemic. Information on the long-term satisfaction with teletherapy in routine clinical practice is missing. METHODS: Caregivers (parents) and psychotherapists of n = 228 patients (4-20 years) treated in a university outpatient clinic completed a follow-up survey on satisfaction with videoconference-delivered cognitive-behavioral treatment (CBT). The follow-up survey (T2) was conducted about 1 year after initial assessment of treatment satisfaction in 2020 (T1). RESULTS: At follow up, therapists reported that 79% of families had received teletherapy as part of a blended treatment approach including in-person and videoconference delivery of CBT. Wilcoxon tests revealed that satisfaction with teletherapy was stable over time. In addition, parent ratings of the impact of teletherapy on treatment satisfaction and the therapeutic relationship did not change over time. Therapists' ratings of the impact of teletherapy on the therapeutic relationship with the caregiver were more negative at T2 compared to T1. Satisfaction with teletherapy was higher for patients with less pandemic-related stress, less externalizing behavior problems, and older age (all r < .35). CONCLUSION: The high level of satisfaction with teletherapy for children and adolescents treated in routine clinical practice reported in 2020 was maintained after social distancing regulations were eased in 2021. Teletherapy provided as part of a blended treatment approach is a well-accepted method of treatment delivery for youths with mental health problems. The study was registered in the German Clinical Trials Register (DRKS00028639).

Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain.

Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.

Cognitive-behavioral teletherapy for children and adolescents with mental disorders and their families during the COVID-19 pandemic: a survey on acceptance and satisfaction.

BACKGROUND: The COVID-19 pandemic is challenging for health care systems around the world. Teletherapy (psychotherapy conducted via videoconference) for children and adolescents offers a promising opportunity not only to provide treatment during social distancing restrictions but also to reduce treatment barriers that might prevent families from seeking care independent of the pandemic. Therefore, it is highly important to examine the implementation and especially the acceptance of and satisfaction with teletherapy. METHODS: Therapists of 561 patients and parents of 227 patients (total 643 patients) aged 3-20 years treated at a university outpatient unit rated their experiences with teletherapy. RESULTS: Following the outbreak of COVID-19, 73% of the patients switched from face-to-face treatment to teletherapy. Both therapists and parents were mainly satisfied with teletherapy and did not report negative impacts on treatment satisfaction or the therapeutic relationship. Stress from COVID-19, age, gender, duration of treatment, psychosocial functioning, and psychopathology were associated with satisfaction, but correlations were low. Sixty-six percent of parents and 53% of therapists intended to use teletherapy in the future. CONCLUSIONS: Teletherapy during the COVID-19 pandemic was well accepted by both parents and therapists. Certain patient characteristics were related to satisfaction. Trial registration The study was retrospectively registered in the German Clinical Trials Register (DRKS00028639).

Extended treatment of multimodal cognitive behavioral therapy in children and adolescents with obsessive-compulsive disorder improves symptom reduction: a within-subject design.

BACKGROUND: Based on the current state of research regarding the treatment in pediatric obsessive-compulsive disorder (OCD), cognitive behavioral therapy (CBT) (in severe cases with additional pharmacotherapy) is considered as the first-line treatment according to internationally recognized guidelines. Research is mostly based on randomized controlled trials (RCTs; efficacy research). Thus, examined treatment conditions, especially the treatment duration, and patients' characteristics do not necessarily correspond to those found within routine care. Studies showed CBT packages as a whole to be efficacious, but less is known about the effects of individual CBT components. Furthermore, effects on comorbid symptoms or psychosocial impairment have been often neglected and different rater perspectives have been hardly considered in previous research. METHODS: This effectiveness study aimed to examine the effects of multimodal CBT in children, adolescents, and young adults (age 6-20 years) with OCD (n = 38) within routine care. Effects on obsessive-compulsive and co-existing symptoms were evaluated in a within-subject design by comparing changes during the assessment phase with 12-week standard treatment and with individually tailored extended treatment. Additionally, within the standard treatment, non-exposure treatment was compared to exposure treatment. Multi-informant assessment was applied, and the analyses included multilevel modeling and t-tests for pre-post comparisons. RESULTS: During the standard treatment and extended treatment, obsessive-compulsive symptoms, strain, and functional impairment significantly decreased. Moreover, a significant reduction of overall comorbid symptoms emerged, particularly regarding internalizing symptoms, including anxiety and depression. Comparisons of treatment components indicated that adding exposure with response prevention (ERP) has an additional positive effect. Clinical improvement and remission rates increased considerably when more treatment sessions were provided. CONCLUSIONS: These results suggest that improvement after an initial 12-week course of treatment may not allow for the prediction of non-responders/non-remitters and for the termination of treatment. Overall, the findings show that results from randomized controlled trials are transferrable to routine care. Trial registration number This study was registered retrospectively at the German Clinical Trials Register ( https://drks.de/search/de/trial/DRKS00030050 ).

Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.

Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists.

Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.

Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor.

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.