Thyroid hormone levels in children with Prader-Willi Syndrome: A randomized controlled Growth Hormone (GH)-trial and 10-year GH study.

CONTEXT: Several endocrine abnormalities were reported in children with Prader-Willi Syndrome (PWS), including hypothyroidism. Growth hormone (GH)-treatment may impact the thyroid-hormone-axis by direct inhibition of T4 or TSH secretion or by increased peripheral conversion of free T4 (FT4) to T3. OBJECTIVE: To evaluate thyroid function during GH-treatment in a large group of children with PWS. METHODS: Serum FT4, T3 and TSH measured in a 2-year randomized-controlled-GH-trial (RCT) and 10-year-longitudinal-GH-study. GH-treatment with 1.0 mg/m²/day (∼0.035mg/kg/day). RESULTS: Forty-nine children with PWS were included in the 2-year RCT (median (IQR) age GH-group 7.44 (5.47-11.80) years, control group 6.04 (4.56-7.39) years). During the first 6 months, median (IQR) FT4 SDS decreased in GH-group from -0.84 (-1.07 to -0.62) to -1.32 (-1.57 to -1.08) (p<0.001) and T3 SDS increased from 0.31 (-0.01 to 0.63) to 0.56 (0.32 to 0.79) (p=0.08), while in control group, FT4 and T3 SDS remained unchanged. In our 10-year-GH-study, 240 children with PWS (median (IQR) age 1.27 (0.54-4.17) years) were included. Between 2-10 years, median (IQR) FT4 SDS remained unchanged, being -0.87 (-0.98 to -0.77) after 2 years and -0.88 (-1.03 to -0.74) after 10 years (p=0.13). TSH SDS decreased from -0.35 (-0.50 to -0.21) after 2 years to -0.68 (-0.84 to -0.53) after 10 years (p<0.001). CONCLUSIONS: Our findings suggest that GH-treatment decreases FT4 levels, due to increased peripheral conversion of FT4 to T3 in the first months of treatment, but thereafter FT4 and T3 normalize and remain stable during long-term GH-treatment in almost all children and adolescents with PWS.

Ultrasonic mapping of midpalatal suture - An ex-vivo study.

OBJECTIVE: Rapid maxillary expansion is a common orthodontic procedure to correct maxillary constriction. Assessing the midpalatal suture (MPS) expansion plays a crucial role in treatment planning to determine its effectiveness. The objectives of this preliminary investigation are to demonstrate a proof of concept that the palatal bone underlying the rugae can be clearly imaged by ultrasound (US) and the reconstructed axial view of the US image accurately maps the MPS patency. METHODS: An ex-vivo US scanning was conducted on the upper jawbones of two piglet's carcasses before and after the creation of bone defects, which simulated the suture opening. The planar images were processed to enhance bone intensity distribution before being orderly stacked to fuse into a volume. Graph-cut segmentation was applied to delineate the palatal bone to generate a bone volume. The accuracy of the reconstructed bone volume and the suture opening was validated by the micro-computed tomography (µCT) data used as the ground truth and compared with cone beam computed tomography (CBCT) data as the clinical standard. Also included in the comparison is the rugae thickness. Correlation and Bland-Altman plots were used to test the agreement between the two methods: US versus µCT/CBCT. RESULTS: The reconstruction of the US palatal bone volumes was accurate based on surface topography comparison with a mean error of 0.19 mm for pre-defect and 0.15 mm and 0.09 mm for post-defect models of the two samples, respectively when compared with µCT volumes. A strong correlation (R2 ≥ 0.99) in measuring MPS expansion was found between US and µCT/CBCT with MADs of less than 0.05 mm, 0.11 mm and 0.23 mm for US, µCT and CBCT, respectively. CONCLUSIONS: It was possible to axially image the MPS opening and rugae thickness accurately using high-frequency ultrasound. CLINICAL SIGNIFICANCE: This study introduces an ionizing radiation-free, low-cost, and portable technique to accurately image a difficult part of oral cavity anatomy. The advantages of conceivable visualization could promise a successful clinical examination of MPS to support the predictable treatment outcome of maxillary transverse deficiency.

[Paediatricians report an increased demand for diagnostic tests for reassurance]. / Kinderartsen zien meer vraag naar diagnostiek ter geruststelling.

OBJECTIVE: Test decisions depend on the context in which health care is delivered. We interviewed paediatricians about perceived societal developments and their influence on diagnostic testing. DESIGN: Qualitative interview study. METHODS: Semi-structured in-depth interviews with 20 practicing Dutch paediatricians. RESULTS: Paediatricians associated societal developments, such as decreased risk acceptance, with perceived pressure from parents to perform tests. They were motivated to restrict unnecessary tests to avoid harming the child. CONCLUSION: Besides motivation and effort of health care providers, appropriate testing requires system-level actions, such as counteracting a culture of blame and considering societal interests in guideline recommendations.

Measured resting energy expenditure by indirect calorimetry and energy intake in long-term growth hormone treated children with PWS.

INTRODUCTION: Severe obesity can develop in children with PWS when food intake is not controlled. Maintenance of body weight requires an energy balance, of which energy intake and energy expenditure are important components. Previous studies described a decreased resting energy expenditure (REE) in growth hormone (GH)-untreated children with PWS. In short-term studies, no difference in REE was found between GH-treated and untreated children with PWS. However, there are limited data on REE in children with PWS who were GH-treated for a long period. METHODS: This study describes measured REE (mREE), energy intake and body composition during long-term GH-treatment in children with PWS. Patients were treated with 1.0 mg GH/m2/day (~0.035mg/kg/day). REE was determined by indirect calorimetry; dietary energy intake was calculated using a 3-day dietary record. Body composition by Dual energy X-ray absorptiometry (DXA) scans. RESULTS: We included 52 GH-treated children with PWS with mean (SD) age of 8.53 (4.35) years and median (IQR) GH-treatment duration of 7 (4-11) years. mREE increased with age, but was not associated with GH-treatment duration. A higher LBM was associated with higher mREE. Mean energy intake was significantly lower compared to daily energy requirements (DER) for age- and sex-matched healthy children (p<0.001), ranging from 23-36% less intake in children aged 3.5-12 years to 49% less intake in children aged 12-18 years. Fifty percent of children had a normal REE, 17.3 % a decreased REE and 32.7% an elevated REE, according to predicted REE based on measured REE in a large group of healthy children. CONCLUSION: In children with PWS, mREE increases with age. GH-treatment duration is not associated, whereas LBM is an important determinant of mREE. Children with PWS have a low to very low energy intake compared to DER for age- and sex-matched children, with a declining intake when becoming older.

Children with Intestinal Failure are at Risk for Psychopathology and Trauma.

OBJECTIVES: The objective of this study is to assess the psychopathology and medical traumatic stress in children with intestinal failure (IF) and identify associated risk factors. METHODS: Two-center study, performed from September 2019 until April 2022 (partly during COVID-19 pandemic), including children (1.5-17 years) with IF, dependent on parenteral nutrition (PN) or weaned off PN, treated by a multidisciplinary IF-team. Psychopathology in children was evaluated with a semi-structured interview assessing psychiatric classifications and validated questionnaires assessing emotional (internalizing) and behavioral (externalizing) problems. Medical traumatic stress was assessed with a validated questionnaire. Problem scores were compared with normative data. Associations between clinical characteristics and outcomes were analyzed with linear regression analyses. RESULTS: Forty-one (of 111 eligible) children were included [median age 8.9 years (interquartile range, IQR 5.5-11.8), 54% female, 73% born preterm]. Median PN-duration was 17.3 months (IQR 6.9-54.0); 17 children (41%) were still PN-dependent. One third of the children met criteria for at least 1 psychiatric classification (compared with 14% in age-matched general population). Anxiety disorders and attention deficit hyperactivity disorder were most common. In school-aged children (n = 29, 6-17 years), significantly increased emotional problems were consistently reported by children ( P = 0.011), parents ( P < 0.001), and teachers ( P = 0.004). In preschool children (n = 12, 1.5-5 years), no significant differences with normative data were found. Subclinical or clinical emotional problems were reported in 19 children (46%). Medical traumatic stress was present in 14%, and 22% of children had received psychological help for trauma before. Lower gastrointestinal related quality of life was associated with more emotional problems, but not PN-duration. CONCLUSIONS: Children with IF, particularly school-aged children, are at risk for psychological problems which is reflected by the high rate of received psychotherapy and the high rate of emotional problems and psychiatric classifications.

Validation of an artificial intelligence-based method to automate Cobb angle measurement on spinal radiographs of children with adolescent idiopathic scoliosis.

BACKGROUND: Accurately measuring the Cobb angle on radiographs is crucial for diagnosis and treatment decisions for adolescent idiopathic scoliosis (AIS). However, manual Cobb angle measurement is time-consuming and subject to measurement variation, especially for inexperienced clinicians. AIM: This study aimed to validate a novel artificial-intelligence-based (AI) algorithm that automatically measures the Cobb angle on radiographs. DESIGN: This is a retrospective cross-sectional study. SETTING: The population of patients attended the Stollery Children's Hospital in Alberta, Canada. POPULATION: Children who: 1) were diagnosed with AIS, 2) were aged between 10 and 18 years old, 3) had no prior surgery, and 4) had a radiograph out of brace, were enrolled. METHODS: A total of 330 spinal radiographs were used. Among those, 130 were used for AI model development and 200 were used for measurement validation. Automatic Cobb angle measurements were validated by comparing them with manual ones measured by a rater with 20+ years of experience. Analysis was performed using the standard error of measurement (SEM), inter-method intraclass correlation coefficient (ICC2,1), and percentage of measurements within clinical acceptance (≤5°). Subgroup analysis was conducted by severity, region, and X-ray system to identify any systematic biases. RESULTS: The AI method detected 346 of 352 manually measured curves (mean±standard deviation: 24.7±9.5°), achieving 91% (316/346) of measurements within clinical acceptance. Excellent reliability was obtained with 0.92 ICC and 0.79° SEM. Comparable performance was found throughout all subgroups, and no systematic biases in performance affecting any subgroup were discovered. The algorithm measured each radiograph approximately 18s on average which is slightly faster than the estimated measurement time of an experienced rater. Radiographs taken by the EOS X-ray system were measured more quickly on average than those taken by a conventional digital X-ray system (10s vs. 26s). CONCLUSIONS: An AI-based algorithm was developed to measure the Cobb angle automatically on radiographs and yielded reliable measurements quickly. The algorithm provides detailed images on how the angles were measured, providing interpretability that can give clinicians confidence in the measurements. CLINICAL REHABILITATION IMPACT: Employing the algorithm in practice could streamline clinical workflow and optimize measurement accuracy and speed in order to inform AIS treatment decisions.

Cognitive function during 3 years of growth hormone in previously growth hormone-treated young adults with Prader-Willi syndrome.

CONTEXT: Most patients with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on cognition in children with PWS. Few studies, however, have investigated the effects of GH on cognitive functioning in adults with PWS. OBJECTIVE: To investigate the effects of 3 years of GH treatment on cognitive functioning and behavior in young adults with PWS who were treated with GH during childhood. DESIGN: Open-label, prospective study. SETTING: Dutch PWS Reference Center. METHODS: Patients were treated with 0.33 mg GH/m²/day (∼0.012 mg/kg/day; 33% of childhood dose). Cognitive functioning was measured by Wechsler Adult Intelligence (WAIS) tests. Behavior was studied by a developmental behavior checklist-parents/caregivers (DBC-P). RESULTS: Forty-six young adults with PWS with a median age of 19 (IQR 17-21) years were investigated. Estimated mean (95% CI) total, verbal, and performance IQ remained stable during 3 years of GH-treatment. Total IQ being 66 (63-69) at the start and 67 (64-71) after 3 years (P = .30); Verbal IQ being 65 (62-68) and 66 (62-70), respectively (P = .31) and performance IQ being 67 (63-70) and 67 (63-72) resp. (P = .42). Estimated mean Total DBC score did not significantly change during 3 years of GH-treatment, being 36.3 at start and 36.5 after 3 years (P = .94) (P50). CONCLUSIONS: Three years of GH-treatment in young adults with PWS with 33% of the pediatric dose, maintains total, verbal, and performance IQ. The emotional and behavioral disturbances remained stable and were similar compared to peers with other intellectual disabilities.

Measuring the alveolar bone level in adolescents: A comparison between ultrasound and cone beam computed tomography.

BACKGROUND: Cone beam computed tomography (CBCT) is an imaging modality, which is used routinely in orthodontic diagnosis and treatment planning but delivers much higher radiation than conventional dental radiographs. Ultrasound is a noninvasive imaging method that creates an image without ionizing radiation. AIM: To investigate the reliability of ultrasound and the agreement between ultrasound and CBCT in measuring the alveolar bone level (ABL) on the buccal/labial side of the incisors in adolescent orthodontic patients. DESIGN: One hundred and eighteen incisors from 30 orthodontic adolescent patients were scanned by CBCT with 0.3-mm voxel size and ultrasound at 20 MHz frequency. The ABL, distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC), was measured twice to evaluate the agreement between ultrasound and CBCT. In addition, the intra- and inter-rater reliabilities in measuring the ABL by four raters were compared. RESULTS: The mean difference (MD) in the ABL between ultrasound and CBCT was -0.07 mm with 95% limit of agreement (LoA) from -0.47 to 0.32 mm for all teeth. For each jaw, the MDs between the ultrasound and CBCT were -0.18 mm (for mandible with 95% LoA from -0.53 to 0.18 mm) and 0.03 mm (for maxilla with 95% LoA from -0.28 to 0.35 mm). In comparison, ultrasound had higher intra-rater (ICC = 0.83-0.90) and inter-rater reliabilities (ICC = 0.97) in ABL measurement than CBCT (ICC = 0.56-0.78 for intra-rater and ICC = 0.69 for inter-rater reliabilities). CONCLUSION: CBCT parameters used in orthodontic diagnosis and treatment planning in adolescents may not be a reliable tool to assess the ABL for the mandibular incisors. On the contrary, ultrasound imaging, an ionizing radiation-free, inexpensive, and portable diagnostic tool, has potential to be a reliable diagnostic tool in assessing the ABL in adolescent patients.

Ultrasound Imaging of Hip Displacement in Children With Cerebral Palsy.

OBJECTIVE: An approach to estimation of hip displacement on ultrasound (US) images is described. Its accuracy is validated through numerical simulation, an in vitro study with 3-D-printed hip phantoms and pilot in vivo data. METHODS: A diagnostic index, migration percentage (MP), is defined by the ratio of acetabulum-femoral head distance to femoral head width. The acetabulum-femoral head distance could be measured directly on hip US images, while the femoral head width was estimated from the diameter of a best-fit circle. Simulation was performed to evaluate the accuracy of circle fitting with noiseless and noisy data. Surface roughness was also considered. Nine hip phantoms (three different sizes of femur head × three MP values) and 10 US hip images were used in this study. RESULTS: The maximum diameter error was 16.1 ± 8.5% when the roughness and noise were 20% of the original radius and 20% of the wavelet peak, respectively. In the phantom study, the percentage errors of MPs between the 3-D-design US and X-ray US were 0.3%-6.6% and 0.0%-5.7%, respectively. From the pilot clinical trial, the mean absolute difference between the X-ray-US MPs was 3.5 ± 2.8% (1%-9%). CONCLUSION: This study indicates that the US method can be used to evaluate hip displacement in children.

Diagnostic testing in children: A qualitative study of pediatricians' considerations.

AIMS AND OBJECTIVES: Studies in adult medicine have shown that physicians base testing decisions on the patient's clinical condition but also consider other factors, including local practice or patient expectations. In pediatrics, physicians and parents jointly decide on behalf of a (young) child. This might demand more explicit and more complex deliberations, with sometimes conflicting interests. We explored pediatricians' considerations in diagnostic test ordering and the factors that influence their deliberation. METHOD: We performed in-depth, semistructured interviews with a purposively selected heterogeneous sample of 20 Dutch pediatricians. We analyzed transcribed interviews inductively using a constant comparative approach, and clustered data across interviews to derive common themes. RESULTS: Pediatricians perceived test-related burden in children higher compared with adults, and reported that avoiding an unjustified burden causes them to be more restrictive and deliberate in test ordering. They felt conflicted when parents desired testing or when guidelines recommended diagnostic tests pediatricians perceived as unnecessary. When parents demanded testing, they would explore parental concern, educate parents about harms and alternative explanations of symptoms, and advocate watchful waiting. Yet they reported sometimes performing tests to appease parents or to comply with guidelines, because of feared personal consequences in the case of adverse outcomes. CONCLUSION: We obtained an overview of the considerations that are weighed in pediatric test decisions. The comparatively strong focus on prevention of harm motivates pediatricians to critically appraise the added value of testing and drivers of low-value testing. Pediatricians' relatively restrictive approach to testing could provide an example for other disciplines. Improved guidelines and physician and patient education could help to withstand the perceived pressure to test.

Ultrasound Imaging of the Periodontium Complex: A Reliability Study.

Background: Ultrasonography is a noninvasive, low-cost diagnostic tool widely used in medicine. Recent studies have demonstrated that ultrasound imaging might have the potential to be used intraorally to assess periodontal biomarkers. Objectives: To evaluate the reliability of interlandmark distance measurements on intraoral ultrasound images of the periodontal tissues. Materials and Methods: Sixty-four patients from the graduate periodontics (n = 33) and orthodontics (n = 31) clinics were recruited. A 20 MHz handheld intraoral ultrasound transducer was used to scan maxillary and mandibular incisors, canines, and premolars. Distances between the alveolar bone crest and cementoenamel junction (ABC-CEJ), gingival thickness (GT), and alveolar bone thickness (ABT) were measured by 3 raters. The intercorrelation coefficient (ICC) and mean absolute deviation (MAD) were calculated among and between the raters. Raters also scored images according to quality. Results: The ICC scores for intrarater reliability were 0.940 (0.932-0.947), 0.953 (0.945-0.961), and 0.859 (0.841-0.876) for ABC-CEJ, GT, and ABT, respectively. The intrarater MAD values were 0.023 (±0.019) mm, 0.014 (±0.005) mm, and 0.005 (±0.003) mm, respectively. The ICC scores for interrater reliability were 0.872 (95% CI: 0.836-0.901), 0.958 (95% CI: 0.946-0.968), and 0.836 (95% CI: 0.789-0.873) for ABC-CEJ, GT, and ABT, respectively. The interrater MAD values were 0.063 (±0.029) mm, 0.023 (±0.018) mm, and 0.027 (±0.012) mm, respectively. Conclusions: The present study showed the high reliability of ultrasound in both intrarater and interrater assessments. Results suggest there might be a potential use of intraoral ultrasound to assess periodontium.

Estimating Crestal Thickness of Alveolar Bones on Intra-oral Ultrasonograms.

OBJECTIVE: Alveolar crestal bone thickness and level provide important diagnostic and prognostic information for orthodontic treatment, periodontal disease management and dental implants. Ionizing radiation-free ultrasound has emerged as a promising clinical tool in imaging oral tissues. However, the ultrasound image is distorted when the wave speed of the tissue of interest is different from the mapping speed of the scanner and, therefore, the subsequent dimension measurements are not accurate. This study was aimed at deriving a correction factor that can be applied to the measurements to correct for discrepancy caused by speed variation. METHODS: The factor is a function of the speed ratio and the acute angle that the segment of interest makes with the beam axis perpendicular to the transducer. The phantom and cadaver experiments were designed to validate the method. DISCUSSION: The comparisons agree well with absolute errors not more than 4.9%. Dimension measurements on ultrasonographs can be properly corrected by applying the correction factor without recourse to the raw signals. CONCLUSION: The correction factor has reduced the measurement discrepancy on the acquired ultrasonographs for the tissue whose speed is different from the scanner's mapping speed.

Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells.

The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains unknown. Here, investigating IL-23R signaling in Tregs specifically, we show that colonic Tregs highly express Il23r compared with Tregs from other compartments and their frequency is reduced upon IL-23 administration and impairs Treg suppressive function. Similarly, colonic Treg frequency is increased in mice lacking Il23r specifically in Tregs and exhibits a competitive advantage over IL-23R-sufficient Tregs during inflammation. Finally, IL-23 antagonizes liver X receptor pathway, cellular cholesterol transporter Abca1, and increases Treg apoptosis. Our results show that IL-23R signaling regulates intestinal Tregs by increasing cell turnover, antagonizing suppression, and decreasing cholesterol efflux. These results suggest that IL-23 negatively regulates Tregs in the intestine with potential implications for promoting chronic inflammation in patients with IBD.

Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.

BACKGROUND: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. METHODS: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. RESULTS: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16 ) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16 -Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. CONCLUSIONS: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.

Real-World Effectiveness of Repeated Ketamine Infusions for Treatment-Resistant Bipolar Depression.

Background: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression. Methods: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5-0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures. Results: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/-1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16-Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. Conclusions: Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.Reprinted from Bipolar Disord 2023; 25:99-109, with permission from John Wiley and Sons. Copyright © 2023.