Delineation and agreement of FET PET biological volumes in glioblastoma: results of the nuclear medicine credentialing program from the prospective, multi-centre trial evaluating FET PET In Glioblastoma (FIG) study-TROG 18.06.

PURPOSE: The O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in Glioblastoma (FIG) trial is an Australian prospective, multi-centre study evaluating FET PET for glioblastoma patient management. FET PET imaging timepoints are pre-chemoradiotherapy (FET1), 1-month post-chemoradiotherapy (FET2), and at suspected progression (FET3). Before participant recruitment, site nuclear medicine physicians (NMPs) underwent credentialing of FET PET delineation and image interpretation. METHODS: Sites were required to complete contouring and dynamic analysis by ≥ 2 NMPs on benchmarking cases (n = 6) assessing biological tumour volume (BTV) delineation (3 × FET1) and image interpretation (3 × FET3). Data was reviewed by experts and violations noted. BTV definition includes tumour-to-background ratio (TBR) threshold of 1.6 with crescent-shaped background contour in the contralateral normal brain. Recurrence/pseudoprogression interpretation (FET3) required assessment of maximum TBR (TBRmax), dynamic analysis (time activity curve [TAC] type, time to peak), and qualitative assessment. Intraclass correlation coefficient (ICC) assessed volume agreement, coefficient of variation (CoV) compared maximum/mean TBR (TBRmax/TBRmean) across cases, and pairwise analysis assessed spatial (Dice similarity coefficient [DSC]) and boundary agreement (Hausdorff distance [HD], mean absolute surface distance [MASD]). RESULTS: Data was accrued from 21 NMPs (10 centres, n ≥ 2 each) and 20 underwent review. The initial pass rate was 93/119 (78.2%) and 27/30 requested resubmissions were completed. Violations were found in 25/72 (34.7%; 13/12 minor/major) of FET1 and 22/74 (29.7%; 14/8 minor/major) of FET3 reports. The primary reasons for resubmission were as follows: BTV over-contour (15/30, 50.0%), background placement (8/30, 26.7%), TAC classification (9/30, 30.0%), and image interpretation (7/30, 23.3%). CoV median and range for BTV, TBRmax, and TBRmean were 21.53% (12.00-30.10%), 5.89% (5.01-6.68%), and 5.01% (3.37-6.34%), respectively. BTV agreement was moderate to excellent (ICC = 0.82; 95% CI, 0.63-0.97) with good spatial (DSC = 0.84 ± 0.09) and boundary (HD = 15.78 ± 8.30 mm; MASD = 1.47 ± 1.36 mm) agreement. CONCLUSION: The FIG study credentialing program has increased expertise across study sites. TBRmax and TBRmean were robust, with considerable variability in BTV delineation and image interpretation observed.

Associations Between Weight and Lower Respiratory Tract Disease Outcomes in Hospitalized Children.

OBJECTIVE: To identify associations between weight status and clinical outcomes in children with lower respiratory tract infection (LRTI) or asthma requiring hospitalization. METHODS: We performed a retrospective cohort study of 2 to 17 year old children hospitalized for LRTI and/or asthma from 2009 to 2019 using electronic health record data from the PEDSnet clinical research network. Children <2 years, those with medical complexity, and those without a calculable BMI were excluded. Children were classified as having underweight, normal weight, overweight, or class 1, 2, or 3 obesity based on Body Mass Index percentile for age and sex. Primary outcomes were need for positive pressure respiratory support and ICU admission. Subgroup analyses were performed for children with a primary diagnosis of asthma. Outcomes were modeled with mixed-effects multivariable logistic regression incorporating age, sex, and payer as fixed effects. RESULTS: We identified 65 132 hospitalizations; 6.7% with underweight, 57.8% normal weight, 14.6% overweight, 13.2% class 1 obesity, 5.0% class 2 obesity, and 2.8% class 3 obesity. Overweight and obesity were associated with positive pressure respiratory support (class 3 obesity versus normal weight odds ratio [OR] 1.62 [1.38-1.89]) and ICU admission (class 3 obesity versus normal weight OR 1.26 [1.12-1.42]), with significant associations for all categories of overweight and obesity. Underweight was also associated with positive pressure respiratory support (OR 1.39 [1.24-1.56]) and ICU admission (1.40 [1.30-1.52]). CONCLUSIONS: Both underweight and overweight or obesity are associated with increased severity of LRTI or asthma in hospitalized children.

Clinical application of the therapeutic ultrasound in urologic disease: Part II of therapeutic ultrasound in urology.

This article aimed to review the clinical application and evidence of the therapeutic ultrasound in detail for urological diseases such as prostate cancer, kidney tumor, erectile dysfunction, and urolithiasis. We searched for articles about high-intensity focused ultrasound (HIFU), extracorporeal shock wave therapy, ultrasound lithotripsy, and extracorporeal shockwave lithotripsy (ESWL) in the MEDLINE and Embase. HIFU may be indicated as a primary treatment for low- or intermediate-risk prostate cancer, and salvage therapy for local recurrence as a promising way to address the limitations of current standard therapies. The application of HIFU in treating kidney tumors has scarcely been reported with unsatisfactory results. Evidence indicates that low-intensity shockwave therapy improves subjective and objective erectile function in patients with erectile dysfunction. Regarding the application of ultrasound in stone management, the novel combination of ultrasound lithotripsy and other energy sources in a single probe promises to be a game-changer in efficiently disintegrating large kidney stones in percutaneous nephrolithotomy. ESWL is losing its role in managing upper urinary tract calculi worldwide. The burst-wave lithotripsy and ultrasound propulsion could be the new hope to regain its position in the lithotripsy field. According to our investigations and reviews, cavitation bubbles of the therapeutic ultrasound are actively being used in the field of urology. Although clinical evidence has been accumulated in urological diseases such as prostate cancer, kidney tumor, erectile dysfunction, and lithotripsy, further development is needed to be a game-changer in treating these diseases.

Measuring BMI change among children and adolescents.

BACKGROUND: Weight control programs for children monitor BMI changes using BMI z-scores that adjust BMI for the sex and age of the child. It is, however, uncertain if BMIz is the best metric for assessing BMI change. OBJECTIVE: To identify which of 6 BMI metrics is optimal for assessing change. We considered a metric to be optimal if its short-term variability was consistent across the entire BMI distribution. SUBJECTS: 285 643 2- to 17-year-olds with BMI measured 3 times over a 10- to 14-month period. METHODS: We summarized each metric's variability using the within-child standard deviation. RESULTS: Most metrics' initial or mean value correlated with short-term variability (|r| ~ 0.3 to 0.5). The metric for which the within-child variability was largely independent (r = 0.13) of the metric's initial or mean value was the percentage of the 50th expressed on a log scale. However, changes in this metric between the first and last visits were highly (r ≥ 0.97) correlated with changes in %95th and %50th. CONCLUSIONS: Log %50 was the metric for which the short-term variability was largely independent of a child's BMI. Changes in log %50th, %95th, and %50th are strongly correlated.

Interrelationships among age at adiposity rebound, BMI during childhood, and BMI after age 14 years in an electronic health record database.

OBJECTIVE: This study compared the importance of age at adiposity rebound versus childhood BMI to subsequent BMI levels in a longitudinal analysis. METHODS: From the electronic health records of 4.35 million children, a total of 12,228 children were selected who were examined at least once each year between ages 2 and 7 years and reexamined after age 14 years. The minimum number of examinations per child was six. Each child's rebound age was estimated using locally weighted regression (lowess), a smoothing technique. RESULTS: Children who had a rebound age < 3 years were, on average, 7 kg/m2 heavier after age 14 years than were children with a rebound age ≥ 7 years. However, BMI after age 14 years was more strongly associated with BMI at the rebound than with rebound age (r = 0.57 vs. -0.44). Furthermore, a child's BMI at age 3 years provided more information on BMI after age 14 years than did rebound age. In addition, rebound age provided no information on subsequent BMI if a child's BMI at age 6 years was known. CONCLUSIONS: Although rebound age is related to BMI after age 14 years, a child's BMI at age 3 years provides more information and is easier to obtain.

Weight Status and Risk of Inpatient Admission for Children With Lower Respiratory Tract Disease.

OBJECTIVES: To identify associations between weight category and hospital admission for lower respiratory tract disease (LRTD), defined as asthma, community-acquired pneumonia, viral pneumonia, or bronchiolitis, among children evaluated in pediatric emergency departments (PEDs). METHODS: We performed a retrospective cohort study of children 2 to <18 years of age evaluated in the PED at 6 children's hospitals within the PEDSnet clinical research network from 2009 to 2019. BMI percentile of children was classified as underweight, healthy weight, overweight, and class 1, 2, or 3 obesity. Children with complex chronic conditions were excluded. Mixed-effects multivariable logistic regression was used to assess associations between BMI categories and hospitalization or 7- and 30-day PED revisits, adjusted for covariates (age, sex, race and ethnicity, and payer). RESULTS: Among 107 446 children with 218 180 PED evaluations for LRTD, 4.5% had underweight, 56.4% had healthy normal weight, 16.1% had overweight, 14.6% had class 1 obesity, 5.5% had class 2 obesity, and 3.0% had class 3 obesity. Underweight was associated with increased risk of hospital admission compared with normal weight (odds ratio [OR] 1.76; 95% confidence interval [CI] 1.69-1.84). Overweight (OR 0.87; 95% CI 0.85-0.90), class 1 obesity (OR 0.88; 95% CI 0.85-0.91), and class 2 obesity (OR 0.91; 95% CI 0.87-0.96) had negative associations with hospital admission. Class 1 and class 2, but not class 3, obesity had small positive associations with 7- and 30-day PED revisits. CONCLUSIONS: We found an inverse relationship between patient weight category and risk for hospital admission in children evaluated in the PED for LRTD.

Snail Upregulates Transcription of FN, LEF, COX2, and COL1A1 in Hepatocellular Carcinoma: A General Model Established for Snail to Transactivate Mesenchymal Genes.

SNA is one of the essential EMT transcriptional factors capable of suppressing epithelial maker while upregulating mesenchymal markers. However, the mechanisms for SNA to transactivate mesenchymal markers was not well elucidated. Recently, we demonstrated that SNA collaborates with EGR1 and SP1 to directly upregulate MMP9 and ZEB1. Remarkably, a SNA-binding motif (TCACA) upstream of EGR/SP1 overlapping region on promoters was identified. Herein, we examined whether four other mesenchymal markers, lymphoid enhancer-binding factor (LEF), fibronectin (FN), cyclooxygenase 2 (COX2), and collagen type alpha I (COL1A1) are upregulated by SNA in a similar fashion. Expectedly, SNA is essential for expression of these mesenchymal genes. By deletion mapping and site directed mutagenesis coupled with dual luciferase promoter assay, SNA-binding motif and EGR1/SP1 overlapping region are required for TPA-induced transcription of LEF, FN, COX2 and COL1A1. Consistently, TPA induced binding of SNA and EGR1/SP1 on relevant promoter regions of these mesenchymal genes using ChIP and EMSA. Thus far, we found six of the mesenchymal genes are transcriptionally upregulated by SNA in the same fashion. Moreover, comprehensive screening revealed similar sequence architectures on promoter regions of other SNA-upregulated mesenchymal markers, suggesting that a general model for SNA-upregulated mesenchymal genes can be established.

A Longitudinal Comparison of Alternatives to Body Mass Index Z-Scores for Children with Very High Body Mass Indexes.

OBJECTIVE: The current Centers for Disease Control and Prevention (CDC) body mass index (BMI) z-scores are inaccurate for BMIs of ≥97th percentile. We, therefore, considered 5 alternatives that can be used across the entire BMI distribution: modified BMI-for-age z-score (BMIz), BMI expressed as a percentage of the 95th percentile (%CDC95th percentile), extended BMIz, BMI expressed as a percentage of the median (%median), and %median adjusted for the dispersion of BMIs. STUDY DESIGN: We illustrate the behavior of the metrics among children of different ages and BMIs. We then compared the longitudinal tracking of the BMI metrics in electronic health record data from 1.17 million children in PEDSnet using the intraclass correlation coefficient to determine if 1 metric was superior. RESULTS: Our examples show that using CDC BMIz for high BMIs can result in nonsensical results. All alternative metrics showed higher tracking than CDC BMIz among children with obesity. Of the alternatives, modified BMIz performed poorly among children with severe obesity, and %median performed poorly among children who did not have obesity at their first visit. The highest intraclass correlation coefficients were generally seen for extended BMIz, adjusted %median, and %CDC95th percentile. CONCLUSIONS: Based on the examples of differences in the BMI metrics, the longitudinal tracking results and current familiarity BMI z-scores and percentiles. Both extended BMIz and extended BMI percentiles may be suitable replacements for the current z-scores and percentiles. These metrics are identical to those in the CDC growth charts for BMIs of <95th percentile and are superior for very high BMIs. Researchers' familiarity with the current CDC z-scores and clinicians with the CDC percentiles may ease the transition to the extended BMI scale.

Disparities in Delaware Caregiver Beliefs about the COVID-19 Vaccine for their Children.

Objective: To describe sociodemographic disparities in caregiver beliefs about the COVID-19 vaccine for their children. Methods: This was a cross-sectional study, linking caregiver-reported data to geocoded sociodemographic data from child EHRs. Caregivers of children receiving care in a Delaware pediatric healthcare system were invited to complete a survey about COVID-19 vaccine beliefs from March 19 to April 16, 2021. Results: 1499 caregivers participated (18% Black, 11% Hispanic, 32% public insurance, 12% rural). 54% of caregivers intended to vaccinate their children, while 34% were unsure and 12% would not. Caregivers of younger children (aOR 3.70, CI 2.36-5.79), Black children (aOR 2.11, CI 1.50-2.96), and from disadvantaged communities (aOR 1.59, CI 1.05-2.42) were more likely to be unsure and not vaccinate their children. Caregivers from rural communities were more likely not to vaccinate their children (aOR 2.51, CI 1.56-4.05). Fewer caregivers of younger children, Black children, and from disadvantaged communities believed in the safety or efficacy of the vaccines (p < 0.001), while fewer caregivers of younger children and from rural communities believed in their children's susceptibility to COVID-19 or risk of getting severe disease from COVID-19 (p < 0.05). While the majority (72%) of caregivers were influenced by health experts, fewer from communities of color and disadvantaged communities were (p<0.001). Conclusions: Caregivers of younger children and from communities of color, rural communities, and disadvantaged communities in Delaware expressed more COVID-19 vaccine hesitancy. Policy implications: This study explores beliefs of different communities in Delaware, which are important to tailoring public health messaging and strategies to increase vaccine uptake in these communities.

Bipolar enucleation of the prostate-step by step.

Bipolar enucleation of prostate (BipolEP) is a useful method for treatment of benign prostatic hyperplasia (BPH). Compared with conventional transurethral resection, the enucleation technique has several advantages. However, since the cost of laser equipment used for enucleation is relatively high, enucleation using bipolar devices has been attempted by many previous surgeons. We consider bipolar enucleation is an effective and safe procedure, and we would like to share our experience of equipment settings and procedures through this article. We will introduce the equipment and settings of BipolEP and then present the actual step-by-step procedures and surgical tips. First, circular incisions are made on bladder neck and mucosa at the level of verumontanum. Then, enucleation is performed in the order of median and lateral lobes as in laser enucleation. Haemostasis should be done throughout the procedure. After enucleation and haemostasis, prostatic tissue is evacuated by morcellator. Currently, there are several types of electrode and morcellator systems. In our experience, BipolEP has a steep learning curve but it is safe and effective procedure for managing BPH. In particular, effective haemostasis is the greatest advantage of BipolEP when compared to traditional TUR or laser enucleation.

How to reduce 'double-firing'-induced scope damage by investigating the relationship between laser fiber core degradation and fiber jacket burn?

PURPOSE: 'Double-firing effect' in which laser firing occurs in the fiber tip and its proximal part is caused by different breakdown rates between fiber jackets and cores. This study investigated a new safe distance concept to prevent scope damage by analyzing the breakdown of the laser fiber jacket and cores. METHODS: Laser fibers were fixed in a benchtop simulation model. The fiber tip was in contact with uniform phantom stones and submerged in saline. Four different energy settings (1.0 or 2.0J x 10Hz or 30Hz) and two different fiber sizes (200 µm and 365 µm) were tested. After three minutes of use at each energy setting, the length of fiber shortening and jacket burn were measured. The fibers were stripped to measure the length of core degradation. RESULTS: Mean degradation lengths were 4.2 to 7.8 mm. There was no statistical difference in the mean lengths of fiber core degradation and jacket burn. However, core degradation was longer than the jacket burn in half of the samples. The mean difference in lengths between core degradation and jacket burn was 0.49 ± 0.90 mm. Lengths of core degradation and the jacket burn were longer at the setting of high-power energy and 200 µm fiber - 2J with 30 Hz. CONCLUSION: To reduce 'double-firing'-induced damage, the authors recommend that laser fiber should be cut 1.0 mm longer than visible jacket burn at high-power settings after 3-min continuous fragmentation. After cutting the fiber, the laser should be checked whether 'double-firing' is no more seen.

Feasibility of Using a Commercial Fitness Tracker as an Adjunct to Family-Based Weight Management Treatment: Pilot Randomized Trial.

BACKGROUND: Fitness trackers can engage users through automated self-monitoring of physical activity. Studies evaluating the utility of fitness trackers are limited among adolescents, who are often difficult to engage in weight management treatment and are heavy technology users. OBJECTIVE: We conducted a pilot randomized trial to describe the impact of providing adolescents and caregivers with fitness trackers as an adjunct to treatment in a tertiary care weight management clinic on adolescent fitness tracker satisfaction, fitness tracker utilization patterns, and physical activity levels. METHODS: Adolescents were randomized to 1 of 2 groups (adolescent or dyad) at their initial weight management clinic visit. Adolescents received a fitness tracker and counseling around activity data in addition to standard treatment. A caregiver of adolescents in the dyad group also received a fitness tracker. Satisfaction with the fitness tracker, fitness tracker utilization patterns, and physical activity patterns were evaluated over 3 months. RESULTS: A total of 88 adolescents were enrolled, with 69% (61/88) being female, 36% (32/88) black, 23% (20/88) Hispanic, and 63% (55/88) with severe obesity. Most adolescents reported that the fitness tracker was helping them meet their healthy lifestyle goals (69%) and be more motivated to achieve a healthy weight (66%). Despite this, 68% discontinued use of the fitness tracker by the end of the study. There were no significant differences between the adolescent and the dyad group in outcomes, but adolescents in the dyad group were 12.2 times more likely to discontinue using their fitness tracker if their caregiver also discontinued use of their fitness tracker (95% CI 2.4-61.6). Compared with adolescents who discontinued use of the fitness tracker during the study, adolescents who continued to use the fitness tracker recorded a higher number of daily steps in months 2 and 3 of the study (mean 5760 vs 4148 in month 2, P=.005, and mean 5942 vs 3487 in month 3, P=.002). CONCLUSIONS: Despite high levels of satisfaction with the fitness trackers, fitness tracker discontinuation rates were high, especially among adolescents whose caregivers also discontinued use of their fitness tracker. More studies are needed to determine how to sustain the use of fitness trackers among adolescents with obesity and engage caregivers in adolescent weight management interventions.

Isolation of Robinsoniella peoriensis from four human specimens.

Robinsoniella peoriensis is a recently described anaerobic, spore-forming, Gram-positive bacillus originally recovered from swine manure. We report four human cases in which R. peoriensis was isolated from clinical samples.

Impact upon clinical outcomes of translation of PNA FISH-generated laboratory data from the clinical microbiology bench to bedside in real time.

Fluorescence in situ hybridization using peptide nucleic acid probes (PNA-FISH) differentiates Staphylococcus aureus from other Gram-positive-cocci in clusters (GPCC). 101/202 patients with GPCC+ blood cultures were randomly assigned to clinician-notification of PNA FISH results. Notification was associated with reduced mortality (8% vs.17%, p = 0.05), further antibiotic use (median -2.5 days, p = 0.01), and trended toward reduced hospital stay and charges.

The efficacy of clarithromycin and the bicyclolide EDP-420 against Mycobacterium avium in a mouse model of pulmonary infection.

Lung disease caused by Mycobacterium avium complex (MAC) is increasing in prevalence. MAC disease occurs in patients with chronic preexisting obstructive pulmonary diseases but is also diagnosed in individuals with no history of lung pathology or identifiable immune defect. Histologically, the disease is characterized by either the development of nodular granulomatous lesions in the peribronchial region or cavitary peripheral disease in smokers. Response to long-term treatment is poor. Limited comparative-efficacy data on treatment exist. A model that resembles nodular MAC disease was established in C57 (bg+/bg+) mice infected intranasally. Therapy with clarithromycin, a compound commonly used to treat MAC disease, was evaluated in parallel with treatment using a new bicyclolide, EDP-420, that achieves high levels of intrapulmonary concentrations. Although clarithromycin administered daily resulted in a reduction in the bacterial load in the lung, EDP-420 administered either daily or twice a week was significantly more effective. These results suggest that this animal model can be used to evaluate novel regimens against MAC disease and that compounds with high concentration in the lung might have a significant impact on the outcome of MAC lung disease.

EDP-420, a bicyclolide (bridged bicyclic macrolide), is active against Mycobacterium avium.

Infection caused by Mycobacterium avium complex (MAC) is common in patients with immunosuppression, such as AIDS, and deficiencies of gamma interferon and interleukin-12, as well as patients with chronic lung diseases. Treatment of MAC disease is limited since few drugs show in vivo activity. We tested a new bridged bicyclic macrolide, EDP-420, against MAC in vitro and in beige mice. EDP-420 was inhibitory in vitro at a concentration ranging from 2 to 8 microg/ml (MIC(50) of 4 microg/ml and MIC(90) of 8 microg/ml). In macrophages, EDP-420 was inhibitory at 0.5 microg/ml, suggesting that the drug concentrates intracellularly. Mice infected with macrolide-susceptible MAC strain 101 were given 100 mg of EDP-420/kg of body weight daily for 4 weeks and showed a significant reduction in the number of bacteria in both liver and spleen which was greater than the reduction observed with clarithromycin treatment at the same dose (P < 0.05). However, macrolide-resistant MAC 101 did not respond to EDP-420 treatment. A combination of EDP-420 with mefloquine was shown to be indifferent; mefloquine alone was active against macrolide-resistant MAC. The frequency of resistance to EDP-420 in MAC 101 was 10(-9), which is significantly less than the emergence of resistance to clarithromycin, approximately 10(-7) (P < 0.05). Further evaluation of EDP-420 in the treatment of MAC disease is warranted.

Prolonged QT interval and torsades de pointes associated with atazanavir therapy.

We report, to our knowledge, the first documented case of torsades de pointes associated with atazanavir therapy. This case serves to highlight the need to monitor patients receiving atazanavir therapy who have risk factors for QT interval prolongation, such as female sex, bradycardia, electrolyte abnormalities, congestive heart failure, and a baseline prolonged QT interval.

Synthesis of novel 6,11-O-bridged bicyclic ketolides via a palladium-catalyzed bis-allylation.

A bridging chemistry process was developed to form an ether bridge between 6-O and 11-O of erythromycin A via a tandem or stepwise palladium-catalyzed bis-pi-allylation. By applying this bridging process, new 6,11-O-bridged bicyclic ketolides (BBKs) were synthesized. These BBKs showed good antibacterial activities against the macrolide-susceptible strains as well as mef-resistant strains and served as a good core for further modifications to study the structure-activity relationship (SAR) and to overcome bacterial resistance. [reaction: see text]