Validation of actigraphy sleep metrics in children aged 8 to 16 years: considerations for device type, placement and algorithms.

BACKGROUND: Actigraphy is often used to measure sleep in pediatric populations, despite little confirmatory evidence of the accuracy of existing sleep/wake algorithms. The aim of this study was to determine the performance of 11 sleep algorithms in relation to overnight polysomnography in children and adolescents. METHODS: One hundred thirty-seven participants aged 8-16 years wore two Actigraph wGT3X-BT (wrist, waist) and three Axivity AX3 (wrist, back, thigh) accelerometers over 24-h. Gold standard measures of sleep were obtained using polysomnography (PSG; Embletta MPRPG, ST + Proxy and TX Proxy) in the home environment, overnight. Epoch by epoch comparisons of the Sadeh (two algorithms), Cole-Kripke (three algorithms), Tudor-Locke (four algorithms), Count-Scaled (CS), and HDCZA algorithms were undertaken. Mean differences from PSG values were calculated for various sleep outcomes. RESULTS: Overall, sensitivities were high (mean ± SD: 91.8%, ± 5.6%) and specificities moderate (63.8% ± 13.8%), with the HDCZA algorithm performing the best overall in terms of specificity (87.5% ± 1.3%) and accuracy (86.4% ± 0.9%). Sleep outcome measures were more accurately measured by devices worn at the wrist than the hip, thigh or lower back, with the exception of sleep efficiency where the reverse was true. The CS algorithm provided consistently accurate measures of sleep onset: the mean (95%CI) difference at the wrist with Axivity was 2 min (-6; -14,) and the offset was 10 min (5, -19). Several algorithms provided accurate measures of sleep quantity at the wrist, showing differences with PSG of just 1-18 min a night for sleep period time and 5-22 min for total sleep time. Accuracy was generally higher for sleep efficiency than for frequency of night wakings or wake after sleep onset. The CS algorithm was more accurate at assessing sleep period time, with narrower 95% limits of agreement compared to the HDCZA (CS:-165 to 172 min; HDCZA: -212 to 250 min). CONCLUSION: Although the performance of existing count-based sleep algorithms varies markedly, wrist-worn devices provide more accurate measures of most sleep measures compared to other sites. Overall, the HDZCA algorithm showed the greatest accuracy, although the most appropriate algorithm depends on the sleep measure of focus.

Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Beta-blockers and mechanical dyssynchrony in heart failure assessed by radionuclide ventriculography.

BACKGROUND: Radionuclide ventriculography (RNVG) can be used to quantify mechanical dyssynchrony and may be a valuable adjunct in the assessment of heart failure with reduced ejection fraction (HFrEF). The study aims to investigate the effect of beta-blockers on mechanical dyssynchrony using novel RNVG phase parameters. METHODS: A retrospective study was carried out in a group of 98 patients with HFrEF. LVEF and dyssynchrony were assessed pre and post beta-blockade. Dyssynchrony was assessed using synchrony, entropy, phase standard deviation, approximate entropy, and sample entropy from planar RNVG phase images. Subgroups split by ischemic etiology were also investigated. RESULTS: An improvement in dyssynchrony and LVEF was measured six months post beta-blockade for both ischemic and non-ischemic groups. CONCLUSIONS: A significant improvement in dyssynchrony and LVEF was measured post beta-blockade using novel measures of dyssynchrony.

Radionuclide ventriculography phase analysis for risk stratification of patients undergoing cardiotoxic cancer therapy.

BACKGROUND: Accurate diagnostic tools to identify patients at risk of cancer therapy-related cardiac dysfunction (CTRCD) are critical. For patients undergoing cardiotoxic cancer therapy, ejection fraction assessment using radionuclide ventriculography (RNVG) is commonly used for serial assessment of left ventricular (LV) function. METHODS: In this retrospective study, approximate entropy (ApEn), synchrony, entropy, and standard deviation from the phase histogram (phase SD) were investigated as potential early markers of LV dysfunction to predict CTRCD. These phase parameters were calculated from the baseline RNVG phase image for 177 breast cancer patients before commencing cardiotoxic therapy. RESULTS: Of the 177 patients, 11 had a decline in left ventricular ejection fraction (LVEF) of over 10% to an LVEF below 50% after treatment had commenced. This patient group had a significantly higher ApEn at baseline to those who maintained a normal LVEF throughout treatment. Of the parameters investigated, ApEn was superior for predicting the risk of CTRCD. Combining ApEn with the baseline LVEF further improved the discrimination between the groups. CONCLUSIONS: The results suggest that RNVG phase analysis using approximate entropy may aid in the detection of sub-clinical LV contraction abnormalities, not detectable by baseline LVEF measurement, predicting a subsequent decline in LVEF.

Self-monitoring has no adverse effect on disordered eating in adults seeking treatment for obesity.

OBJECTIVES: Although monitoring is considered a key component of effective behaviour change, the development of apps has allowed consumers to constantly evaluate their own diet, with little examination of what this might mean for eating behaviour. The aim of this study was to investigate whether self-monitoring of diet using the app MyFitnessPal or daily self-weighing increases the reported occurrence of eating disorders in adults with overweight/obesity following a weight loss programme. METHODS: Two hundred fifty adults with body mass index ≥ 27 kg/m2 received diet and exercise advice and were randomized to one of four monitoring strategies (daily self-weighing, MyFitnessPal, brief monthly consults or self-monitoring hunger) or control for 12 months. The Eating Disorder Examination Questionnaire 6.0 was used to assess eating disorder symptoms and behaviours for the previous 28 d at 0 and 12 months. RESULTS: There were no significant differences in the global Eating Disorder Examination Questionnaire score or the subscales between those in the four monitoring groups and the control at 12 months (all p ≥ 0.164), nor were there differences in binge eating, self-induced vomiting, laxative misuse or excessive exercise at 12 months (p ≥ 0.202). The overall prevalence of one or more episodes of binge eating was 53.6% at baseline and 50.6% at 12 months, with no change over time (p = 0.662). CONCLUSIONS: There was no evidence that self-monitoring, including using diet apps like MyFitnessPal or daily self-weighing, increases the reported occurrence of eating disorder behaviours in adults with overweight/obesity who are trying to lose weight.

Training reproductive health providers to talk about intimate partner violence and reproductive coercion: an exploratory study.

To explore the effect of provider communication-skills training on frequency of intimate partner violence (IPV) and reproductive coercion (RC) assessment, four family planning clinics were randomized to IPV/RC communication-skills building workshop or standard knowledge-based IPV/RC training and compared to historical controls from the same clinics (before any training). Female patients aged 16-29 completed after-visit surveys. Primary outcomes included provider discussion about IPV/RC, receipt of safety card with IPV/RC resources and patient disclosure of IPV/RC. Chi-square tests were used to compare groups that received training and historical controls. Participants (training: n = 103; historical control: n = 576) were predominantly white with mean age of 22. More patients reported discussion about healthy relationships in both training groups (78-90%) compared to historical controls (49-52%, P < 0.001 for both). Discussion on birth control sabotage and pregnancy coercion was infrequent with patient-participants in both groups (6-17 and 4-13%, respectively). More patients in the clinics that received training reported receiving a safety card (72-84%) as compared to historical controls (9%, P < 0.001 for both). Overall, in this exploratory study, both communication-skills and standard training improved frequency of IPV communication when compared to historical controls but with few differences when compared to each other.

Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke.

Experimental stroke leads to microglia activation and progressive neuronal loss at sites of secondary neurodegeneration (SND). These lesions are remote from, but synaptically connected to, primary infarction sites. Previous studies have demonstrated that immune cells are present in sites of infarction in the first hours and days after stroke, and are associated with increased neurodegeneration in peri-infarct regions. However, it is not known whether immune cells are also present in more distal sites where SND occurs. Our study aimed to investigate whether immune cells are present in sites of SND and, if so, how these cell populations compare to those in the peri-infarct zone. Cells were isolated from the thalamus, the main site of SND, and remaining brain tissue 14days post-stroke. Analysis was performed using flow cytometry to quantify microglia, myeloid cell and lymphocyte numbers. We identified a substantial infiltration of immune cells in the ipsilateral (stroked) compared to the contralateral (control) thalamus, with a significant increase in the percentage of CD4+ and CD8+ T cells. This result was further quantified using immunofluorescent labelling of fixed tissue. In the remaining ipsilateral hemisphere tissue, there were significant increases in the frequency of CD4+ and CD8+ T lymphocytes, B lymphocytes, Ly6G+ neutrophils and both Ly6G-Ly6CLO and Ly6G-Ly6CHI monocytes. Our results indicate that infiltrating immune cells persist in ischemic tissue after the acute ischemic phase, and are increased in sites of SND. Importantly, immune cells have been shown to play pivotal roles in both damage and repair processes after stroke. Our findings indicate that immune cells may also be involved in the pathogenesis of SND and further clinical studies are warranted to characterise the nature of inflammatory cell infiltrates in human disease.

Effectiveness of slow motion video compared to real time video in improving the accuracy and consistency of subjective gait analysis in dogs.

Objective measures of canine gait quality via force plates, pressure mats or kinematic analysis are considered superior to subjective gait assessment (SGA). Despite research demonstrating that SGA does not accurately detect subtle lameness, it remains the most commonly performed diagnostic test for detecting lameness in dogs. This is largely because the financial, temporal and spatial requirements for existing objective gait analysis equipment makes this technology impractical for use in general practice. The utility of slow motion video as a potential tool to augment SGA is currently untested. To evaluate a more accessible way to overcome the limitations of SGA, a slow motion video study was undertaken. Three experienced veterinarians reviewed video footage of 30 dogs, 15 with a diagnosis of primary limb lameness based on history and physical examination, and 15 with no indication of limb lameness based on history and physical examination. Four different videos were made for each dog, demonstrating each dog walking and trotting in real time, and then again walking and trotting in 50% slow motion. For each video, the veterinary raters assessed both the degree of lameness, and which limb(s) they felt represented the source of the lameness. Spearman's rho, Cramer's V, and t-tests were performed to determine if slow motion video increased either the accuracy or consistency of raters' SGA relative to real time video. Raters demonstrated no significant increase in consistency or accuracy in their SGA of slow motion video relative to real time video. Based on these findings, slow motion video does not increase the consistency or accuracy of SGA values. Further research is required to determine if slow motion video will benefit SGA in other ways.

Identifying and preparing the next generation of part-time clinical teachers from dental practice.

Part-time general dental practitioners (GDPs) and dental care professionals (DCPs) working in practice are being increasingly utilised to deliver undergraduate clinical dental education to both dental and hygiene/therapy students. As such, there is a need for appropriate recruitment processes and ongoing staff development in the different and complex role of the clinical teacher. Recently a group of experienced dental practitioners, making a journey from GDP to part-time clinical teacher, identified common themes, experiences, challenges and realisations. These were: 'what is clinical dental education?'; 'me as a clinical teacher'; and 'specific teaching issues'. The themes highlighted the complexity of dental education and the different environment of the teaching clinic from general practice. Some of the themes identified could be a starting point for the induction process to facilitate an easier transition from experienced GDP to clinical teacher. With the current demands from both students and patients alike, the 'three way dynamic of patient, student and teacher' needs to be supported if dental schools are to attract and develop the highest quality clinical teachers. It is of critical importance to give an exceptional experience to students in their clinical education as well as to patients in terms of excellent and appropriate treatment. The challenge for deans and directors of education is to find the resources to properly fund teacher recruitment, induction and the development of part-time GDPs in order to produce the expert teachers of tomorrow.

A combined vascular surgical and clinical genetics approach to diffuse aneurysmal disease.

We report two patients who presented with extensive aneurysmal disease, in association with minimal external physical signs. Patient 1 remained genetically undiagnosed despite multiple structural, biochemical and genetic investigations. He made a good recovery following surgery for popliteal and left axillary artery aneurysms. Patient 2 was diagnosed with vascular type Ehlers-Danlos syndrome, associated with a high degree of tissue and blood vessel fragility, and is being managed conservatively. Early multidisciplinary assessment of such patients facilitates accurate diagnosis and management.

Bioelectrical impedance as a measure of change in body composition in young children.

BACKGROUND AND OBJECTIVES: The ability of bioelectrical impedance (BIA) to measure change in body composition in children has rarely been examined. METHODS: Body composition was estimated by BIA (Tanita BC-418) and dual-energy x-ray absorptiometry (DXA) in 187 children aged 4-8 years at baseline and at 12 months. Change in body composition was compared between the two methods using mixed models. RESULTS: Estimates of change in fat mass did not differ between BIA and DXA for overweight girls (mean difference between methods, 95% confidence interval: 0.04 kg, -0.19 to 0.28) or boys (0.07 kg, -0.14 to 0.27). BIA was also able to accurately detect change in fat-free mass, with no significant differences between methods (-0.14 kg, -0.10 to 0.38 in girls and -0.07 kg, -0.35 to -0.20 in boys). Change in percentage fat produced similar estimates in both genders (0.18%, -0.82 to 0.46 in girls and 0.38%, -0.37 to 1.13 in boys). BIA/DXA comparisons in normal weight children were also not significantly different, with the exception of percentage fat in girls, where BIA slightly underestimated change compared with DXA (0.7%, 0.02-0.37). CONCLUSION: BIA performed well as a measure of change in body composition, providing confidence for its use as an outcome measure in children.

Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition.

Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growth of dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies have shown associations of the KALRN gene with schizophrenia. Our data point to an essential role of phosphorylation in kalirin-7's C terminus as the critical site for these effects. As reduced interneuron dendrite length occurs in schizophrenia, understanding how NRG1-erbB4 signaling modulates interneuron dendritic morphogenesis might shed light on disease-related alterations in cortical circuits.

Muscle gene expression associated with increased marbling in beef cattle.

The objective of this study was to identify specific bovine genes expressed within skeletal muscle that are associated with intramuscular fat deposition. Twenty-eight Angus-Simmental cross steers and heifers were harvested at the University of Illinois Meat Science Laboratory. Four pairs of animals were identified based on similar adjusted backfat thickness but differing amounts of intramuscular fat within each pair. RNA was extracted from muscle samples devoid of visible fat and microarray analysis was performed. Based on this analysis, 9 genes were selected and expression was subsequently confirmed by qPCR. Expression levels of MYH3, HOXD10, MXRA8, and CASQ2 were increased in animals with high marbling, whereas levels of NPNT, MRC1, DNER, and CYPB4 were decreased in high marbled animals. The remaining gene, ACTN2 was determined to be a false positive and was, therefore, excluded from further study. Despite the positive results of the preliminary study, associations between gene expression and intramuscular fat content did not extend to the larger population of cattle. A significant negative association existed between expression of MRC1 and marbling level (P = 0.04). Therefore, this study was unable to identify a particular skeletal muscle gene set whose expression correlated well with marbling levels in the larger population of beef cattle.

Pharmacological characterization of a novel positive modulator at alpha 4 beta 3 delta-containing extrasynaptic GABA(A) receptors.

The in vitro and in vivo pharmacological effects of [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504), which is a close analogue of retigabine, have been investigated. AA29504 induced a rightward shift of the activation threshold at cloned KCNQ2, 2/3 and 4 channels expressed in Xenopus oocytes, with a potency 3-4fold lower than retigabine. AA29504 (1 muM) had no agonist activity when tested at alpha(1)beta(3)gamma(2s) or alpha(4)beta(3)delta GABA(A) receptors expressed in Xenopus oocytes, but left-shifted the EC(50) for GABA and gaboxadol (THIP) at both receptors. The maximum GABA response at alpha(1)beta(3)gamma(2s) receptors was unchanged by AA29504 (1 muM), but increased 3-fold at alpha(4)beta(3)delta receptors. In slices prepared from the prefrontal cortex of adult rats AA29504 had no effect alone on the average IPSC or the tonic current in layer II/III pyramidal neurons, but potentiated the effect of gaboxadol on both phasic and tonic currents. Thus, the effects of gaboxadol could be positively modulated by AA29504. Systemic administration of AA29504 at doses relevant for modulating GABA transmission produced anxiolytic effects and reduced motor coordination consistent with activity at GABA(A) receptors. We conclude that AA29504 exerts a major action via alpha(4)beta(3)delta-containing GABA(A) receptors, which will be important for interpreting its effect in vivo.

First Report of the Pathogenicity of Colletotrichum gloeosporioides on Invasive Ferns, Lygodium microphyllum and L. japonicum, in Florida.

Lygodium microphyllum (Cav.) R.Br. (Old World climbing fern) and L. japonicum (Thunb.) Sw. (Japanese climbing fern), in the family Schizaeaceae, are among the most invasive weeds in Florida (1). L. microphyllum invades fresh water and moist habitats in south Florida, while L. japonicum has spread in relatively well-drained habitats from Texas to North Carolina and central Florida. Some potted plants of both Lygodium spp. grown in shadehouse as well as in full sunlight developed discolored spots on pinnules (foliage), which coalesced and resulted in browning and dieback of severely infected vines. Symptomatic foliage obtained from these plants was surface-sterilized by immersing in a 15% solution of commercial bleach for 90 s, followed by a series of four rinses with sterile deionized distilled water. Disks (4 mm in diameter) of pinnules were cut from the junction of discolored and healthy tissues and placed on potato dextrose agar (PDA). A fungus, Colletotrichum gloeosporioides (Penz.) Penz. & Sacc. was consistently isolated from these disks. Fungal colonies produced abundant conidia on PDA. Conidia were hyaline, straight, cylindrical, averaging 14.7 µm (range 12.5 to 17.5 µm) × 5.0 µm (range 3.8 to 7.5 µm), and similar to those described for C. gloeosporioides (2). To confirm the pathogenicity of C. gloeosporioides on L. microphyllum and L. japonicum, Koch's postulates were performed. A fungal isolate was grown on PDA for 3 weeks, after which 10 ml of sterile deionized distilled water was added to the culture and agitated to dislodge conidia. The conidial suspension was strained through three layers of cheesecloth to remove hyphal fragments, and its concentration was adjusted to 1.7 × 106 conidia/ml. Foliage of healthy L. microphyllum and L. japonicum plants grown in 500-ml containers was sprayed with the conidial suspension until runoff. Plants were covered with plastic bags whose inner sides were misted with water to maintain high humidity and placed in a growth chamber under 12 h of fluorescent light per day. Temperature and relative humidity in the chamber ranged from 26 to 29°C and 44 to 73%, respectively. Plastic bags were removed after 3 days, and plants were further incubated for 3 weeks in the same growth chamber. Control plants were sprayed with sterile water, covered with plastic bags, and exposed to the same temperature, light, and humidity regime as those of the fungus-inoculated plants. Small, discolored foliar spots appeared 3 days after fungus inoculation. These spots were similar to those observed on pinnules of potted plants that originated from shadehouse and outdoor environments. Within 3 weeks after inoculation, the foliage of L. japonicum developed abundant discolored spots that led to edge browning and wilting of the pinnules. L. microphyllum had similar but more severe symptoms, with plants suffering as much as 50% dieback. C. gloeosporioides was consistently reisolated from the symptomatic tissues of both fern species. No symptoms appeared on the water-inoculated plants. To our knowledge, this is the first record of C. gloeosporioides pathogenicity on L. microphyllum and L. japonicum. References: (1) R. W. Pemberton and A. P. Ferriter. Am. Fern J. 88:165, 1998. (2) B. C. Sutton. Colletotrichum: Biology, Pathology and Control. CAB International, Wallingford, Oxon, UK, 1992.