Ability of a multi-segment foot model to measure kinematic differences in cavus, neutrally aligned, asymptomatic planus, and symptomatic planus foot types.

BACKGROUND: Multi-segment foot models (MFMs) provide a better understanding of the intricate biomechanics of the foot, yet it is unclear if they accurately differentiate foot type function during locomotion. RESEARCH QUESTION: We employed an MFM to detect subtle kinematic differences between foot types, including: pes cavus, neutrally aligned, and asymptomatic and symptomatic pes planus. The study investigates how variable the results of this MFM are and if it can detect kinematic differences between pathologic and non-pathologic foot types during the stance phase of gait. METHODS: Independently, three raters instrumented three subjects on three days to assess variability. In a separate cohort, each foot type was statically quantified for ten subjects per group. Each subject walked while instrumented with a four-segment foot model to assess static alignment and foot motion during the stance phase of gait. Statistical analysis performed with a linear mixed effects regression. RESULTS: Model variability was highest for between-day and lowest for between-rater, with all variability measures being within the true sample variance. Almost all static measures (radiographic, digital scan, and kinematic markers) differed significantly by foot type. Sagittal hindfoot to leg and forefoot to leg kinematics differed between foot types during late stance, as well as coronal hallux to forefoot range of motion. The MFM had low between-rater variability and may be suitable for multiple raters to apply to a single study sample without introducing significant error. The model, however, only detected a few dynamic differences, with the most dramatic being the hallux to forefoot coronal plane range of motion. SIGNIFICANCE: Results only somewhat aligned with previous work. It remains unclear if the MFM is sensitive enough to accurately detect different motion between foot types (pathologic and non-pathologic). A more accurate method of tracking foot bone motion (e.g., biplane fluoroscopy) may be needed to address this question.

Nanosecond infrared laser (NIRL) for cutting roots of human teeth: thermal effects and quality of cutting edges.

A nanosecond infrared laser (NIRL) was investigated in cutting dental roots. The focus of the investigation was defining the preparation accuracy and registration of thermal effects during laser application. Ten teeth were processed in the root area using a NIRL in several horizontal, parallel incisions to achieve tooth root ablation as in an apicoectomy. Temperature change was monitored during ablation and the quality of the cutting edges in the roots were studied by means of micro-CT, optical coherence tomography, and histology of decalcified and undecalcified specimens. NIRL produced clearly defined cut surfaces in dental hard tissues. The automated guidance of the laser beam created regular, narrow dentin defects that tapered in a V-shape towards the ablation plane. A biologically significant increase in the temperature of the object and its surroundings did not occur during the laser application. Thermal dentin damage was not detected in histological preparations of treated teeth. Defined areas of the tooth root may be ablated using a NIRL. For clinical translation of NIRL in apicoectomy, it would be necessary to increase energy delivered to hard tissue and develop beam application facilitating beam steering for oral treatment.

Influence of the transverse tarsal arch on radiological components of progressive collapsing foot deformity.

The importance of the transverse tarsal arch (TTA) has recently been extensively reevaluated and has even been considered to play a greater role in foot stability than the medial longitudinal arch (MLA). However, the relevance of this observation in the context of common clinical foot disorders, such as progressive collapsing foot deformity (PCFD), has not yet been fully clarified. In this biomechanical study, we examined ten pairs of human cadaveric feet by serial weight-bearing cone-beam computed tomography under controlled loading using a custom-designed testing machine. The MLA and TTA were transected separately, alternating the order in two study groups. A semiautomated three-dimensional evaluation of their influence on three components of PCFD, namely collapse of the longitudinal arch (sagittal Meary's angle), hindfoot alignment (sagittal talocalcaneal angle), and forefoot abduction (axial Meary's angle), was performed. Both arches had a relevant effect on collapse of the longitudinal arch, however the effect of transecting the MLA was stronger compared to the TTA (sagittal Meary's angle, 7.4° (95%CI 3.8° to 11.0°) vs. 3.2° (95%CI 0.5° to 5.9°); p = 0.021). Both arches had an equally pronounced effect on forefoot abduction (axial Meary's angle, 4.6° (95%CI 2.0° to 7.1°) vs. 3.0° (95%CI 0.6° to 5.3°); p = 0.239). Neither arch showed a consistent effect on hindfoot alignment. In conclusion, weakness of the TTA has a decisive influence on radiological components of PCFD, but not greater than that of the MLA. Our findings contribute to a deeper understanding and further development of treatment concepts for flatfoot disorders.

Clinical Impact of Contouring Variability for Prostate Cancer Tumor Boost.

PURPOSE: The focal radiation therapy (RT) boost technique was shown in a phase III randomized controlled trial (RCT) to improve prostate cancer outcomes without increasing toxicity. This technique relies on the accurate delineation of prostate tumors on MRI. A recent prospective study evaluated radiation oncologists' accuracy when asked to delineate prostate tumors on MRI and demonstrated high variability in tumor contours. We sought to evaluate the impact of contour variability and inaccuracy on predicted clinical outcomes. We hypothesized that radiation oncologists' contour inaccuracies would yield meaningfully worse clinical outcomes. METHODS AND MATERIALS: Forty-five radiation oncologists and 2 expert radiologists contoured prostate tumors on 30 patient cases. Of these cases, those with CT simulation or diagnostic CT available were selected for analysis. A knowledge-based planning model was developed to generate focal RT boost plans for each contour per the RCT protocol. The probability of biochemical failure (BF) was determined using a model from the RCT. The primary metric evaluated was delta BF (DBF = Participant BF - Expert BF). An absolute increase in BF ≥5% was considered clinically meaningful. RESULTS: Eight patient cases and 394 target volumes for focal RT boost planning were included in this analysis. In general, participant plans were associated with worse predicted clinical outcomes compared to the expert plan, with an average absolute increase in BF of 4.3%. Of participant plans, 37% were noted to have an absolute increase in BF of 5% or more. CONCLUSIONS: Radiation oncologists' attempts to contour tumor targets for focal RT boost are frequently inaccurate enough to yield meaningfully inferior clinical outcomes for patients.

Immediate Effect of Wearable Balance Training Device on Muscle Co-Contraction and Postural Control During Standing.

Postural control is one of the primary body functions for fall prevention. Unexpected perturbation-based balance training is effective for improving postural control. However, the effect of perturbation-based training using assistive devices on muscle activity and co-contraction for standing balance is still unclear. This training is also difficult to perform easily because it requires large instruments or expert guidance. The purpose of this study is to demonstrate the effect of perturbation-based balance training using a wearable balance training device (WBTD) on postural control. In this study, fourteen healthy young adult males were assigned to either a WBTD group or a sham group. In the intervention session, participants in the WBTD group were perturbed either left or right direction at random timing by the WBTD during tandem stance balance training. Participants in the Sham group did not receive external perturbation during tandem stance balance training. Before and after the intervention session, participants of both groups underwent unexpected lateral perturbation postural control testing (pre- and post-test). The normalized integral of electromyography (IEMG), co-contraction index (CCI), and center of pressure (COP) parameters were measured in the pre- and post-test. Experimental results showed that the WBTD group in the post-test significantly decreased left Gluteus Medius IEMG, CCI of both Gluteus Medius, and peak [Formula: see text] velocity, compared to those of the pre-test ( [Formula: see text], p =0.024 , p =0.031 , respectively). We conclude that balance training using WBTD could improve flexible postural control adjustment via cooperative muscle activation.

Effects of evening smartphone use on sleep and declarative memory consolidation in male adolescents and young adults.

Exposure to short-wavelength light before bedtime is known to disrupt nocturnal melatonin secretion and can impair subsequent sleep. However, while it has been demonstrated that older adults are less affected by short-wavelength light, there is limited research exploring differences between adolescents and young adults. Furthermore, it remains unclear whether the effects of evening short-wavelength light on sleep architecture extend to sleep-related processes, such as declarative memory consolidation. Here, we recorded polysomnography from 33 male adolescents (15.42 ± 0.97 years) and 35 male young adults (21.51 ± 2.06 years) in a within-subject design during three different nights to investigate the impact of reading for 90 min either on a smartphone with or without a blue-light filter or from a printed book. We measured subjective sleepiness, melatonin secretion, sleep physiology and sleep-dependent memory consolidation. While subjective sleepiness remained unaffected, we observed a significant melatonin attenuation effect in both age groups immediately after reading on the smartphone without a blue-light filter. Interestingly, adolescents fully recovered from the melatonin attenuation in the following 50 min before bedtime, whereas adults still, at bedtime, exhibited significantly reduced melatonin levels. Sleep-dependent memory consolidation and the coupling between sleep spindles and slow oscillations were not affected by short-wavelength light in both age groups. Nevertheless, adults showed a reduction in N3 sleep during the first night quarter. In summary, avoiding smartphone use in the last hour before bedtime is advisable for adolescents and young adults to prevent sleep disturbances. Our research empirically supports general sleep hygiene advice and can inform future recommendations regarding the use of smartphones and other screen-based devices before bedtime.

A brief bout of moderate intensity physical activity improves preadolescent children's behavioral inhibition but does not change their energy intake.

Children in rural communities consume more energy-dense foods relative to their urban peers. Identifying effective interventions for improving energy intake patterns are needed to address these geographic disparities. The primary aim of this study was to harness the benefits of physical activity on children's executive functioning to see if these improvements lead to acute changes in eating behaviors. In a randomized crossover design, 91 preadolescent (8-10y; M age = 9.48 ± 0.85; 50.5% female; 85.7% White, 9.9% Multiracial, 9.9% Hispanic) children (86% rural) completed a 20-minute physical activity condition (moderate intensity walking) and time-matched sedentary condition (reading and/or coloring) ~ 14 days apart. Immediately following each condition, participants completed a behavioral inhibition task and then eating behaviors (total energy intake, relative energy intake, snack intake) were measured during a multi-array buffet test meal. After adjusting for period and order effects, body fat (measured via DXA), and depressive symptoms, participants experienced significant small improvements in their behavioral inhibition following the physical activity versus sedentary condition (p = 0.04, Hedge's g = 0.198). Eating behaviors did not vary by condition, nor did improvements in behavioral inhibition function as a mediator (ps > 0.09). Thus, in preadolescent children, small improvements in behavioral inhibition from physical activity do not produce acute improvements in energy intake. Additional research is needed to clarify whether the duration and/or intensity of physical activity sessions would produce different results in this age group, and whether intervention approaches and corresponding mechanisms of change vary by individual factors, like age and degree of food cue responsivity.

Skeletal Muscle Compliance and Echogenicity in Resistance-Trained and Nontrained Women.

ABSTRACT: Mongold, SJ, Ricci, AW, Hahn, ME, and Callahan, DM. Skeletal muscle compliance and echogenicity in resistance-trained and nontrained women. J Strength Cond Res 38(4): 671-680, 2024-Noninvasive assessment of muscle mechanical properties in clinical and performance settings tends to rely on manual palpation and emphasizes examination of musculotendinous stiffness. However, measurement standards are highly subjective. The purpose of the study was to compare musculotendinous stiffness in adult women with varying resistance training history while exploring the use of multiple tissue compliance measures. We identified relationships between tissue stiffness and morphology, and tested the hypothesis that combining objective measures of morphology and stiffness would better predict indices of contractile performance. Resistance-trained (RT) women (n = 11) and nontrained (NT) women (n = 10) participated in the study. Muscle echogenicity and morphology were measured using B-mode ultrasonography (US). Vastus lateralis (VL) and patellar tendon (PT) stiffness were measured using digital palpation and US across submaximal isometric contractions. Muscle function was evaluated during maximal voluntary isometric contraction (MVIC) of the knee extensors (KEs). Resistance trained had significantly greater PT stiffness and reduced echogenicity (p < 0.01). Resistance trained also had greater strength per body mass (p < 0.05). Muscle echogenicity was strongly associated with strength and rate of torque development (RTD). Patellar tendon passive stiffness was associated with RTD normalized to MVIC (RTDrel; r = 0.44, p < 0.05). Patellar tendon stiffness was greater in RT young women. No predictive models of muscle function incorporated both stiffness and echogenicity. Because RTDrel is a clinically relevant measure of rehabilitation in athletes and can be predicted by digital palpation, this might represent a practical and objective measure in settings where RTD may not be easy to measure directly.

Spectral Slope and Lempel-Ziv Complexity as Robust Markers of Brain States during Sleep and Wakefulness.

Nonoscillatory measures of brain activity such as the spectral slope and Lempel-Ziv complexity are affected by many neurological disorders and modulated by sleep. A multitude of frequency ranges, particularly a broadband (encompassing the full spectrum) and a narrowband approach, have been used especially for estimating the spectral slope. However, the effects of choosing different frequency ranges have not yet been explored in detail. Here, we evaluated the impact of sleep stage and task engagement (resting, attention, and memory) on slope and complexity in a narrowband (30-45 Hz) and broadband (1-45 Hz) frequency range in 28 healthy male human subjects (21.54 ± 1.90 years) using a within-subject design over 2 weeks with three recording nights and days per subject. We strived to determine how different brain states and frequency ranges affect slope and complexity and how the two measures perform in comparison. In the broadband range, the slope steepened, and complexity decreased continuously from wakefulness to N3 sleep. REM sleep, however, was best discriminated by the narrowband slope. Importantly, slope and complexity also differed between tasks during wakefulness. While narrowband complexity decreased with task engagement, the slope flattened in both frequency ranges. Interestingly, only the narrowband slope was positively correlated with task performance. Our results show that slope and complexity are sensitive indices of brain state variations during wakefulness and sleep. However, the spectral slope yields more information and could be used for a greater variety of research questions than Lempel-Ziv complexity, especially when a narrowband frequency range is used.

A unifying theory explains seemingly contradictory biases in perceptual estimation.

Perceptual biases are widely regarded as offering a window into the neural computations underlying perception. To understand these biases, previous work has proposed a number of conceptually different, and even seemingly contradictory, explanations, including attraction to a Bayesian prior, repulsion from the prior due to efficient coding and central tendency effects on a bounded range. We present a unifying Bayesian theory of biases in perceptual estimation derived from first principles. We demonstrate theoretically an additive decomposition of perceptual biases into attraction to a prior, repulsion away from regions with high encoding precision and regression away from the boundary. The results reveal a simple and universal rule for predicting the direction of perceptual biases. Our theory accounts for, and yields, new insights regarding biases in the perception of a variety of stimulus attributes, including orientation, color and magnitude. These results provide important constraints on the neural implementations of Bayesian computations.

Quantitative MRI biomarker for classification of clinically significant prostate cancer: calibration for reproducibility across echo times.

Background: Restriction Spectrum Imaging restriction score (RSIrs) is a quantitative biomarker for detecting clinically significant prostate cancer (csPCa). However, the quantitative value of the RSIrs is affected by imaging parameters such as echo time (TE). Purpose: The purpose of the present study is to develop a calibration method to account for differences in echo times and facilitate use of RSIrs as a quantitative biomarker for the detection of csPCa. Methods: This study included 197 consecutive patients who underwent MRI and biopsy examination; 97 were diagnosed with csPCa (grade group ≥ 2). RSI data were acquired three times during the same session: twice at minimum TE∼75ms and once at TE=90ms (TEmin 1 , TEmin 2 , and TE90, respectively). A proposed calibration method, trained on patients without csPCa, estimated a linear scaling factor (f) for each of the four diffusion compartments (C) of the RSI signal model. A linear regression model was determined to match C-maps of TE90 to the reference C-maps of TEmin 1 within the interval ranging from 95 th to 99 th percentile of signal intensity within the prostate. RSIrs comparisons were made at 98 th percentile within each patient's prostate. We compared RSIrs from calibrated TE90 (RSIrs TE90corr ) and uncorrected TE90 (RSIrs TE90 ) to RSIrs from reference TEmin 1 (RSIrs TEmin1 ) and repeated TEmin 2 (RSIrs TEmin2 ). Calibration performance was evaluated with sensitivity, specificity, area under the ROC curve, positive predicted value, negative predicted value, and F1-score. Results: Scaling factors for C 1 , C 2 , C 3 , and C 4 were estimated as 1.70, 1.38, 1.03, and 1.19, respectively. In non-csPCa cases, the 98 th percentile of RSIrs TEmin2 and RSIrs TEmin1 differed by 0.27±0.86SI (mean±standard deviation), whereas RSIrs TE90 differed from RSIrs TEmin1 by 1.81±1.20SI. After calibration, this bias was reduced to -0.41±1.20SI, representing a 78% reduction in absolute error. For patients with csPCa, the difference was 0.54±1.98SI between RSIrs TEmin2 and RSIrs TEmin1 and 2.28±2.06SI between RSIrs TE90 and RSIrs TEmin1 . After calibration, the mean difference decreased to -0.86SI, a 38% reduction in absolute error. At the Youden index for patient-level classification of csPCa (8.94SI), RSIrs TEmin1 has a sensitivity of 66% and a specificity of 72%. Prior to calibration, RSIrs TE90 at the same threshold tended to over-diagnose benign cases (sensitivity 44%, specificity 88%). Post-calibration, RSIrs TE90corr performs more similarly to the reference (sensitivity 71%, specificity 62%). Conclusion: The proposed linear calibration method produces similar quantitative biomarker values for acquisitions with different TE, reducing TE-induced error by 78% and 38% for non-csPCa and csPCa, respectively.

Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Vaginal morphology and position associated with prolapse recurrence after vaginal surgery: A secondary analysis of the DEMAND study.

OBJECTIVE: To identify vaginal morphology and position factors associated with prolapse recurrence following vaginal surgery. DESIGN: Secondary analysis of magnetic resonance images (MRI) of the Defining Mechanisms of Anterior Vaginal Wall Descent cross-sectional study. SETTING: Eight clinical sites in the US Pelvic Floor Disorders Network. POPULATION OR SAMPLE: Women who underwent vaginal mesh hysteropexy (hysteropexy) with sacrospinous fixation or vaginal hysterectomy with uterosacral ligament suspension (hysterectomy) for uterovaginal prolapse between April 2013 and February 2015. METHODS: The MRI (rest, strain) obtained 30-42 months after surgery, or earlier for participants with recurrence who desired reoperation before 30 months, were analysed. MRI-based prolapse recurrence was defined as prolapse beyond the hymen at strain on MRI. Vaginal segmentations (at rest) were used to create three-dimensional models placed in a morphometry algorithm to quantify and compare vaginal morphology (angulation, dimensions) and position. MAIN OUTCOME MEASURES: Vaginal angulation (upper, lower and upper-lower vaginal angles in the sagittal and coronal plane), dimensions (length, maximum transverse width, surface area, volume) and position (apex, mid-vagina) at rest. RESULTS: Of the 82 women analysed, 12/41 (29%) in the hysteropexy group and 22/41 (54%) in the hysterectomy group had prolapse recurrence. After hysteropexy, women with recurrence had a more laterally deviated upper vagina (p = 0.02) at rest than women with successful surgery. After hysterectomy, women with recurrence had a more inferiorly (lower) positioned vaginal apex (p = 0.01) and mid-vagina (p = 0.01) at rest than women with successful surgery. CONCLUSIONS: Vaginal angulation and position were associated with prolapse recurrence and suggestive of vaginal support mechanisms related to surgical technique and potential unaddressed anatomical defects. Future prospective studies in women before and after prolapse surgery may distinguish these two factors.

Sleep spindle maturity promotes slow oscillation-spindle coupling across child and adolescent development.

The synchronization of canonical fast sleep spindle activity (12.5-16 Hz, adult-like) precisely during the slow oscillation (0.5-1 Hz) up peak is considered an essential feature of adult non-rapid eye movement sleep. However, there is little knowledge on how this well-known coalescence between slow oscillations and sleep spindles develops. Leveraging individualized detection of single events, we first provide a detailed cross-sectional characterization of age-specific patterns of slow and fast sleep spindles, slow oscillations, and their coupling in children and adolescents aged 5-6, 8-11, and 14-18 years, and an adult sample of 20- to 26-year-olds. Critically, based on this, we then investigated how spindle and slow oscillation maturity substantiate age-related differences in their precise orchestration. While the predominant type of fast spindles was development-specific in that it was still nested in a frequency range below the canonical fast spindle range for the majority of children, the well-known slow oscillation-spindle coupling pattern was evident for sleep spindles in the adult-like canonical fast spindle range in all four age groups-but notably less precise in children. To corroborate these findings, we linked personalized measures of fast spindle maturity, which indicate the similarity between the prevailing development-specific and adult-like canonical fast spindles, and slow oscillation maturity, which reflects the extent to which slow oscillations show frontal dominance, with individual slow oscillation-spindle coupling patterns. Importantly, we found that fast spindle maturity was uniquely associated with enhanced slow oscillation-spindle coupling strength and temporal precision across the four age groups. Taken together, our results suggest that the increasing ability to generate adult-like canonical fast sleep spindles actuates precise slow oscillation-spindle coupling patterns from childhood through adolescence and into young adulthood.

Cells in the brain are wired together like an electric circuit that can relay information from one area of the brain to the next. Even when sleeping, the human brain continues to send signals to process information it has encountered during the day. This results in two patterns of electrical activity that define the sleeping brain: slowly repeating waves (or slow oscillations) and rapid bursts of activity known as sleep spindles. Although slow oscillations and sleep spindles are generated in different regions of the brain, they often happen at the same time. This syncing of activity is thought to help different parts of the brain to communicate with each other. Such communication is essential for new memories to become stable and last a long time. In children, slow oscillations and sleep spindles appear together less frequently, suggesting that these co-occurring patterns of electrical activity develop as humans grow into adults. Here, Joechner et al. set out to understand what drives slow oscillations and sleep spindles to start happening at the same time. The team used a technique called electroencephalography (or EEG for short) to study the brain activity of children, teenagers and adults as they slept. This revealed that slow oscillations and sleep spindles occur together less often in children compared to teenagers and adults. Moreover, the slow oscillations and sleep spindles observed in the children had very different physical characteristics to those observed in adults. Further analyses showed that the more similar the children's sleep spindles were to adult spindles, the more consistently they appeared at the same time as the slow oscillations. The findings of Joechner et al. suggest that as children grow up, their sleep spindles become more adult-like, causing the spindles to happen at the same time as slow oscillations more consistently. This indicates that brain circuits that generate sleep spindles may play an essential role in developing successful communication networks in the human brain. In the future, this work may ultimately provide new insights into how age-related changes to the brain contribute to cognitive development, and suggests sleep as a potential intervention target for neurodevelopmental disorders.

Restriction spectrum imaging with elastic image registration for automated evaluation of response to neoadjuvant therapy in breast cancer.

Purpose: Dynamic contrast-enhanced MRI (DCE) and apparent diffusion coefficient (ADC) are currently used to evaluate treatment response of breast cancer. The purpose of the current study was to evaluate the three-component Restriction Spectrum Imaging model (RSI3C), a recent diffusion-weighted MRI (DWI)-based tumor classification method, combined with elastic image registration, to automatically monitor breast tumor size throughout neoadjuvant therapy. Experimental design: Breast cancer patients (n=27) underwent multi-parametric 3T MRI at four time points during treatment. Elastically-registered DWI images were used to generate an automatic RSI3C response classifier, assessed against manual DCE tumor size measurements and mean ADC values. Predictions of therapy response during treatment and residual tumor post-treatment were assessed using non-pathological complete response (non-pCR) as an endpoint. Results: Ten patients experienced pCR. Prediction of non-pCR using ROC AUC (95% CI) for change in measured tumor size from pre-treatment time point to early-treatment time point was 0.65 (0.38-0.92) for the RSI3C classifier, 0.64 (0.36-0.91) for DCE, and 0.45 (0.16-0.75) for change in mean ADC. Sensitivity for detection of residual disease post-treatment was 0.71 (0.44-0.90) for the RSI3C classifier, compared to 0.88 (0.64-0.99) for DCE and 0.76 (0.50-0.93) for ADC. Specificity was 0.90 (0.56-1.00) for the RSI3C classifier, 0.70 (0.35-0.93) for DCE, and 0.50 (0.19-0.81) for ADC. Conclusion: The automatic RSI3C classifier with elastic image registration suggested prediction of response to treatment after only three weeks, and showed performance comparable to DCE for assessment of residual tumor post-therapy. RSI3C may guide clinical decision-making and enable tailored treatment regimens and cost-efficient evaluation of neoadjuvant therapy of breast cancer.

The need for an intersectionality framework in precision medicine research.

Precision medicine research has seen growing efforts to increase participation of communities that have been historically underrepresented in biomedical research. Marginalized racial and ethnic communities have received particular attention, toward the goal of improving the generalizability of scientific knowledge and promoting health equity. Against this backdrop, research has highlighted three key issues that could impede the promise of precision medicine research: issues surrounding (dis)trust and representation, challenges in translational efforts to improve health outcomes, and the need for responsive community engagement. Existing efforts to address these challenges have predominantly centered on single-dimensional demographic criteria such as race, ethnicity, or sex, while overlooking how these and additional variables, such as disability, gender identity, and socioeconomic factors, can confound and jointly impact research participation. We argue that increasing cohort diversity and the responsiveness of precision medicine research studies to community needs requires an approach that transcends conventional boundaries and embraces a more nuanced, multi-layered, and intersectional framework for data collection, analyses, and implementation. We draw attention to gaps in existing work, highlight how overlapping layers of marginalization might shape and substantiate one another and affect the precision-medicine research cycle, and put forth strategies to facilitate equitable advantages from precision-medicine research to diverse participants and internally heterogeneous communities.

The sGC Activator Runcaciguat Has Kidney Protective Effects and Prevents a Decline of Kidney Function in ZSF1 Rats.

Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance. ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcaciguat. Furthermore, oxidative stress was compared in the ZSF1 rat kidney with kidney samples from DKD patients. Within the duration of the 12-week treatment study, kidney function was significantly decreased in obese ZSF1 rats, indicated by a 20-fold increase in proteinuria, compared to lean ZSF1 rats. Runcaciguat dose-dependently and significantly attenuated the development of proteinuria in ZSF1 rats with reduced uPCR at the end of the study by -19%, -54%, and -70% at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo treatment. Additionally, average blood glucose levels measured as HbA1C, triglycerides, and cholesterol were increased by five times, twenty times, and four times, respectively, in obese ZSF1 compared to lean rats. In obese ZSF1 rats, runcaciguat reduced HbA1c levels by -8%, -34%, and -76%, triglycerides by -42%, -55%, and -71%, and cholesterol by -16%, -17%, and -34%, at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo. Concomitantly, runcaciguat also reduced kidney weights, morphological kidney damage, and urinary and plasma biomarkers of kidney damage. Beneficial effects were accompanied by changes in gene expression that indicate reduced fibrosis and inflammation and suggest improved endothelial stabilization. In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061).

Glycome profiling and immunohistochemistry uncover changes in cell walls of Arabidopsis thaliana roots during spaceflight.

A large and diverse library of glycan-directed monoclonal antibodies (mAbs) was used to determine if plant cell walls are modified by low-gravity conditions encountered during spaceflight. This method called glycome profiling (glycomics) revealed global differences in non-cellulosic cell wall epitopes in Arabidopsis thaliana root extracts recovered from RNA purification columns between seedlings grown on the International Space Station-based Vegetable Production System and paired ground (1-g) controls. Immunohistochemistry on 11-day-old seedling primary root sections showed that ten of twenty-two mAbs that exhibited spaceflight-induced increases in binding through glycomics, labeled space-grown roots more intensely than those from the ground. The ten mAbs recognized xyloglucan, xylan, and arabinogalactan epitopes. Notably, three xylem-enriched unsubstituted xylan backbone epitopes were more intensely labeled in space-grown roots than in ground-grown roots, suggesting that the spaceflight environment accelerated root secondary cell wall formation. This study highlights the feasibility of glycomics for high-throughput evaluation of cell wall glycans using only root high alkaline extracts from RNA purification columns, and subsequent validation of these results by immunohistochemistry. This approach will benefit plant space biological studies because it extends the analyses possible from the limited amounts of samples returned from spaceflight and help uncover microgravity-induced tissue-specific changes in plant cell walls.