Stochastic modeling of the human middle ear dynamics under pathological conditions.

BACKGROUND: Although the dynamics of the middle ear (ME) have been modeled since the mid-twentieth century, only recently stochastic approaches started to be applied. In this study, a stochastic model of the ME was utilized to predict the ME dynamics under both healthy and pathological conditions. METHODS: The deterministic ME model is based on a lumped-parameter representation, while the stochastic model was developed using a probabilistic non-parametric approach that randomizes the deterministic model. Subsequently, the ME model was modified to represent the ME under pathological conditions. Furthermore, the simulated data was used to develop a classifier model of the ME condition based on a machine learning algorithm. RESULTS: The ME model under healthy conditions exhibited good agreement with statistical experimental results. The ranges of probabilities from models under pathological conditions were qualitatively compared to individual experimental data, revealing similarities. Moreover, the classifier model presented promising results. DISCUSSION: The results aimed to elucidate how the ME dynamics, under different conditions, can overlap across various frequency ranges. Despite the promising results, improvements in the stochastic and classifier models are necessary. Nevertheless, this study serves as a starting point that can yield valuable tools for researchers and clinicians.

Association between perinatal and obstetric factors and early age at diagnosis of type 1 diabetes mellitus: a cohort study.

OBJECTIVES: To evaluate the association between perinatal and obstetric factors as potential triggers for the early onset of T1DM. METHODS: This was a retrospective cohort study enrolling 409 patients diagnosed with T1DM, in Bauru, São Paulo, Brazil, from 1981 to 2023. Data were retrieved from medical records, regarding sociodemographic parameters as age, sex, ethnicity, and socioeconomic status. Perinatal and obstetric factors as delivery type, gestational age, filiation order, length of exclusive breastfeeding, maternal age, maternal and fetal blood types, and occurrence of maternal gestational diabetes were also analyzed. An adapted survival analysis was employed to gauge the impact of each assessed variable at the age of T1DM diagnosis. RESULTS: The median age of T1DM diagnosis was 10.3 years with an interquartile range between 6.4 and 15.5 years. Delivery type and filiation order were the only factors statistically significantly associated with an early age at T1DM diagnosis. Patients who were born through cesarean section and who were firstborns showed a 28.6 and 18.0 % lower age at T1DM diagnosis, respectively, compared to those born through vaginal delivery and those that were nonfirstborns. CONCLUSIONS: Being born by cesarean section and being firstborn showed to be statistically significant factors to determine an early T1DM diagnosis.

Outcomes of Repeat Conventional Transarterial Chemoembolization in Patients with Liver Metastases.

INTRODUCTION AND OBJECTIVES: Although unlimited sessions of conventional transarterial chemoembolization (cTACE) may be performed for liver metastases, there is no data indicating when treatment becomes ineffective. This study aimed to determine the optimal number of repeat cTACE sessions for nonresponding patients before abandoning cTACE in patients with liver metastases. MATERIALS AND METHODS: In this retrospective, single-institutional analysis, patients with liver metastases from neuroendocrine tumors (NET), colorectal carcinoma (CRC), and lung cancer who underwent consecutive cTACE sessions from 2001 to 2015 were studied. Quantitative European Association for Study of the Liver (qEASL) criteria were utilized for response assessment. The association between the number of cTACE and 2-year, 5-year, and overall survival was evaluated to estimate the optimal number of cTACE for each survival outcome. RESULTS: Eighty-five patients underwent a total of 186 cTACE sessions for 117 liver metastases, of which 30.7% responded to the first cTACE. For the target lesions that did not respond to the first, second, and third cTACE sessions, response rates after the second, third, and fourth cTACE sessions were 33.3%, 23%, and 25%, respectively. The fourth cTACE session was the optimal number for 2-year survival (HR 0.40; 95%CI: 0.16-0.97; p=0.04), 5-year survival (HR 0.31; 95%CI: 0.11-0.87; p=0.02), and overall survival (HR 0.35; 95%CI: 0.13-0.89; p=0.02). CONCLUSIONS: Repeat cTACE in the management of liver metastases from NET, CRC, and lung cancer was associated with improved patient survival. We recommend at least four cTACE sessions before switching to another treatment for nonresponding metastatic liver lesions.

Heparin Dose Intensity and Organ Support-Free Days in Patients Hospitalized for COVID-19.

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.

Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food.

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.

Ternary Complexes of BiI3/CuI and SbI3/CuI with Tetrahydrothiophene.

Reactions of BiI3/CuI mixtures with tetrahydrothiophene (THT) in toluene produce 2-D sheet networks BiCu3I6(THT)n (n = 2, 3, or 4), depending on reaction conditions. All three structures are based on BiI6 octahedra, which share pairs of (µ2-I)2 with Cu3(THT)n units. BiCu3I6(THT)2 features Cu2(µ2-I)2 rhombs with close Cu···Cu interactions and is accompanied by formation of the very complex HBi3Cu12I22(THT)8. Reactions of SbI3/CuI with THT in toluene produced a SbCu3I6(THT)2 network shows Cu3(µ2-THT)2 units, like its Bi congener, but Cu6(µ2-I)6 barrels rather than rhombs. Isolated SbI3 units are stacked above the Cu6I6 barrels. A molecular compound, Sb3Cu3I12(THT)6 consists of a face-sharing Sb3I12 stack, in which the Cu-THT units are bonded in asymmetric fashion about the central SbI6. Metal-halide bonds were investigated via QTAIM and NLMO analyses, demonstrating that these bonds are largely ionic and occur between the Bi/Sb and I p orbitals. Hirshfeld analysis shows significant H···H and H···I interactions. Diffuse reflectance spectroscopy (DRS) reveals band edges for the Bi species of 1.71-1.82 eV, while those for the neutral Sb complexes are in the range of 1.94-2.06 eV. Mapping of the electronic structure via density of state calculations indicates population of antibonding Bi/Sb-I orbitals in the excited state.

Incomplete lineage sorting and hybridization underlie tree discordance in Petunia and related genera (Petunieae, Solanaceae).

Despite the overarching history of species divergence, phylogenetic studies often reveal distinct topologies across regions of the genome. The sources of these gene tree discordances are variable, but incomplete lineage sorting (ILS) and hybridization are among those with the most biological importance. Petunia serves as a classic system for studying hybridization in the wild. While field studies suggest that hybridization is frequent, the extent of reticulation within Petunia and its closely related genera has never been examined from a phylogenetic perspective. In this study, we used transcriptomic data from 11 Petunia, 16 Calibrachoa, and 10 Fabiana species to illuminate the relationships between these species and investigate whether hybridization played a significant role in the diversification of the clade. We inferred that gene tree discordance within genera is linked to hybridization events along with high levels of ILS due to their rapid diversification. Moreover, network analyses estimated deeper hybridization events between Petunia and Calibrachoa, genera that have different chromosome numbers. Although these genera cannot hybridize at the present time, ancestral hybridization could have played a role in their parallel radiations, as they share the same habitat and life history.

Balance, Landing Biomechanics, and Functional Movement Screen Characteristics With and Without Knee Exoskeleton in Military Soldiers.

INTRODUCTION: A light-weight pneumatic-powered knee exoskeleton could augment mobility and lifting capabilities for a variety of occupational settings. However, added weight/bulkiness and artificially produced knee extension torque could compromise sensorimotor characteristics. MATERIALS AND METHODS: Ten healthy participants conducted 3 visits within 10 days to the biomechanics laboratory. Participants were asked to complete the following tasks on each visit: single-leg balance, single-leg drop-landing, and select functional movement tasks. Balance characteristics (the ground reaction forces variability and center-of-pressure velocity) were derived from force plates while knee flexion angles during drop-landing and functional movement tasks were captured using a motion capture system. Descriptive statistics as well as paired t-tests or Wilcoxon signed-rank tests were used to compare between conditions. Significance was set at P < .05 a priori. RESULTS: During single-leg balance, the ground reaction force variabilities were significantly increased (P = .013-.019) and the center of pressure velocity was decreased (P = .001-.017) when wearing knee exoskeleton. During single-leg drop-landing, the exoskeleton condition showed lower knee flexion angles at the initial contact (P = .004-.021) and peak (P = .006-.010). Additionally, the peak vertical ground reaction force was higher in the exoskeleton condition (P = .007). During functional movement tasks, the exoskeleton condition showed less knee flexion range-of-motion during the overhead squat (P = .007-.033) and hurdle step-over (P = .004-.005). CONCLUSIONS: Participants exhibited stiffer landing technique with the exoskeleton. Given that these compromised sensorimotor characteristics have been associated with musculoskeletal injury risk, modifications to exoskeletons to promote softer landing and greater knee flexion range-of-motion during dynamic activities may be warranted.

Medical calculators derived synthetic cohorts: a novel method for generating synthetic patient data.

This study shows that we can use synthetic cohorts created from medical risk calculators to gain insights into how risk estimations, clinical reasoning, data-driven subgrouping, and the confidence in risk calculator scores are connected. When prediction variables aren't evenly distributed in these synthetic cohorts, they can be used to group similar cases together, revealing new insights about how cohorts behave. We also found that the confidence in predictions made by these calculators can vary depending on patient characteristics. This suggests that it might be beneficial to include a "normalized confidence" score in future versions of these calculators for healthcare professionals. We plan to explore this idea further in our upcoming research.

Exploring the transcriptome of immature stages of Ornithodoros hermsi, the soft-tick vector of tick-borne relapsing fever.

Blood-feeding behavior has independently evolved in arthropods multiple times. Unlike hard ticks, soft ticks employ a rapid-feeding strategy for hematophagy, and there are comparatively limited studies on the transcriptomes of these organisms. This study investigates the soft tick Ornithodoros hermsi, conducting histopathological examinations at bitten skin sites and tick whole-body transcriptomic analyses across various developmental and feeding stages, including larvae, 1st-nymphal, and 2nd-nymphal stages. The results revealed the ability of O. hermsi to induce skin hemorrhage at the bite sites. Transcriptomic analyses identified three consistent transcriptional profiles: unfed, early-fed (6 h, 12 h, 24 h), and late-fed (5 days). The unfed profile exhibited high transcriptional activity across most of the functional classes annotated. In contrast, early-fed stages exhibited decreased expression of most functional classes, except for the unknown, which is highly expressed. Finally, transcriptional expression of most functional classes increased in the late-fed groups, resembling the baseline expression observed in the unfed groups. These findings highlight intense pre-feeding transcriptional activity in O. hermsi ticks, aligning with their rapid-feeding strategy. Moreover, besides shedding light on the temporal dynamics of key pathways during blood meal processing and tick development, this study contributes significantly to the transcriptome repertoire of a medically relevant soft tick species with relatively limited prior knowledge.

Tailored electrochemical biosensor with poly-diallydimethylammonium chloride-functionalised multiwalled carbon nanotubes/gold nanoparticles/manganese dioxide, and haemoglobin for sensitive hydrogen peroxide detection.

A very sensitive electrochemical biosensor, with haemoglobin (Hb) as its basis, has been created to quantify hydrogen peroxide (H2O2), an essential marker in environmental monitoring, food safety, and medical diagnosis. The sensor uses a simple, eco-friendly preparation method. Hb was immobilised on manganese dioxide nanostructure/gold nanoparticles/poly-diallydimethylammonium chloride-functionalised multiwalled carbon nanotubes (PDDA-MWCNT/AuNP/MnO2), characterised using various techniques: amperometry, voltammetry, X-ray diffraction (XRD), and transmission electron microscopy (TEM). Nafion was used as a binder membrane to preserve the biological and electrochemical properties of the protein on the modified electrode. In comparison to earlier research, the novel biosensor had a lower detection limit (1.83 µM) and a limit of quantification (6.11 µM) (S/N = 3) for H2O2. It also exhibited notable reproducibility, long-term stability, and repeatability. It was effectively used to measure the amount of H2O2 in cow milk and orange juice, yielding recoveries in the order of 98.90-99.53 % with RSDs less than 5.0 %, which makes it a promising biosensor for food control.

The use of a real-time computer-aided detection system for visible lesions in the Barrett's esophagus during live endoscopic procedures: a pilot study (video).

BACKGROUND AND AIMS: This pilot study evaluated the performance of a recently developed computer-aided detection (CADe) system for Barrett's neoplasia during live endoscopic procedures. METHODS: Fifteen patients with a visible lesion and 15 without were included in this study. A CAD-assisted workflow was used that included a slow pullback video recording of the entire Barrett's segment with live CADe assistance, followed by CADe-assisted level-based video recordings every 2 cm of the Barrett's segment. Outcomes were per-patient and per-level diagnostic accuracy of the CAD-assisted workflow, in which the primary outcome was per-patient in vivo CADe sensitivity. RESULTS: In the per-patient analyses, the CADe system detected all visible lesions (sensitivity 100%). Per-patient CADe specificity was 53%. Per-level sensitivity and specificity of the CADe assisted workflow were 100% and 73%, respectively. CONCLUSIONS: In this pilot study, detection by the CADe system of all potentially neoplastic lesions in Barrett's esophagus was comparable to that of an expert endoscopist. Continued refinement of the system may improve specificity. External validation in larger multicenter studies is planned. (Clinical trial registration number: NCT05628441.).

Transcranial electric stimulation modulates firing rate at clinically relevant intensities.

BACKGROUND: Notwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. OBJECTIVE: To measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow. METHODS: Current flow models were calibrated on electric field measures in the motor cortex (n = 2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 µA of applied skull currents). RESULTS: Electric fields of as low as 0.35 V/m (0.25-0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2-18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. CONCLUSION: In awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility.

COMPUTER-AIDED DIAGNOSIS IMPROVES CHARACTERIZATION OF BARRETT'S NEOPLASIA BY GENERAL ENDOSCOPISTS.

BACKGROUND & AIMS: Characterization of visible abnormalities in Barrett esophagus (BE) patients can be challenging, especially for unexperienced endoscopists. This results in suboptimal diagnostic accuracy and poor inter-observer agreement. Computer-aided diagnosis (CADx) systems may assist endoscopists. We aimed to develop, validate and benchmark a CADx system for BE neoplasia. METHODS: The CADx system received pretraining with ImageNet with consecutive domain-specific pretraining with GastroNet which includes 5 million endoscopic images. It was subsequently trained and internally validated using 1,758 narrow-band imaging (NBI) images of early BE neoplasia (352 patients) and 1,838 NBI images of non-dysplastic BE (173 patients) from 8 international centers. CADx was tested prospectively on corresponding image and video test sets with 30 cases (20 patients) of BE neoplasia and 60 cases (31 patients) of non-dysplastic BE. The test set was benchmarked by 44 general endoscopists in two phases (phase 1: no CADx assistance; phase 2: with CADx assistance). Ten international BE experts provided additional benchmark performance. RESULTS: Stand-alone sensitivity and specificity of the CADx system were 100% and 98% for images and 93% and 96% for videos, respectively. CADx outperformed general endoscopists without CADx assistance in terms of sensitivity (p=0.04). Sensitivity and specificity of general endoscopist increased from 84% to 96% and 90 to 98% with CAD assistance (p<0.001), respectively. CADx assistance increased endoscopists' confidence in characterization (p<0.001). CADx performance was similar to Barrett experts. CONCLUSION: CADx assistance significantly increased characterization performance of BE neoplasia by general endoscopists to the level of expert endoscopists. The use of this CADx system may thereby improve daily Barrett surveillance.

An Atypical Presentation of a Saddle Embolism in the Setting of Malignancy.

A 52-year-old male presented to the emergency room with acute abdominal pain. Imaging determined acute appendicitis, with an incidental finding of a renal mass. The biopsy was positive for renal cell carcinoma, and the patient underwent simultaneous appendectomy and nephrectomy. Postoperatively, the patient developed hypoxia at night with exertion, requiring oxygen supplementation. The remainder of his vital signs were stable. Due to renal function, a ventilation/perfusion (V/Q) scan was conducted, which showed a high probability of pulmonary embolism (PE). Follow-up computed tomography angiography of the chest showed a massive saddle embolism. Interventional radiology performed an uncomplicated thrombectomy, oxygen saturations improved, and the patient was discharged on apixaban.

Bidirectional brain-body interactions during natural story listening.

Narratives can synchronize neural and physiological signals between individuals, but the relationship between these signals, and the underlying mechanism, is unclear. We hypothesized a top-down effect of cognition on arousal and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size, and heart rate were all associated with anterior-central brain signals. Together, these results suggest bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal.