BACKGROUND: Cardiovascular disease (CVD) risk scores provide point estimates of individual risk without uncertainty quantification. The objective of the current study was to demonstrate the feasibility and clinical utility of calculating uncertainty surrounding individual CVD-risk predictions using Bayesian methods.
METHODS: Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). In 8,355 individuals, followed for median of 8.2 years (IQR 4.2-12.5), a Bayesian Weibull model was derived to predict the 10-year risk of recurrent CVD events.
RESULTS: Model coefficients and individual predictions from the Bayesian model were very similar to that of a traditional (\'frequentist\') model but the Bayesian model also predicted 95% credible intervals (CIs) surrounding individual risk estimates. The median width of the individual 95%CrI was 5.3% (IQR 3.6-6.5) and 17% of the population had a 95%CrI width of 10% or greater. The uncertainty decreased with increasing sample size used for derivation of the model. Combining the Bayesian Weibull model with sampled hazard ratios based on trial reports may be used to estimate individual estimates of absolute risk reduction with uncertainty measures and the probability that a treatment option will result in a clinically relevant risk reduction.
CONCLUSIONS: Estimating uncertainty surrounding individual CVD risk predictions using Bayesian methods is feasible. The uncertainty regarding individual risk predictions could have several applications in clinical practice, like the comparison of different treatment options or by calculating the probability of the individual risk being below a certain treatment threshold. However, as the individual uncertainty measures only reflect sampling error and no biases in risk prediction, physicians should be familiar with the interpretation before widespread clinical adaption.

OBJECTIVE: Clinical registries have great potential for quality control of medical procedures regarding the indications, therapeutic processes and results, including their possible complications. This is particularly true when providing patients with severe hearing loss or deafness with a cochlear implant (CI). This treatment represents a lifelong care process that requires continuous quality control over time. On the initiative of the Executive Committee of the German Society of Otorhinolaryngology (Deutsche Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e.V., DGHNO-KHC), a national German CI registry (Deutsches Cochlear Implant Register, DCIR) was established in January 2022. This article focuses on the first demographic and baseline data of the DCIR.
METHODS: The DCIR covers the complete therapeutic process from indication, surgery, fitting and lifelong aftercare in CI therapy. By the end of 2022, 75 hospitals in Germany had agreed to contribute to the DCIR.
RESULTS: During the year 2022, 63 hospitals actively contributed data to the DCIR. Pseudonymized data from 2,292 CI implantations (2,176 primary implantations, 99 explantations with immediate re-implantations and 17 re-implantations following an earlier explantation) in 2,108 patients were documented. Cochlear implantation was accomplished in 1,807 adults (≥ 18 years) and 301 children (< 18 years). Fourty patients (1,9%) were children < 1 year of age and 55 (2,6%) were patients > 85 years. From the total of 2,292 implantations, 226 (9.9%) were performed as simultaneous bilateral implantations (CI implantation in both ears of 113 patients on the same day of surgery) and 412 implantations (19.1% of 2,162 implantations with data provided on the contralateral ear\'s hearing status) were in patients with single sided deafness (normal hearing in the contralateral ear). In addition, the reported complications in 2022 were also evaluated. Seven reports (0.4%) of mild to moderate severe facial nerve dysfunctions were documented. No reports of severe or total facial nerve dysfunction (House-Brackmann grade V/VI), meningitis or death related to CI therapy were documented.
CONCLUSIONS: Although still in the start-up phase, these initial DCIR data already provide an interesting first insight into the demographic structure and baseline data of CI therapy in Germany. The successful implementation of the DCIR represents an important step towards continuous quality control of CI care.

Plague is an endemic infectious disease caused by Yersinia pestis. In this study, we isolated fourteen phages with similar sequence arrangements to phage 186; these phages exhibited different lytic abilities in Enterobacteriaceae strains. To illustrate the phylogenetic relationships and evolutionary relationships between previously designated 186-type phages, we analysed the complete sequences and important genes of the phages, including whole-genome average nucleotide identity (ANI) and collinearity comparison, evolutionary analysis of four conserved structural genes (V, T, R, and Q genes), and analysis of the regulatory genes (cI, apl, and cII) and integrase gene (int). Phylogenetic analysis revealed that thirteen of the newly isolated phages belong to the genus Eganvirus and one belongs to the genus Felsduovirus in the family Peduoviridae, and these Eganvirus phages can be roughly clustered into three subgroups. The topological relationships exhibited by the whole-genome and structural genes seemed similar and stable, while the regulatory genes presented different topological relationships with the structural genes, and these results indicated that there was some homologous recombination in the regulatory genes. These newly isolated 186-type phages were mostly isolated from dogs, suggesting that the resistance of Canidae to Y. pestis infection may be related to the wide distribution of phages with lytic capability.

BACKGROUND: Cerebral ischemia (CI) induces a profound neuroinflammatory response, but the underlying molecular mechanism remains unclear. Exosomes from adipose-derived stem cells (ADSC-exos) have been found to play a crucial role in cell communication by transferring molecules including microRNAs (miRNAs), which have been shown to modulate the inflammatory response after CI and are viable molecular targets for altering brain function. The current study aimed to explore the contribution of ADSC-exosomal miR-21-5p to the neuroinflammation after CI.
METHODS: The differentially expressed miR-21-5p in CI was screened based on literature search. The target mRNAs of miR-21-5p were predicted using online databases and verified by luciferase reporter assay. Then, BV2 cells were treated with hemin to simulate the inflammatory response after CI, and its animal model was induced using the MCAO method. Ischemia was evaluated in rats using 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining. ADSCs-exos were further isolated and identified by western blot analysis and transmission electron microscope.
RESULTS: MiR-21-5p was significantly down-regulated in CI and alleviated neuropathic damage after CI by the PIK3R1/PI3K/AKT signaling axis. And miR-21-5p derived from ADSCs-exos alleviated neuroinflammation after CI via promoting microglial M2 polarization.
CONCLUSIONS: We demonstrated that ADSC-exosomal miR-21-5p mitigated post-CI inflammatory response through the PIK3R1/PI3K/AKT signaling axis and could offer neuroprotection after CI through promoting polarization of M2 microglia.

UNASSIGNED: To investigate the magnetic resonance imaging (MRI) features of women with prior second-trimester pregnancy loss, and to establish a nomogram prediction model for subsequent miscarriage.
UNASSIGNED: A retrospective cohort study of women with prior second-trimester pregnancy loss from January 2018 to December 2021 in Second Affiliated Hospital of Soochow University was performed. A total of 245 patients were included. Data from January 2018 to December 2019 were used to construct the model, and data from January 2020 to December 2021 were used to evaluate the model. Data on maternal demographic characteristics, MRI cervical measurements were extracted. The prediction model was constructed with independent variables determined by multivariate logistic regression analyses. Through receiver-operating characteristic (ROC) curve analysis, the predictive ability of the model for subsequent second trimester pregnancy loss in women was evaluated, and internal validation was performed through validation data.
UNASSIGNED: Thin cervix was observed in 77 (31.42%) women with prior second-trimester pregnancy loss, the mean longitudinal diameter of cervical canal on MRI was 11.76±2.75mm. The model reached a sensitivity of 80%, specificity of 75.90%, positive predictive value (PPV) of 55.80% and negative predictive value of 90.90%; ROC characteristics proved that the model was superior to any single parameter with an AUC of 0.826.
UNASSIGNED: Our observations showed that thin cervix and longitudinal diameter of cervical canal reliably predicted second trimester pregnancy loss. We developed and validated a nomogram model to predict the individual probability of second trimester pregnancy loss in the next pregnancy and hopefully improve the prediction and indication of interventions.

A cerebral infarction (CI), often known as a stroke, is a cognitive impairment in which a group of brain cells perishes from a lack of blood supply. The early prediction and evaluation of this problem are essential to avoid atrial fibrillation, heart valve disease, and other cardiac disorders. Different clinical strategies like Computerized tomography (CT) scans, Magnetic resonance imaging (MRI), and Carotid (ka-ROT-id) ultrasound are available to diagnose this problem. However, these methods are time-consuming and expensive. Wearable devices based on photoplethysmography (PPG) are gaining prevalence in diagnosing various cardiovascular diseases. This work uses the PPG signal to classify the CI subjects from the normal. We propose an automated framework and fiducial point-independent approach to predict CI with sufficient accuracy. The experiment is performed with a publicly available database having PPG and other physiological data of 219 individuals. The best validation and test accuracy of 91.8% and 91.3% are obtained after diagnosis with Coarse Gaussian SVM. The proposed work aims to extract cerebral infarction pathology by extracting relevant entropy features from higher order PPG derivatives for the prediction of CI and offers a simple, automated and inexpensive approach for early detection of CI and promotes awareness for the subjects to undergo further treatment to avoid major disorders.

OBJECTIVE: This study investigated neuroplastic changes induced by postlingual single-sided deafness (SSD) and the effects of a cochlear implantation for the deaf ear. Neural processing of acoustic signals from the normal hearing ear to the brain was studied before and after implantation using a positron emission tomography (PET)/CT scanner.
METHODS: Eight patients with postlingual SSD received a cochlear implant (CI) in a prospective clinical trial. Dynamic imaging was performed in a PET/CT scanner using radioactively labeled water ([15O]H2O) to localize changes in the regional cerebral blood flow (rCBF) with and without an auditory task of logatomes containing speech-like elements without meaningful context. The normal hearing ear was stimulated before implantation and after the use of the cochlear implant for at least 8 months (mean 13.5, range 8.1-26.6). Eight age- and gender-matched subjects with normal hearing on both sides served as healthy control subjects (HCS).
RESULTS: When the normal hearing ear of SSD patients was stimulated before CI implantation, the [15O]H2O-PET showed a more symmetrical rCBF in the auditory regions of both hemispheres in comparison to the HCS. The use of CI increased the asymmetry index (AI) in six of eight patients indicating an increase of activity of the contralateral hemisphere. Non-parametric statistics revealed a significant difference in the AI between patients before CI implantation and HCS (p < .01), which disappeared after CI implantation (p = .195).
CONCLUSIONS: The functional neuroimaging data showed a tendency towards normalization of neuronal activity after CI implantation, which supports the effectiveness of CI in SSD patients.
BACKGROUND: ClinicalTrials.gov Identifier: NCT01749592, December 13, 2012.

Despite substantial technical advances and wider clinical use, cochlear implant (CI) users continue to report high and elevated listening effort especially under challenging noisy conditions. Among all the objective measures to quantify listening effort, pupillometry is one of the most widely used and robust physiological measures. Previous studies with normally hearing (NH) and hearing-impaired (HI) listeners have shown that the relation between speech performance in noise and listening effort (as measured by peak pupil dilation) is not linear and exhibits an inverted-U shape. However, it is unclear whether the same psychometric relation exists in CI users, and whether individual differences in auditory sensitivity and central cognitive capacity affect this relation. Therefore, we recruited 17 post-lingually deaf CI adults to perform speech-in-noise tasks from 0 to 20 dB SNR with a 4 dB step size. Simultaneously, their pupillary responses and self-reported subjective effort were recorded. To characterize top-down and bottom-up individual variabilities, a spectro-temporal modulation task and a set of cognitive abilities were measured. Clinical word recognition in quiet and Quality of Life (QoL) were also collected. Results showed that at a group level, an inverted-U shape psychometric curve between task difficulty (SNR) and peak pupil dilation (PPD) was not observed. Individual shape of the psychometric curve was significantly associated with some individual factors: CI users with higher clinical word and speech-in-noise recognition showed a quadratic decrease of PPD over increasing SNRs; CI users with better non-verbal intelligence and lower QoL showed smaller average PPD. To summarize, individual differences in CI users had a significant impact on the psychometric relation between pupillary response and task difficulty, hence affecting the interpretation of pupillary response as listening effort (or engagement) at different task difficulty levels. Future research and clinical applications should further characterize the possible effects of individual factors (such as motivation or engagement) in modulating CI users\' occurrence of \'tipping point\' on their psychometric functions, and develop an individualized method for reliably quantifying listening effort using pupillometry.

In this study, we investigated the metabolic signatures of different mitochondrial defects (two different complex I and complex V, and the one MDH2 defect) in human skin fibroblasts (HSF). We hypothesized that using a selective culture medium would cause defect specific adaptation of the metabolome and further our understanding of the biochemical implications for the studied defects. All cells were cultivated under galactose stress condition and compared to glucose-based cell culture condition. We investigated the bioenergetic profile using Seahorse XFe96 cell analyzer and assessed the extracellular metabolic footprints and the intracellular metabolic fingerprints using NMR. The galactose-based culture condition forced a bioenergetic switch from a glycolytic to an oxidative state in all cell lines which improved overall separation of controls from the different defect groups. The extracellular metabolome was discriminative for separating controls from defects but not the specific defects, whereas the intracellular metabolome suggests CI and CV changes and revealed clear MDH2 defect-specific changes in metabolites associated with the TCA cycle, malate aspartate shuttle, and the choline metabolism, which are pronounced under galactose condition.

A percentage (i.e., 5.6%) of Cochlear Implant (CI) users reportedly experience unwanted facial nerve stimulation (FNS). For some, the effort to control this problem results in changing stimulation parameters, thereby reducing their hearing performance. For others, the only viable solution is to deactivate the CI completely. A growing body of evidence in the form of case reports suggests that undesired FNS can be effectively addressed through re-implantation with an Oticon Medical (OM) Neuro-Zti implant. However, the root of this benefit is still unknown: is it due to surgical adjustments, such as varied array geometries and/or positioning, or does it stem from differences in stimulation parameters and/or grounding? The OM device exhibits two distinct features: (1) unique stimulation parameters, including anodic leading pulses and loudness controlled by pulse duration-not current-resulting in lower overall current amplitudes; and (2) unconventional grounding, including both passive (capacitive) discharge, which creates a pseudo-monophasic pulse shape, and a \'distributed-all-polar\' (DAP) grounding scheme, which is thought to reduce current spread. Unfortunately, case reports alone cannot distinguish between surgical factors and these implant-related ones. In this paper, we present a novel follow-up study of two CI subjects who previously experienced FNS before re-implantation with Neuro-Zti implants. We used the Oticon Medical Research Platform (OMRP) to stimulate a single electrode in each subject in two ways: (1) with traditional monopolar biphasic cathodic-first pulses, and (2) with distinct OM clinical stimulation. We progressively increased the stimulation intensity until FNS occurred or the sound became excessively loud. Non-auditory/FNS sensations were observed with the traditional stimulation but not with the OM clinical one. This provides the first direct evidence demonstrating that stimulation parameters and/or grounding-not surgical factors-play a key role in mitigating FNS.