Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023.

OBJECTIVES: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions. DESIGN: Ambidirectional multisite cohort study. SETTING: Four tertiary children's hospitals. PATIENTS: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication ( p < 0.0001) and contributed to a decision to consult palliative care ( p < 0.02). CONCLUSIONS: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management.

Machine learning approaches for the optimization of packing densities in granular matter.

The fundamental question of how densely granular matter can pack and how this density depends on the shape of the constituent particles has been a longstanding scientific problem. Previous work has mainly focused on empirical approaches based on simulations or mean-field theory to investigate the effect of shape variation on the resulting packing densities, focusing on a small set of pre-defined shapes like dimers, ellipsoids, and spherocylinders. Here we discuss how machine learning methods can support the search for optimally dense packing shapes in a high-dimensional shape space. We apply dimensional reduction and regression techniques based on random forests and neural networks to find novel dense packing shapes by numerical optimization. Moreover, an investigation of the regression function in the dimensionally reduced shape representation allows us to identify directions in the packing density landscape that lead to a strongly non-monotonic variation of the packing density. The predictions obtained by machine learning are compared with packing simulations. Our approach can be more widely applied to optimize the properties of granular matter by varying the shape of its constituent particles.

Enhanced Optical Response of SnS/SnS2 Layered Heterostructure.

The SnS/SnS2 heterostructure was fabricated by the chemical vapor deposition method. The crystal structure properties of SnS2 and SnS were characterized by X-ray diffraction (XRD) pattern, Raman spectroscopy, and field emission scanning electron microscopy (FESEM). The frequency dependence photoconductivity explores its carrier kinetic decay process. The SnS/SnS2 heterostructure shows that the ratio of short time constant decay process reaches 0.729 with a time constant of 4.3 × 10-4 s. The power-dependent photoresponsivity investigates the mechanism of electron-hole pair recombination. The results indicate that the photoresponsivity of the SnS/SnS2 heterostructure has been increased to 7.31 × 10-3 A/W, representing a significant enhancement of approximately 7 times that of the individual films. The results show the optical response speed has been improved by using the SnS/SnS2 heterostructure. These results indicate an application potential of the layered SnS/SnS2 heterostructure for photodetection. This research provides valuable insights into the preparation of the heterostructure composed of SnS and SnS2, and presents an approach for designing high-performance photodetection devices.

HwMR is a novel magnesium-associated protein.

Microbial rhodopsins (MRho) are vital proteins in Haloarchaea for solar light sensing in extreme living environments. Among them, Haloquadratum walsbyi (Hw) is a species known to survive high MgCl2 concentrations, with a total of three MRhos identified, including a high-acid-tolerance light-driven proton outward pump, HwBR, a chloride-insensitive chloride pump, HwHR, and a functionally unknown HwMR. Here, we showed that HwMR is the sole magnesium-sensitive MRho among all tested MRho proteins from Haloarchaea. We identified at least D84 as one of the key residues mediating such magnesium ion association in HwMR. Sequence analysis and molecular modeling suggested HwMR to have an extra H8 helix in the cytosolic region like those in signal-transduction-type MRho of deltarhodopsin-3 (dR-3) and Anabaena sensory rhodopsin (ASR). Further, HwMR showed a distinctly prolonged M-state formation under a high concentration of Mg2+. On the other hand, an H8 helix truncated mutant preserved photocycle kinetics like the wild type, but it led to missing M-state structure. Our findings clearly suggested not only that HwMR is a novel Mg2+-associated protein but that the association with both Mg2+ and the H8 domain stabilizes M-state formation in HwMR. We conclude that Mg2+ association and H8 are crucial in stabilizing HwMR M state, which is a well-known photoreceptor signaling state.

Dynamic Nuclear Structure Emerges from Chromatin Cross-Links and Motors.

The cell nucleus houses the chromosomes, which are linked to a soft shell of lamin protein filaments. Experiments indicate that correlated chromosome dynamics and nuclear shape fluctuations arise from motor activity. To identify the physical mechanisms, we develop a model of an active, cross-linked Rouse chain bound to a polymeric shell. System-sized correlated motions occur but require both motor activity and cross-links. Contractile motors, in particular, enhance chromosome dynamics by driving anomalous density fluctuations. Nuclear shape fluctuations depend on motor strength, cross-linking, and chromosome-lamina binding. Therefore, complex chromosome dynamics and nuclear shape emerge from a minimal, active chromosome-lamina system.

Spongelike Rigid Structures in Frictional Granular Packings.

We show how rigidity emerges in experiments on sheared two-dimensional frictional granular materials by using generalizations of two methods for identifying rigid structures. Both approaches, the force-based dynamical matrix and the topology-based rigidity percolation, agree with each other and identify similar rigid structures. As the system becomes jammed, at a critical contact number z_{c}=2.4±0.1, a rigid backbone interspersed with floppy, particle-filled holes of a broad range of sizes emerges, creating a spongelike morphology. While the pressure within rigid structures always exceeds the pressure outside the rigid structures, they are not identified with the force chains of shear jamming. These findings highlight the need to focus on mechanical stability arising through arch structures and hinges at the mesoscale.

Dielectric Polymer Property Prediction Using Recurrent Neural Networks with Optimizations.

Despite the growing success of machine learning for predicting structure-property relationships in molecules and materials, such as predicting the dielectric properties of polymers, it is still in its infancy. We report on the effectiveness of solving structure-property relationships for a computer-generated database of dielectric polymers using recurrent neural network (RNN) models. The implementation of a series of optimization strategies was crucial to achieving high learning speeds and sufficient accuracy: (1) binary and nonbinary representations of SMILES (Simplified Molecular Input Line System) fingerprints and (2) backpropagation with affine transformation of the input sequence (ATransformedBP) and resilient backpropagation with initial weight update parameter optimizations (iRPROP- optimized). For the investigated database of polymers, the binary SMILES representation was found to be superior to the decimal representation with respect to the training and prediction performance. All developed and optimized Elman-type RNN algorithms outperformed nonoptimized RNN models in the efficient prediction of nonlinear structure-activity relationships. The average relative standard deviation (RSD) remained well below 5%, and the maximum RSD did not exceed 30%. Moreover, we provide a C++ codebase as a testbed for a new generation of open programming languages that target increasingly diverse computer architectures.

Advances in intervention methods and brain protection mechanisms of in situ and remote ischemic postconditioning.

Ischemic postconditioning (PostC) conventionally refers to a series of brief blood vessel occlusions and reperfusions, which can induce an endogenous neuroprotective effect and reduce cerebral ischemia/reperfusion (I/R) injury. Depending on the site of adaptive ischemic intervention, PostC can be classified as in situ ischemic postconditioning (ISPostC) and remote ischemic postconditioning (RIPostC). Many studies have shown that ISPostC and RIPostC can reduce cerebral IS injury through protective mechanisms that increase cerebral blood flow after reperfusion, decrease antioxidant stress and anti-neuronal apoptosis, reduce brain edema, and regulate autophagy as well as Akt, MAPK, PKC, and KATP channel cell signaling pathways. However, few studies have compared the intervention methods, protective mechanisms, and cell signaling pathways of ISPostC and RIPostC interventions. Thus, in this article, we compare the history, common intervention methods, neuroprotective mechanisms, and cell signaling pathways of ISPostC and RIPostC.

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models.

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

Total Synthesis of (+)-Lycoricidine and Conduramine B-1, ent-C-1, C-4, D-1, ent-F-1, and ent-F-4, and Formal Synthesis of (-)-Laminitol: a C2-Symmetric Chiral-Pool-Based Flexible Strategy.

A facile and diversity-oriented synthetic strategy toward aminocyclitol natural products from inexpensive C2-symmetric l-tartaric acid was developed. The pivotal epoxide was used as a common intermediate to accomplish eight diverse target molecules in six to eleven steps. Various allyl-amine-type conduramines were synthesized in a diastereoselective manner. Heck arylation was explored to construct a phenanthridone ring in a concise synthesis of (+)-lycoricidine. In addition, a highly efficient formal synthesis of (-)-laminitol was developed.

Na+ Ions Induce the Pirouetting Motion and Catalytic Activity of [2]Rotaxanes.

We have prepared [2]rotaxanes, the behavior of which as switchable catalysts depends on their pirouetting motion, which can be controlled through the addition and removal of Na+ ions. At least three sequential on/off cycles of a Michael reaction can be performed in situ when using the NaTFPB/[2.2.2]cryptand reagent pair to switch "on" and "off" the catalytic ability of the [2]rotaxanes.

Synthesis and biological assay of erlotinib analogues and BSA-conjugated erlotinib analogue.

A series of erlotinib analogues that have structural modification at 6,7-alkoxyl positions is efficiently synthesized. The in vitro anti-tumor activity of synthesized compounds is studied in two non-small cell lung cancer (NSCLC) cell lines (A549 and H1975). Among the synthesized compounds, the iodo compound 6 (ETN-6) exhibits higher anti-cancer activity compared to erlotinib. An efficient method is developed for the conjugation of erlotinib analogue-4, alcohol compound, with protein, bovine serum albumin (BSA), via succinic acid linker. The in vitro anti-tumor activity of the protein attached erlotinib analogue, 8 (ETN-4-Suc-BSA), showed stronger inhibitory activity in both A549 and H1975 NSCLC cell lines.

Incarceration of Higher-Order Fullerenes within Cyclotriveratrylene-Based Hemicarcerands Allows Selective Isolation of C76 , C78 , and C84 from a Commercial Fullerene Mixture.

Size-complementary cyclotriveratrylene (CTV)-based hosts can incarcerate C76 , C78 , and C84 , thus allowing the selective isolation of these higher-order fullerenes from a commercially available mixture of fullerenes. The hemicarceplexes, formed after the encapsulation of the size-complementary fullerenes within the hosts, are isolated by column chromatography and released at elevated temperature, thereby leading to the isolation of C76 /C78 and C84 in good purities (up to 95 and 88 %, respectively).

[Rapid identification of the different constituents in Fructus Schisandrae Chinensis before and after processing by UHPLC-QTOF/MS~E combining with metabonomics].

This study was performed to use UHPLC-QTOF/MSE technology to rapidly search and identify variations of chemical ingredients between Fructus Schisandrae Chinensis and its processed products. The present study provides a basis for the study of Chinese herbal medicine processing with a focus on the impact of processing on chemical components. Using a time-dependent data scan mode (MSE) couple with metabolomics technology, we acquired accurate data and identified the potential chemical markers. A total of 12 chemical markers were identified in the crude, vinegar-processed and wine-processed Schisandra chinensis fruit; The results showed that the levels of 6-O-benzoylgomisin O, schisantherin B, schisantherin C, schisantherin D and neokadsuranic acid are the highest in crude Schisandra chinensis fruit; thelevels of schizandrin A, schizandrin B, schizandrin C, gomisin D and gomisin T are the highest in wine-processed Schisandra chinensis fruit; the levels of schisantherin A and schisandrin are the highest in vinegar-processed Schisandra chinensis fruit. There were significant changes of chemical components between Fructus Schisandrae Chinensis and their processed products, and these findings may offer a reasonable explanation for variation of efficacy and clinical applications in the processed products of Fructus Schisandrae Chinensis.

Microwave-assisted efficient conjugation of nanodiamond and paclitaxel.

Nanodiamond has recently received considerable attention due to the various possible applications in medical field such as drug delivery and bio-labeling. For this purpose suitable and effective surface functionalization of the diamond material are required. A versatile and reproducible surface modification method of nanoscale diamond is essential for functionalization. We introduce the input of microwave energy to assist the functionalization of nanodiamond surface. The feasibility of such a process is illustrated by comparing the biological assay of ND-paclitaxel synthesized by conventional and microwave irradiating. Using a microwave we manage to have approximately doubled grafted molecules per nanoparticle of nanodiamond.

Application of a smartphone nurse call system for nursing care.

BACKGROUND: Traditionally, a patient presses the nurse call button and alerts the central nursing station. This system cannot reach the primary care nurse directly. The aim of this study was to apply a new smartphone system through the cloud system and information technology that linked a smartphone and a mobile nursing station for nursing care service. MATERIALS AND METHODS: A smartphone and mobile nursing station were integrated into a smartphone nurse call system through the cloud and information technology for better nursing care. RESULTS: Waiting time for a patient to contact the most responsible nurse was reduced from 3.8 min to 6 s. The average time for pharmacists to locate the nurse for medication problem was reduced from 4.2 min to 1.8 min by the new system. CONCLUSIONS: After implementation of the smartphone nurse call system, patients received a more rapid response. This improved patients' satisfaction and reduced the number of complaints about longer waiting time due to the shortage of nurses.

Fecal Incontinence and Quality of Life in Adults With Rectal Cancer After Lower Anterior Resection.

PURPOSE: The purpose of this study was to explore the prevalence of fecal incontinence (FI) and its impact on health-related quality of life in rectal cancer patients following low anterior resection surgery for colorectal cancer. DESIGN: Descriptive, cross-sectional study. SUBJECTS AND SETTING: Patients who were diagnosed with rectal cancer and underwent low anterior resection were recruited from a 1264-bed hospital in southern Taiwan. Potential participants were mailed a questionnaire survey. They were followed up 8 to 16 months postoperatively. Some clinical data were collected via retrospective review of their medical records. METHODS: Questionnaires were mailed to 172 patients, and 71 with colorectal cancer underwent low anterior resection and agreed to participate and completed questionnaires in the research, reflecting a return rate of 41%. Data were collected on demographic characteristics and disease-related variables. Participants were asked if they had experienced FI during the past week. Fecal incontinence health-related quality of life was measured using the Cleveland Clinic Incontinence Score (CCIS) and the Fecal Incontinence Quality of Life Index. Completion of the questionnaire required approximately 15 minutes. RESULTS: More than half of the 71 participants (n = 45; 63.4%) experienced incontinence of flatus, 42.3% (n = 30) reported incontinence of liquid stool, and 14.1% (n = 10) stated that they experienced incontinence of solid stool. Based on mean CCIS scores, 35.2% (n = 25) experienced moderate to severe FI. One-third wore pads to contain FI and 21.1% changed daily activities because of FI. Nearly two-thirds reported FI during the week prior to completing the research questionnaire. The average Fecal Incontinence Quality of Life Index cumulative score was significantly lower in the FI group (2.62 ± 0.61) than in the without-FI group (3.32 ± 0.77; P < .001), as were all subscale mean scores (all P < .01-.001). CONCLUSIONS: Fecal incontinence is prevalent among persons undergoing low anterior resection for colorectal cancer. Persons with FI report poor health-related quality of life compared to persons who retained fecal continence. Health care providers should assess these patients for FI and treat or refer those who experience this common problem.

Shorter daily dwelling time in peritoneal dialysis attenuates the epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: Peritoneal dialysis (PD) therapy is known to induce morphological and functional changes in the peritoneal membrane. Long-term exposure to conventional bio-incompatible dialysate and peritonitis is the main etiology of inflammation. Consequently, the peritoneal membrane undergoes structural changes, including angiogenesis, fibrosis, and hyalinizing vasculopathy, which ultimately results in technique failure. The epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs) plays an important role during the above process; however, the clinical parameters associated with the EMT process of MCs remain to be explored. METHODS: To investigate the parameters impacting EMT during PD therapy, 53 clinical stable PD patients were enrolled. EMT assessments were conducted through human peritoneal MCs cultured from dialysate effluent with one consistent standard criterion (MC morphology and the expression of an epithelial marker, cytokeratin 18). The factors potentially associated with EMT were analyzed using logistic regression analysis. Primary MCs derived from the omentum were isolated for the in vitro study. RESULTS: Forty-seven percent of the patients presented with EMT, 28% with non-EMT, and 15% with a mixed presentation. Logistic regression analysis showed that patients who received persistent PD therapy (dwelling time of 24 h/day) had significantly higher EMT tendency. These results were consistent in vitro. CONCLUSIONS: Dwelling time had a significant effect on the occurrence of EMT on MCs.

Define SNP thresholds for delineation of tuberculosis transmissions using whole-genome sequencing.

For facilitating tuberculosis (TB) control, we used a whole-genome sequencing (WGS)-based approach to delineate transmission networks in a country with an intermediate burden of TB. A cluster was defined as Mycobacterium tuberculosis isolates with identical genotypes, and an outbreak was defined as clustered cases with epidemiological links (epi-links). To refine a cluster predefined using space oligonucleotide typing and mycobacterial interspersed repetitive unit variable tandem repeat typing, we analyzed one pansusceptible TB (C1) and three multidrug-resistant (MDR)-TB (C2-C4) clusters from different scenarios. Pansusceptible TB cluster (C1) consisting of 28 cases had ≤5 single nucleotide polymorphisms (SNPs) difference between their isolates. C1 was a definite outbreak, with cases attending the same junior high school in 2012. Three MDR-TB clusters (C2-C4) with distinct genotypes were identified, each consisting of 12-22 cases. Some of the cases had either ≤5 or ≤15 SNPs difference with clear or probable epi-links. Of note, even though WGS could effectively assist TB contact tracing, we still observed missing epi-links in some cases within the same cluster. Our results showed that thresholds of ≤5 and ≤15 SNPs difference between isolates were used to categorize definite and probable TB transmission, respectively. Furthermore, a higher SNP threshold might be required to define an MDR-TB outbreak. WGS still needs to be combined with classical epidemiological methods for improving outbreak investigations. Importantly, different SNP thresholds have to be applied to define outbreaks. IMPORTANCE: TB is a chronic disease. Depending on host factors and TB burden, clusters of cases may continue to increase for several years. Conventional genotyping methods overestimate TB transmission, hampering precise detection of outbreaks and comprehensive surveillance. WGS can be used to obtain SNP information of M. tuberculosis to improve discriminative limitations of conventional methods and to strengthen delineation of transmission networks. It is important to define the country-specific SNP thresholds for investigation of transmission. This study demonstrated the use of thresholds of ≤5 and ≤15 SNPs difference between isolates to categorize definite and probable transmission, respectively. Different SNP thresholds should be applied while a higher cutoff was required to define an MDR-TB outbreak. The utilization of SNP thresholds proves to be crucial for guiding public health interventions, eliminating the need for unnecessary public health actions, and potentially uncovering undisclosed TB transmissions.

Unusual extrahepatic metastatic site of hepatocellular carcinoma with post-therapy disseminating metastases presenting as a primary soft tissue sarcoma: case report.

Introduction and importance: Hepatocellular carcinoma (HCC) is a highly malignant primary hepatic tumor. However, extrahepatic metastatic sites of HCC with post-therapy dissemination of metastases mimicking primary soft tissue sarcomas with rib metastases are extremely rare. Case presentation: The authors report a unique case of hepatitis B virus (HBV)-positive HCC with bilateral lung involvement and widespread right-flank soft tissue and rib metastases. The pathological diagnosis after surgical resection confirmed extrahepatic HCC metastasis. Subsequently, adjuvant-targeted and immune-checkpoint inhibitor therapies were still initiated. Clinical discussion: Extrahepatic HCC metastasis, which initially presents at distant sites, is uncommon. HCC commonly metastasizes to the lungs, bones, lymph nodes, kidneys, adrenal glands, and peritoneum/omentum. HCC with aggressive post-scheduled adjuvant therapy to the lungs and hypochondriac soft tissue with rib metastasis is very rare and has a poor prognosis. Conclusion: Although most patients with HCC have disseminated extrahepatic metastases, primary HCC should still be treated. Thus, a review of the history and imaging, histopathology, and immunohistochemical findings is crucial for the definite and differential diagnosis of this tumor.