Effect of Time-Dose-Matched Virtual Reality Therapy on Upper Limb Dysfunction in Patients Poststroke: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To investigate the efficacy and acceptability of virtual reality (VR) with time-dose-matched conventional therapy (CT) in patients poststroke with upper limb dysfunction. DATA SOURCES: Cochrane, PubMed, Web of Science, Embase, and ProQuest were systematically searched up to May 24, 2021. STUDY SELECTION: Randomized controlled trials comparing VR with time-dose-matched CT in patients poststroke with upper limb dysfunction were included. DATA EXTRACTION: The extracted data included efficacy (mean change in structure/function, activity, and participation scores), acceptability (dropouts for all reasons), adverse events, and characteristics of the included studies. The Cochrane risk of bias assessment tool was used to assess the risk of bias. DATA SYNTHESIS: Thirty-one randomized controlled trails were included. VR was superior to time-dose-matched CT in terms of the World Health Organization's International Classification of Functioning, Disability and Health structure/function, with a standardized mean difference (SMD) of 0.35, but not activity and participation. Subgroup analyses demonstrated that virtual environment was superior to CT in structure/function (SMD=0.38) and activity (SMD=0.27), whereas there were no significant differences between commercial gaming and CT in any World Health Organization International Classification of Functioning, Disability and Health domain. VR mixed with CT was more effective than time-dose-matched CT in structure/function (SMD=0.56), whereas VR only was not significantly different from CT. There were no significant differences in the incidence of adverse events and dropout rates between VR and CT. CONCLUSIONS: The results suggest that VR is superior to time-dose-matched CT in terms of recovery of upper extremity motor function, especially when a virtual environment is used or VR is mixed with CT. However, VR (VR only or mixed with CT) does not improve patients' daily activity performance and participation compared with CT. Overall, VR appears to be safe and acceptable as CT. Large-scale definitive trials are needed to verify or refute these findings.

Preparation and Properties of Double-Crosslinked Hydroxyapatite Composite Hydrogels.

Natural polymer hydrogels have good mechanical properties and biocompatibility. This study designed hydroxyapatite-enhanced photo-oxidized double-crosslinked hydrogels. Hyaluronic acid (HA) and gelatin (Gel) were modified with methacrylate anhydride. The catechin group was further introduced into the HA chain inspired by the adhesion chemistry of marine mussels. Hence, the double-crosslinked hydrogel (HG) was formed by the photo-crosslinking of double bonds and the oxidative-crosslinking of catechins. Moreover, hydroxyapatite was introduced into HG to form hydroxyapatite-enhanced hydrogels (HGH). The results indicate that, with an increase in crosslinking network density, the stiffness of hydrogels became higher; these hydrogels have more of a compact pore structure, their anti-degradation property is improved, and swelling property is reduced. The introduction of hydroxyapatite greatly improved the mechanical properties of hydrogels, but there is no change in the stability and crosslinking network structure of hydrogels. These inorganic phase-enhanced hydrogels were expected to be applied to tissue engineering scaffolds.

Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation.

HYPOTHESIS: Phosphorus and vitamin D (calcitriol) supplementation in the Phex mouse, a murine model for endolymphatic hydrops (ELH), will improve otic capsule mineralization and secondarily ameliorate the postnatal development of ELH and sensorineural hearing loss (SNHL). BACKGROUND: Male Phex mice have X-linked hypophosphatemic rickets (XLH), which includes osteomalacia of the otic capsule. The treatment for XLH is supplementation with phosphorus and calcitriol. The effect of this treatment has never been studied on otic capsule bone and it is unclear if improving the otic capsule bone could impact the mice's postnatal development of ELH and SNHL. METHODS: Four cohorts were studied: 1) wild-type control, 2) Phex control, 3) Phex prevention, and 4) Phex rescue. The control groups were not given any dietary supplementation. The Phex prevention group was supplemented with phosphorus added to its drinking water and intraperitoneal calcitriol from postnatal day (P) 7-P40. The Phex rescue group was also supplemented with phosphorus and calcium but only from P20 to P40. At P40, all mice underwent auditory brainstem response (ABR) testing, serum analysis, and temporal bone histologic analysis. Primary outcome was otic capsule mineralization. Secondary outcomes were degree of SNHL and presence ELH. RESULTS: Both treatment groups had markedly improved otic capsule mineralization with less osteoid deposition. The improved otic capsule mineralized did not prevent the development of ELH or SNHL. CONCLUSION: Supplementation with phosphorus and calcitriol improves otic capsule bone morphology in the Phex male mouse but does not alter development of ELH or SNHL.

Digenic inheritance of deafness caused by 8J allele of myosin-VIIA and mutations in other Usher I genes.

Inherited hearing loss in mice has contributed substantially to our understanding of inner-ear function. We identified a new allele at the Myo7a locus, Myo7a(sh1-8J); genomic characterization indicated that Myo7a(sh1-8J) arose from complex deletion encompassing exons 38-40 and 42-46. Homozygous mutant mice had no detectable auditory brainstem response, displayed highly disorganized hair-cell stereocilia and had no detectable MYO7A protein. We generated mice that were digenic heterozygotes for Myo7a(sh1-8J) and one of each Cdh23(v-2J), Ush1g(js) or Pcdh15(av-3J) alleles, or an Ush1c null allele. Significant levels of age-related hearing loss were detected in +/Myo7a(sh1-8J) +/Ush1g(js), +/Myo7a(sh1-8J) +/Cdh23(v-2J) and +/Myo7a(sh1-8J) +/Pcdh15(av-3J) double heterozygous mice compared with age-matched single heterozygous animals, suggesting epistasis between Myo7a and each of the three loci. +/Pcdh15(av-3J) +/Ush1g(js) double heterozygous mice also showed elevated hearing loss, suggesting Pcdh15-Ush1g epistasis. While we readily detected MYO7A, USH1C, CDH23 and PCDH15 using mass spectrometry of purified chick utricle hair bundles, we did not detect USH1G. Consistent with that observation, Ush1g microarray signals were much lower in chick cochlea than those of Myo7a, Ush1c, Cdh23 and Pcdh15 and were not detected in the chick utricle. These experiments confirm the importance of MYO7A for the development and maintenance of bundle function and support the suggestion that MYO7A, USH1G (Sans) and CDH23 form the upper tip-link complex in adult mice, likely in combination with USH1C (harmonin). MYO7A, USH1G and PCDH15 may form another complex in stereocilia. USH1G may be a limiting factor in both complexes.

Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies.

Genetic predisposition is recognized as an important pathogenetic factor in otitis media (OM) and associated diseases. Mutant Lmna mice heterozygous for the disheveled hair and ears allele (Lmna(Dhe/+)) exhibit early-onset, profound hearing deficits and other pathological features mimicking human laminopathy associated with the LMNA mutation. We assessed the effects of the Lmna(Dhe/+) mutation on development of OM and pathological abnormalities characteristic of laminopathy. Malformation and abnormal positioning of the eustachian tube, accompanied by OM, were observed in all of the Lmna(Dhe/+) mice (100% penetrance) as early as postnatal day P12. Scanning electronic microscopy revealed ultrastructural damage to the cilia in middle ears that exhibited OM. Hearing assessment revealed significant hearing loss, paralleling that in human OM. Expression of NF-κB, TNF-α, and TGF-ß, which correlated with inflammation and/or bony development, was up-regulated in the ears or in the peritoneal macrophages of Lmna(Dhe/+) mice. Rugous, disintegrative, and enlarged nuclear morphology of peritoneal macrophages and hyperphosphatemia were found in Lmna(Dhe/+) mutant mice. Taken together, these features resemble the pathology of human laminopathies, possibly revealing some profound pathology, beyond OM, associated with the mutation. The Lmna(Dhe/+) mutant mouse provides a novel model of human OM and laminopathy.

Holotransferrin enhances selective anticancer activity of artemisinin against human hepatocellular carcinoma cells.

Artemisinin, also termed qinghaosu, is extracted from the traditional Chinese medicine artemesia annua L. (the blue-green herb) in the early 1970s, which has been confirmed for effectively treating malaria. Additionally, emerging data prove that artemisinin exhibits anti-cancer effects against many types of cancers such as leukemia, melanoma, etc. Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells with increased intracellular iron concentrations. This study is aimed to investigate the selective inhibitory effects of artemisinin on SMMC-7721 cells in vitro and determine the effect of holotransferrin, which increases the concentration of ferrous iron in cancer cells, combined with artemisinin on the anticancer activity. MTT assay was used for assessing the proliferation of SMMC-7721 cells treated with artemisinin. The induction of apoptosis and inhibition of colony formation in SMMC-7721 cells treated with artemisinin were determined by TdT-mediated dUTP nick end labeling (TUNEL) and colony formation assay, respectively. The results showed that artemisinin at various concentrations significantly inhibited growth, colony formation and cell viability of SMMC-7721 cells (P<0.05), likely due to induction of apoptosis of SMMC-7721 cells. Of interest, it was found that incubation of artemisinin combined with holotransferrin sensitized the growth inhibitory effect of artemisinin on SMMC-7721 cells (P<0.01). Our data suggest that treatment with artemisinin leads to inhibition of viability and proliferation, and apoptosis of SMMC-7721 cells. Furthermore, we observed that holotransferrin significantly enhanced the anti-cancer activity of artemisinin. This study may provide a potential therapeutic choice for liver cancer.

[Effects of Quercetin-3-O-ß-D-Glucuronide on Platelet Apoptosis and Activation in Mice with Immune-Mediated Bone Marrow Failure via PI3K/AKT Pathway].

OBJECTIVE: To investigate the effect of quercetin-3-O-ß-D-glucuronide(QG) on platelet apoptosis and activation in mice with immune-mediated bone marrow failure via PI3K/AKT pathway. METHODS: An immune-mediated bone marrow failure mice model was established and forty C57BL/6 mice were randomly assigned into 4 groups: normal group, model group,cyclosporine (CsA) group and QG group, with 10 mice in each group.The mice in CsA group were intragastrically administered with 0.027 g/kg CsA daily and the mice in QG group were intragastrically administered with 0.2 g/kg QG daily, while the mice in the normal group and model group were intragastrically administered with normal saline, respectively. After three days of modeling, the mice were euthanized, and the blood was collected through the tail vein. Part of the blood was used for blood routine examination, and the other part was used to prepare washed platelets. Some of the prepared washed platelets were used to detect the expressions of BAX, BAD, caspase-9, phosphatidylserine (PS), platelet activated complex-1 (PAC-1) and P-selectin by flow cytometry; some of washed platelets was used to determine the protein contents of PI3K, p-PI3k, AKT and p-AKT by Western blot; the other part of the washed platelets was used to measure the expressions of PI3K mRNA and AKT mRNA by real-time quantitative PCR (RT-qPCR). RESULTS: In the model group, the absolute platelet count of the mice was significantly decreased, and the levels of BAX, BAD, caspase-9, PS, PAC-1, and P-selectin in the washed platelets were significantly increased, compared to the normal group (P<0.05). At the same time, the expression levels of PI3K, p-PI3K, AKT, p-AKT proteins and PI3K mRNA, AKT mRNA in model group were significantly reduced, compared to the normal group (P<0.05). In the CsA group and QG group, the expression levels of BAX, BAD, caspase-9, PS, PAC-1, and P-selectin in the washed platelets were significantly reduced (P<0.05), while the levels of PI3K, p-PI3K, AKT, p-AKT and PI3K mRNA, AKT mRNA were significantly increased, compared to the model group (P<0.05). CONCLUSION: QG can reduce platelet apoptosis in mice with immune-mediated bone marrow failure, and activation of some platelets is involved, which may be related to the regulation of PI3K/AKT pathway.

Effectiveness and feasibility of continuous positive airway pressure in patients with stroke and sleep apnea: a meta-analysis of randomized trials.

STUDY OBJECTIVES: This meta-analysis aimed to investigate the feasibility and effectiveness of continuous positive airway pressure (CPAP) treatment in stroke patients with sleep apnea. METHODS: PubMed, EMBASE, and the Cochrane Library were searched from inception until July 28, 2022, for randomized controlled trials comparing the use of CPAP and usual treatment in patients with stroke or transient ischemic attack and sleep apnea. The primary outcome measures were the feasibility of CPAP therapy, neurological function, and functional status. RESULTS: After screening 5,747 studies, 14 studies with 1,065 patients were included in this meta-analysis. Overall, 8 of the 14 studies recorded CPAP use, and the mean CPAP use was 4.47 hours per night (95% confidence interval [CI]: 3.85-5.09). The risk ratio of discontinuing CPAP was 1.50 (95% CI: 0.76-2.94; P = .24). Analysis of the neurofunctional scales showed that CPAP treatment improved neurological function (standardized mean difference: 0.28; 95% CI: 0.02-0.53), but there was substantial heterogeneity (I2 = 57%, P = .03) across the studies. CPAP treatment had no significant effect on functional status vs the control (standardized mean difference: 0.25; 95% CI: -0.01 to 0.51), but the studies also had substantial heterogeneity (I2 = 55%, P = .06). CONCLUSIONS: CPAP treatment is feasible in patients with stroke and sleep apnea and may improve neurological outcomes in these patients. However, this finding should be interpreted with caution because of the substantial heterogeneity of current trials. CITATION: Fu S, Peng X, Li Y, Yang L, Yu H. Effectiveness and feasibility of continuous positive airway pressure in patients with stroke and sleep apnea: a meta-analysis of randomized trials. J Clin Sleep Med. 2023;19(9):1685-1696.

Development and validation of a combined hypoxia and ferroptosis prognostic signature for breast cancer.

Background: Hypoxia is involved in tumor biological processes and disease progression. Ferroptosis, as a newly discovered programmed cell death process, is closely related to breast cancer (BC) occurrence and development. However, reliable prognostic signatures based on a combination of hypoxia and ferroptosis in BC have not been developed. Method: We set The Cancer Genome Atlas (TCGA) breast cancer cohort as training set and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) BC cohort as the validation set. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression approaches were used to construct ferroptosis-related genes (FRGs) and hypoxia-related genes (HRGs) prognostic signature (HFRS). The CIBERSORT algorithm and ESTIMATE score were used to explore the relationship between HFRS and tumor immune microenvironment. Immunohistochemical staining was used to detect protein expression in tissue samples. A nomogram was developed to advance the clinical application of HFRS signature. Results: Ten ferroptosis-related genes and hypoxia-related genes were screened to construct the HFRS prognostic signature in TCGA BC cohort, and the predictive capacity was verified in METABRIC BC cohort. BC patients with high-HFRS had shorter survival time, higher tumor stage, and a higher rate of positive lymph node. Moreover, high HFRS was associated with high hypoxia, ferroptosis, and immunosuppression status. A nomogram that was constructed with age, stage, and HFRS signature showed a strong prognostic capability to predict overall survival (OS) for BC patients. Conclusion: We developed a novel prognostic model with hypoxia and ferroptosis-related genes to predict OS, and characterize the immune microenvironment of BC patients, which might provide new cures for clinical decision-making and individual treatment of BC patients.

Discoloration Mechanisms of Natural Rubber and Its Control.

Color is an important indicator for evaluating the quality of natural rubber (NR). Light-colored standard rubbers are widely used in high-grade products and have high economic value. This paper first introduces the history and test standards of the standard light-colored rubber. The origin of color deepening in NR processing, color substances, and its biosynthetic pathway are reviewed. Then, the discoloration mechanism of NR is studied from the perspectives of enzymatic browning (caused by polyphenol oxidase and polyphenols) and non-enzymatic browning (including Maillard reaction and lipid oxidation). Finally, the strategies to control the discoloration of NR will be described.

Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma.

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV- HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

gom1 Mutant Mice as a Model of Otitis Media.

Otitis media (OM) disease is a common cause of hearing loss that is primarily the result of middle ear infection. At present, our understanding of the mechanisms leading to OM is limited due to the lack of animal models of OM with effusion (OME). Here, we report that the mice with genetic otitis media one (gom1) mutants are prone to OM. gom1 Mice were produced by the N-ethyl-N-nitrosourea (ENU) mutagenesis program as an animal model to study OM. These mice demonstrate many common features of OM, such as middle ear effusion and hearing impairment. We revealed that gom1 mice display various signs of middle ear and inner ear dysfunctions, including elevated thresholds of auditory-evoked brainstem response (ABR) and lack of cochlear microphonic responses. Decreased compliance in tympanometry measurements indicates tympanic membrane and ossicular chain malfunction. We confirmed through histological examinations of middle ear structures that 34/34 (100 %) of the mutant mice suffered from severe OME. While individual ears had different levels of effusion and inflammatory cells in the middle ear cavity, all had thickened middle ear mucosa and submucosa compared to control mice (B6). Moreover, the mutant mice displayed cochlear hair cell loss. These observations also suggested the craniofacial abnormalities in the gom1 mouse model. Together, these results indicate that gom1 mice could be valuable for investigating the genetic contribution to the development of middle ear disease.

FeNiP nanoparticle/N,P dual-doped carbon composite as a trifunctional catalyst towards high-performance zinc-air batteries and overall water electrolysis.

A composite catalyst with a novel construction of bimetallic phosphide FeNiP nanoparticles embedded in an N,P double-doped carbon matrix was prepared. It was demonstrated to be a trifunctional catalyst that can efficiently catalyze the oxygen reduction reaction (ORR), oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). It was found that the introduction of oleylamine during the preparation can adjust the catalytic sites and finally lead to ideal catalytic performances. The obtained catalyst exhibited efficient ORR catalytic performance that surpassed the commercial Pt/C catalyst, with the OER performance comparable to that of RuO2 as well as excellent HER performance. The ORR half-wave potential is 0.879 V (vs. RHE) in 0.1 M KOH solution, while the OER overpotential at a current density of 10 mA cm-2 is only 280 mV in 1 M KOH solution. The potential gap between the ORR and OER was only 0.700 V in 0.1 M KOH solution. This trifunctional catalyst was further evaluated in energy devices including zinc-air batteries and water electrolysis. The liquid zinc-air battery assembly achieved a power density of 169 mW cm-2 and stably undergoes charge-discharge cycles for 210 hours. The solid-state zinc-air battery achieved a power density of 70 mW cm-2 and stably undergoes charge-discharge cycles for 40 hours. These performances surpassed the batteries assembled with a Pt/C-RuO2 mixed catalyst. This work established a foundation of composite catalysts coupled with bimetallic phosphide and hybrid carbon substrates, which will promote the development of high-performance multifunctional catalysts and their application in energy devices.

Anticoagulant management by low-dose of low molecular weight heparin in patients with nonvalvular atrial fibrillation following hemorrhagic transformation and complicated with venous thrombosis: Five case reports and literature review.

ABSTRACT: For patients with nonvalvular atrial fibrillation (NVAF) following hemorrhagic infarction (HI)/hemorrhage transformation (HT) and complicated with venous thrombosis, the management of anticoagulation is controversial. Our study intends to explore the safety and effectiveness of using low-dose of low molecular weight heparin (LMWH) to treat NVAF patients with HI (or HT) and complicated with venous thrombosis.Between January 2018 and January 2019, NVAF related acute ischemic stroke patients with HT/HI, hospitalized in the department of neurology or rehabilitation in our hospital, are enrolled retrospectively. Among them, those who were found to have venous thrombosis and undergo anticoagulation (LMWH) during the treatment were extracted. We investigate the efficacy and safety in those patients who have been treated with anticoagulant of LMWH.Five cases accepted LMWH within 3 weeks attributed to the appearance of venous thrombosis, and all of them did not display new symptomatic bleeding or recurrent stroke. However, based on the results of a head computed tomography scan, there were 2 cases of slightly increased intracranial hemorrhage, and then we reduced the dose of anticoagulant. In addition, color ultrasound showed that venous thrombosis disappeared or became stable.Patients with NVAF following HI/HT have a higher risk of thromboembolism. Early acceptance of low-dose LMWH as an anticoagulant is relatively safe and may gain benefit. However, in the process of anticoagulant therapy, we should follow-up head computed tomography/magnetic resonance imaging frequently, as well as D-dimer values, limb vascular ultrasound. Besides, the changes of symptoms and signs should be focused to judge the symptomatic bleeding or recurrent stroke. Furthermore, it is better to adjust anticoagulant drug dosage according to specific conditions.

Characteristics and outcomes of hemodialysis patients with COVID-19: a retrospective single center study.

BACKGROUND: The coronavirus 19 (COVID-19) pandemic has heightened the threat to the health and lives of patients with comorbid diseases. Infection by COVID-19 is especially detrimental to patients on hemodialysis. In this study, we evaluated the clinical characteristics, laboratory findings, treatments and prognoses of hemodialysis patients with COVID-19. METHODS: A total of 16 hemodialysis patients with COVID-19 were recruited from Wuhan Fourth Hospital from 5 February to 20 March 2020 for a retrospective, single-center study. A total of 62 non-dialysis patients with COVID-19 were the control group. We collected data on the clinical characteristics, laboratory findings, treatments, and clinical outcomes of patients affected by the virus. RESULTS: Hemodialysis patients with COVID-19 had a lower incidence of fever (P = 0.001) and relatively higher incidence of pre-admission comorbidities and shortness of breath than non-dialysis patients with COVID-19 (75% vs. 61%, P = 0.467 50% vs. 33.87%, P = 0.248 ). Hemodialysis patients had lower levels of hemoglobin (P < 0.001), white blood cell counts (P = 0.015), neutrophils (P = 0.016), AST (P = 0.037), ALT (P < 0.001) and procalcitonin (P < 0.001), and higher levels of D-dimer (P < 0.001) and thrombin time (P < 0.001). Hemodialysis patients had a higher incidence of pulmonary effusion, cord-like high-density shadows, pleural thickening, and atelectasis (P < 0.05). Hemodialysis patients also had relatively higher rates of mortality and prolonged hospital stays compared with the control group. CONCLUSIONS: Hemodialysis patients typically present with multiple comorbidities and are considered to be a high-risk group for COVID-19 infections. Hemodialysis patients with COVID-19 may have prolonged hospital stays and unfavorable prognoses and should be closely monitored.

Clinical Characteristics and Outcomes of 74 Patients With Severe or Critical COVID-19.

BACKGROUND: The outbreak of the coronavirus disease (COVID-19) has led to a major concern and caused a pandemic globally. The goal of this study was to clarify the clinical characteristics of recovery and death in patients with severe or critical COVID-19. MATERIALS AND METHODS: In this retrospective single-center study, clinical data were collected from 74 severe or critical COVID-19 patients in Wuhan Fourth Hospital between Jan. 25th and Feb. 26th, 2020. All patients were divided into a recovery group or a death group according to clinical outcomes, and the differences between the groups were compared. RESULTS: Of the 74 patients enrolled in the study, 48 (64.9%) were severe cases and 26 (35.1%) were critical cases. Sixty (81.1%) patients were recovered and 14 (18.9%) died. Compared with recovery patients, patients in the death group were older, and had higher incidences of hypertension, coronary disease and dyspnea at admission. Laboratory tests for lactate dehydrogenase, creatine kinase, myoglobin, brain natriuretic peptide and D-dimer indicated higher levels in the death group. The PaO2:FiO2 ratio and minimum SpO2 were lower in the death group, and a higher proportion of these patients received noninvasive mechanical ventilation, invasive mechanical ventilation and extracorporeal membrane oxygenation treatment. CONCLUSIONS: Elderly patients with comorbidities are at higher risk of severe COVID-19 or death. Patients with a low blood gas index and poor coagulation function at admission had a high mortality rate. For such patients, comprehensive treatment should be performed as soon as possible to improve the prognosis and reduce mortality.

A descriptive study of random forest algorithm for predicting COVID-19 patients outcome.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) that occurred in Wuhan, China, has become a global public health threat. It is necessary to identify indicators that can be used as optimal predictors for clinical outcomes of COVID-19 patients. METHODS: The clinical information from 126 patients diagnosed with COVID-19 were collected from Wuhan Fourth Hospital. Specific clinical characteristics, laboratory findings, treatments and clinical outcomes were analyzed from patients hospitalized for treatment from 1 February to 15 March 2020, and subsequently died or were discharged. A random forest (RF) algorithm was used to predict the prognoses of COVID-19 patients and identify the optimal diagnostic predictors for patients' clinical prognoses. RESULTS: Seven of the 126 patients were excluded for losing endpoints, 103 of the remaining 119 patients were discharged (alive) and 16 died in the hospital. A synthetic minority over-sampling technique (SMOTE) was used to correct the imbalanced distribution of clinical patients. Recursive feature elimination (RFE) was used to select the optimal subset for analysis. Eleven clinical parameters, Myo, CD8, age, LDH, LMR, CD45, Th/Ts, dyspnea, NLR, D-Dimer and CK were chosen with AUC approximately 0.9905. The RF algorithm was built to predict the prognoses of COVID-19 patients based on the best subset, and the area under the ROC curve (AUC) of the test data was 100%. Moreover, two optimal clinical risk predictors, lactate dehydrogenase (LDH) and Myoglobin (Myo), were selected based on the Gini index. The univariable logistic analysis revealed a substantial increase in the risk for in-hospital mortality when Myo was higher than 80 ng/ml (OR = 7.54, 95% CI [3.42-16.63]) and LDH was higher than 500 U/L (OR = 4.90, 95% CI [2.13-11.25]). CONCLUSION: We applied an RF algorithm to predict the mortality of COVID-19 patients with high accuracy and identified LDH higher than 500 U/L and Myo higher than 80 ng/ml to be potential risk factors for the prognoses of COVID-19 patients in the early stage of the disease.

Role for Toll-like receptor 2 in the immune response to Streptococcus pneumoniae infection in mouse otitis media.

Streptococcus pneumoniae is the most common pathogen associated with otitis media. To examine the role of Toll-like receptor 2 (TLR2) in host defense against Streptococcus pneumoniae infection in the middle ear, wild-type (WT; C57BL/6) and TLR2-deficient (TLR2(-/-)) mice were inoculated with Streptococcus pneumoniae (1 x 10(6) CFU) through the tympanic membrane. Nineteen of 37 TLR2(-/-) mice showed bacteremia and died within 3 days after the challenge, compared to only 4 of 32 WT mice that died. Of those that survived, more severe hearing loss in the TLR2(-/-) mice than in the WT mice was indicated by an elevation in auditory-evoked brain stem response thresholds at 3 or 7 days postinoculation. The histological pathology was characterized by effusion and tissue damage in the middle ear, and in the TLR2(-/-) mice, the outcome of infection became more severe at 7 days. At both 3 and 7 days postchallenge, the TLR2(-/-) mice had higher blood bacterial titers than the WT mice (P < 0.05), and typical bacteria were identified in the effusion from both ears of both mouse groups by acridine orange staining. Moreover, by 3 days postchallenge, the mRNA accumulation levels of NF-kappaB, tumor necrosis factor alpha, interleukin 1beta, MIP1alpha, Muc5ac, and Muc5b were significantly lower in the ears of TLR2(-/-) mice than in WT mice. In summary, TLR2(-/-) mice may produce relatively low levels of proinflammatory cytokines following pneumococcal challenge, thus hindering the clearance of bacteria from the middle ear and leading to sepsis and a high mortality rate. This study provides evidence that TLR2 is important in the molecular pathogenesis and host response to otitis media.

Otitis media in a mouse model for Down syndrome.

The Ts65Dn mouse shares many phenotypic characteristics of human Down syndrome. Here, we report that otitis media, characterized by effusion in the middle ear and hearing loss, was prevalent in Ts65Dn mice. Of the 53 Ts65Dn mice tested, 81.1% had high auditory-evoked brainstem response (ABR) thresholds for at least one of the stimulus frequencies (click, 8 kHz, 16 kHz and 32 kHz), in at least one ear. The ABR thresholds were variable and showed no tendency toward increase with age, from 2 to 7 months of age. Observation of pathology in mice, aged 3-4 months, revealed middle ear effusion in 11 of 15 Ts65Dn mice examined, but only in two of 11 wild-type mice. The effusion in each mouse varied substantially in volume and inflammatory cell content. The middle ear mucosae were generally thickened and goblet cells were distributed with higher density in the epithelium of the middle ear cavity of Ts65Dn mice as compared with those of wild-type controls. Bacteria of pathogenic importance to humans also were identified in the Ts65Dn mice. This is the first report of otitis media in the Ts65Dn mouse as a model characteristic of human Down syndrome.

A locus on distal chromosome 11 (ahl8) and its interaction with Cdh23 ahl underlie the early onset, age-related hearing loss of DBA/2J mice.

The DBA/2J inbred strain of mice is used extensively in hearing research, yet little is known about the genetic basis for its early onset, progressive hearing loss. To map underlying genetic factors we analyzed recombinant inbred strains and linkage backcrosses. Analysis of 213 mice from 31 BXD recombinant inbred strains detected linkage of auditory brain-stem response thresholds with a locus on distal chromosome 11, which we designate ahl8. Analysis of 225 N2 mice from a backcross of (C57BL/6JxDBA/2J) F1 hybrids to DBA/2J mice confirmed this linkage (LOD>50) and refined the ahl8 candidate gene interval. Analysis of 214 mice from a backcross of (B6.CAST-Cdh23 Ahl+ xDBA/2J) F1 hybrids to DBA/2J mice demonstrated a genetic interaction of Cdh23 with ahl8. We conclude that ahl8 is a major contributor to the hearing loss of DBA/2J mice and that its effects are dependent on the predisposing Cdh23 ahl genotype of this strain.