Dictys: dynamic gene regulatory network dissects developmental continuum with single-cell multiomics.
Gene regulatory networks (GRNs) are key determinants of cell function and identity and are dynamically rewired during development and disease. Despite decades of advancement, challenges remain in GRN inference, including dynamic rewiring, causal inference, feedback loop modeling and context specificity. To address these challenges, we develop Dictys, a dynamic GRN inference and analysis method that leverages multiomic single-cell assays of chromatin accessibility and gene expression, context-specific transcription factor footprinting, stochastic process network and efficient probabilistic modeling of single-cell RNA-sequencing read counts. Dictys improves GRN reconstruction accuracy and reproducibility and enables the inference and comparative analysis of context-specific and dynamic GRNs across developmental contexts. Dictys' network analyses recover unique insights in human blood and mouse skin development with cell-type-specific and dynamic GRNs. Its dynamic network visualizations enable time-resolved discovery and investigation of developmental driver transcription factors and their regulated targets. Dictys is available as a free, open-source and user-friendly Python package.


Synergistic antibacterial mechanism of the Lactobacillus crispatus surface layer protein and nisin on Staphylococcus saprophyticus.
SlpB, a surface layer protein isolated from Lactobacillus crispatus, has the potential to enhance the antimicrobial activity of nisin. Previous research indicated that, when combined with nisin, SlpB acted synergistically to inhibit Staphylococcus saprophyticus growth, thus extending the shelf life of chicken meat. In order to understand how SlpB enhances the antibacterial activity of nisin, electron microscopy, confocal laser scanning microscopy, flow cytometry and transmembrane electrical potential analysis were used to study cell wall organization and cell membrane integrity. No remarkable bacteriolytic effects were observed, indicating that cell death could not be attributed to cell lysis, although SlpB caused dramatic modifications of cell wall, thereby altering cell shape. The combination of SlpB and nisin also induced the release of ATP or UV-absorbing materials, as well as sudden dissipation of the transmembrane electrical potential by compromising membrane integrity. Considering that SlpB led to structural disorganization of the cell wall, and nisin access is enhanced to form a stable pore, cell death is a predictable outcome. SlpB significantly enhanced the effect of nisin at half of the minimum inhibitory concentration, which resulted in cell death by destroying the cell wall and cell membrane, therefore providing a new, feasible approach in food preservation.


Induction of congenital malformation in mice by parental irradiation: transmission to later generations.
In order to investigate the genetic basis of the increased incidence of congenital malformations in the offspring of irradiated mice, the frequency of malformations among the offspring of individual F1 sons of irradiated females was studied in detail. Among 90 fully tested F1 sons of females which had been mated 15-21 days after receiving 360 cGy X-rays 4 were definite or probable carriers of dominant genes giving a low penetrance of malformations. This confirms that the malformations seen in the first generation are of genetic origin and can be transmitted to later generations. However, the incidence and penetrance of the mutant genes detected were too low to account for all the anomalies found in the first generation. It was concluded that the genetic basis of the original anomalies was heterogeneous, with some due to genetic changes of high penetrance and rapidly eliminated, and others due to genes of low penetrance like those found in this work. Other malformations, in both the irradiated and control series, were probably of non-genetic origin.


ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease.
Aberrant chromatin remodeling is involved in the pathogenesis of Huntington's disease (HD) but the mechanism is not known. Herein, we report that mutant huntingtin (mtHtt) induces the transcription of alpha thalassemia/mental retardation X linked (ATRX), an ATPase/helicase and SWI/SNF-like chromatin remodeling protein via Cdx-2 activation. ATRX expression was elevated in both a cell line model and transgenic model of HD, and Cdx-2 occupancy of the ATRX promoter was increased in HD. Induction of ATRX expanded the size of promyelocytic leukemia nuclear body (PML-NB) and increased trimethylation of H3K9 (H3K9me3) and condensation of pericentromeric heterochromatin, while knockdown of ATRX decreased PML-NB and H3K9me3 levels. Knockdown of ATRX/dXNP improved the hatch rate of fly embryos expressing mtHtt (Q127). ATRX/dXNP overexpression exacerbated eye degeneration of eye-specific mtHtt (Q127) expressing flies. Our findings suggest that transcriptional alteration of ATRX by mtHtt is involved in pericentromeric heterochromatin condensation and contributes to the pathogenesis of HD.


Assessing intermediate left main coronary lesions using intravascular ultrasound.
Angiographic assessment of a left main coronary artery stenosis (LMCS) is often difficult and unreliable. We aimed to evaluate the severity of ambiguous LMCSs by intravascular ultrasound (IVUS) and to clarify how frequently significant stenosis occurs in the "real world". We retrospectively found 115 consecutive patients in our clinical IVUS database with a de novo, angiographically ambiguous, intermediate LMCS who underwent IVUS evaluation. Quantitative coronary angiography (QCA) and IVUS analyses were performed. We define a significant LMCS as a diameter stenosis >50% by QCA and a minimal lumen area <6.0 mm2 by IVUS. Ostial, mid, and distal LMCSs were seen in 44 (38.3%), 6 (5.2%), and 65 (56.5%) lesions. Overall, IVUS minimal lumen area and plaque burden measured 6.8 +/- 2.6 mm2 and 63% +/- 14%. A significant LMCS was seen in 51 (44.3%) lesions by IVUS but in only 15 (13.0%) lesions by QCA. In particular, only 36.4% of ostial lesions had a significant IVUS stenosis, and minimal lumen diameter by QCA was less well correlated with IVUS in ostial lesions than in other lesion locations. This real-world IVUS analysis showed that less than half of intermediate LMCSs had significant stenoses by IVUS assessment, especially for lesions located at the left main ostium. Such patients deserve IVUS assessment or physiologic assessment before blindly proceeding to revascularization.


Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function.
To examine the correlation of plasma fibroblast growth factor (FGF)-23 and serum fetuin A levels with the coronary artery calcification score (CACS) in patients with normal kidney function. Vascular calcification is an active process that may be aggravated by hyperphosphataemia and hypercalcaemia. FGF-23 and human fetuin-A have been associated with calcifying arteriosclerosis in renal failure. Plasma FGF-23 was identified as an independent factor negatively associated with peripheral vascular calcification. Fetuin-A acts as a systemic inhibitor of ectopic calcification in dialysis patients and can be correlated to the survival of these patients. Very few data exists on the role of FGF-23 and fetuin-A in coronary calcification of patients without impaired kidney function. Sixty-four patients, 21 females and 43 males, were subjected to 64-slice coronary computed tomography (CT) to evaluate coronary artery calcification (CAC). Plasma intact FGF-23 was determined by ELISA. Serum fetuin-A concentration were evaluated nephelometrically. Mean plasma FGF-23 level was 20.4 +/- 9.1 pg/ml and serum fetuin-A was 0.46 +/- 0.09 g/l. There was no correlation between FGF-23 (P = 0.777) and fetuin-A (P = 0.767) levels and the CACS. No correlation was found between the presence of noncalcified plaques and coronary artery stenosis (CAS) >or= 50%, and FGF-23 (P = 0.313 and P = 0.775) and fetuin-A levels (P = 0.601 and P = 0.659). Plasma intact FGF-23 and serum fetuin-A concentration do not correlate with the CACS, the grade of stenosis or presence of noncalcified plaques of the coronary arteries in patients with normal kidney function.


A contribution of sparse matrices tools to matrix population model analysis.
When one wants to study the dynamics of structured populations, matrix type models are widely used. The complexity of such models increases with the number of classes of individuals considered, and a mathematical analysis becomes difficult to perform when a further heterogeneous spatial structure is introduced. The use of efficient computational tools is also required for numerical simulations. In this note we deal with the contribution of sparse matrices tools which allow to numerically simulate and to numerically perform stability analysis of large sized structured population models including density dependence and spatial heterogeneities. Our main motivation through this work is to show that such numerical tools can be useful when mathematical methods become difficult to employ.


Eukaryotic origin of a metabolic pathway in virus by horizontal gene transfer.
Horizontal gene transfer, the movement of genetic materials across the normal mating barriers between organisms occurs frequently and contributes significantly to the evolution of both eukaryotic and prokaryotic genomes. However, few concurrent transfers of functionally related genes implemented in a pathway from eukaryotes to prokaryotes are observed. Here, we did phylogenetic analyses to support that the genes, i.e. dihydrofolate reductase, glycine hydroxymethyltransferase, and thymidylate synthase involved in thymidylate metabolism, in Hz-1 virus were obtained from insect genome recently by independent horizontal gene transfers. In addition, five other related genes in nucleotide metabolism show evidences of horizontal gene transfers. These genes demonstrate similar expression pattern, and they may have formatted a functionally related pathway (e.g. thymidylate synthesis, and DNA replication) in Hz-1 virus. In conclusion, we provide an example of horizontal gene transfer of functionally related genes in a pathway to prokaryote from eukaryote.


Association between hospital competition and quality of prostate cancer care.
Hospitals account for approximately 6% of United States' gross domestic product. We examined the association between hospital competition and outcomes in elderly with localized prostate cancer (PCa). We also assessed if race moderated this association. Retrospective study using Surveillance, Epidemiology, and End Results (SEER) - Medicare database. Cohort included fee-for-service, African American and white men aged ≥ 66, diagnosed with localized PCa between 1998 and 2011 and their claims between 1997 and 2016. We used Hirschman-Herfindahl index (HHI) to measure of hospital competition. Outcomes were emergency room (ER) visits, hospitalizations, Medicare expenditure and mortality assessed in acute survivorship phase (two years post-PCa diagnosis), and long-term mortality. We used Generalized Linear Models for analyzing expenditure, Poisson models for ER visits and hospitalizations, and Cox models for mortality. We used propensity score to minimize bias. Among 253,176 patients, percent change in incident rate of ER visit was 17% higher for one unit increase in HHI (IRR: 1.17, 95% CI: 1.15-1.19). Incident rate of ER was 24% higher for whites and 48% higher for African Americans. For one unit increase in HHI, hazard of short-term all-cause mortality was 7% higher for whites and 11% lower for African Americans. The hazard of long-term all-cause mortality was 10% higher for whites and 13% higher for African Americans. Lower hospital competition was associated with impaired outcomes of localized PCa care. Magnitude of impairment was higher for African Americans, compared to whites. Future research will explore process through which competition affects outcomes and racial disparity.


Studies on the cytotoxic mechanisms of ginkgetin in a human ovarian adenocarcinoma cell line.
The cytotoxic effects of ginkgetin, a natural biflavone isolated from Selaginella moellendorffii Hieron, were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in three different human cell lines: ovarian adenocarcinoma (OVCAR-3), cervical carcinoma (HeLa) and foreskin fibroblast (FS-5). The concentrations of ginkgetin required to induce 50% death (EC50) in OVCAR-3, HeLa, and FS-5 were 3.0, 5.2, and 8.3 microg/ml, respectively. Morphological changes in cells and their nuclei, DNA fragmentation with a characteristic pattern of inter-nucleosomal ladder, and double-stranded DNA breaks were detected following treatment with 3 microg/ml of this biflavone for 24 h. Incubation with 5 microg/ml ginkgetin led to increased intracellular levels of hydrogen peroxide as early as 30 min. The cytotoxicity of ginkgetin was partially inhibited by pretreating cells with vitamin C, vitamin E or catalase. Catalase not only afforded the best protective effect among three antioxidants, but also reduced both the DNA fragmentation and double-stranded DNA breakage induced by ginkgetin. Moreover, the involvement of caspase(s) in ginkgetin-induced apoptosis was demonstrated by the activation of caspase 3 after drug treatment and the suppression of cell death by a broad-spectrum caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk). However, the protective effects of z-VAD-fmk and catalase were not additive. Taken together, our results indicated that the apoptosis induced by ginkgetin (especially at 5 microg/ml) is mediated mainly through the activation of caspase(s) by the hydrogen peroxide generated possibly through autooxidation of this biflavone.


Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.
The rate of onset of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH) has been reported recently to be comparable to that of patients with chronic hepatitis C. However, the precise mechanism contributing to carcinogenesis in the former remains unclear. Although increased oxidative stress is presumed to play a role in carcinogenesis in patients with NASH, this relationship remains to be directly proven. In this study, we investigated the involvement of oxidative DNA damage in hepatocarcinogenesis in patients with NASH. Patients with nonalcoholic fatty liver disease who were treated at our university hospital were eligible for enrolment in the study(n = 49). The study cohort included 30 patients with NASH without HCC (NASH without HCC), six HCC patients with NASH (NASH-HCC), and 13 patients with simple steatosis. Quantitative immunohistochemistry with a KS-400 image analyzing system was used for 8-hydroxy-2'-deoxyguanosine (8-OHdG) detection. The 8-OHdG content in the liver tissue of NASH-HCC patients was significantly different from that in the other patients. The median immunostaining intensity was 8.605 in the NASH-HCC cases, which was significantly higher than that in the cases of NASH without HCC (4.845; P = 0.003). Multivariate analysis using hepatic 8-OHdG content as a factor in addition to age and fasting blood sugar revealed a significant difference in clinicopathological factors between NASH-HCC and NASH without HCC cases. Old age (P = 0.015) and high relative immunostaining intensity for intrahepatic 8-OHdG (P = 0.037) were identified as independent factors. 8-OHdG content in liver tissue may serve a marker of oxidative stress and could be a particularly useful predictor of hepatocarcinogenesis.


Cardial myxomas: a clinical diagnostic challenge.
Our experience consists of seven intracardiac myxomas in five patients seen over an 8 year period. It includes one patient who had three primary tumors, each anatomically distinct, occurring at 4 year intervals. The initial clinical presentation included embolic phenomena, unexplained neurologic symptoms, hemodynamic obstruction, and vague systemic illness. Preoperative diagnosis was confirmed by echocardiography or angiocardiography in all cases. At operation, only two of seven tumors were found to arise from the vicinity of the fossa ovalis; the other five arose from the atrial wall or ventricular septum. Wide resection of the tumors constituted the key to successful treatment. All patients have done well for periods of follow-up ranging from 6 months to 8 years. Awareness of cardiac myxoma is the key to diagnosis; treatment should be uniformly successful in all instances once the proper diagnosis has been made. Although recurrences are rare, all patients must be followed up closely for the development of new tumors, and a thorough investigation of all chambers must be conducted in patients with suspected recurrence.


Neural correlates of reflection on actual versus ideal self-discrepancy.
Subjective feelings of actual/ideal self-discrepancy vary across individuals and influence one's own affective states. However, the neural correlates of actual/ideal self-discrepancy and their genetic individual differences remain unknown. We investigated neural correlates of actual/ideal self-discrepancy and their associations with the serotonin transporter promoter polymorphism (5-HTTLPR) that moderates human affective states during self-reflection. We scanned short/short and long/long allele carriers of 5-HTTLPR, using functional MRI, during reflection on the distance between actual and ideal self in personality traits. We found that larger actual/ideal self-discrepancy was associated with activations in the ventral/dorsal striatum and dorsal medial and lateral prefrontal cortices. Moreover, these brain activities were stronger in short/short than long/long allele carriers and predicted self-report of life satisfaction in short/short carriers but trait depression in long/long carriers. Our findings revealed neural substrates of actual/ideal self-discrepancy and their associations with affective states that are sensitive to individuals' genetic makeup.


Sex Differences in Diabetes Mellitus Mortality Trends in Brazil, 1980-2012.
To investigate the hypothesis that the change from the female predominance of diabetes mellitus to a standard of equality or even male preponderance can already be observed in Brazilian mortality statistics. Data on deaths for which diabetes mellitus was listed as the underlying cause were obtained from the Brazilian Mortality Information System for the years 1980 to 2012. The mortality data were also analyzed according to the multiple causes of death approach from 2001 to 2012. The population data came from the Brazilian Institute of Geography and Statistics. The mortality rates were standardized to the world population. We used a log-linear joinpoint regression to evaluate trends in age-standardized mortality rates (ASMR). From 1980 to 2012, we found a marked increment in the diabetes ASMR among Brazilian men and a less sharp increase in the rate among women, with the latter period (2003-2012) showing a slight decrease among women, though it was not statistically significant. The results of this study suggest that diabetes mellitus in Brazil has changed from a pattern of higher mortality among women compared to men to equality or even male predominance.


Hyperbaric oxygen preconditioning ameliorates blood-brain barrier damage induced by hypoxia through modulation of tight junction proteins in an in vitro model.
To explore the effects of hyperbaric oxygen preconditioning (HBOP) on the permeability of blood-brain barrier (BBB) and expression of tight junction proteins under hypoxic conditions in vitro. A BBB in vitro model was constructed using the hCMEC/D3 cell line and used when its trans-endothelial electrical resistance (TEER) reached 80-120 Ω · cm2 (tested by Millicell-Electrical Resistance System). The cells were randomly divided into the control group cultured under normal conditions, the group cultured under hypoxic conditions (2%O2) for 24 h (hypoxia group), and the group first subjected to HBOP for 2 h and then to hypoxia (HBOP group). Occludin and ZO-1 expression were analyzed by immunofluorescence assay. Normal hCMEC/D3 was spindle-shaped and tightly integrated. TEER was significantly reduced in the hypoxia (P=0.001) and HBOP group (P=0.014) compared to control group, with a greater decrease in the hypoxia group. Occludin membranous expression was significantly decreased in the hypoxia group (P=0.001) compared to the control group, but there was no change in the HBOP group. ZO-1 membranous expression was significantly decreased (P=0.002) and cytoplasmic expression was significantly increased (P=0.001) in the hypoxia group compared to the control group, although overall expression levels did not change. In the HBOP group, there was no significant change in ZO-1 expression compared to the control group. Hyperbaric oxygen preconditioning protected the integrity of BBB in an in vitro model through modulation of occludin and ZO-1 expression under hypoxic conditions.


Antireflection coating with UV-protective properties for polycarbonate.
Polycarbonate is the chosen material for covers of automotive displays because it combines high transparency with high breaking strength. The requirements for coatings include an improvement of the scratch resistance and antireflection properties as well as high stability for challenging environmental conditions. A coating that involves all required properties has been developed and deposited onto polycarbonate by plasma-ion assisted deposition.


Reconstruction of a maxillary defect using the remnant bone of mandibular angle ostectomy.
The buttress is the cornerstone of the midface both functionally and aesthetically. Therefore, fracture of the buttress requires surgery. A patient wanted cosmetic surgery simultaneously with a reduction of facial bone fracture. To achieve this, we reconstructed the defect of the maxillary buttress using the remnant bone of the mandible angle ostectomy. A 27-year-old man presented with a left maxilla fracture and defect at the maxillary buttress. Since the patient was considering cosmetic surgery to alter his square face, we planned a mandibular angle ostectomy and used the remnant bone as an onlay bone graft for maxillary reconstruction. There was no complication and the patient was satisfied with both the functional and aesthetical look of the reconstructive surgery. We reconstructed the defect of the maxillary buttress successfully using the remnant bone of the mandible angle ostectomy. Although this technique cannot be applied to every patient, reconstruction of facial bone defects with the remnant bone of the mandibular angle ostectomy may be a potential option in some cases.


Molecular genomic landscape of pediatric solid tumors in Chinese patients: implications for clinical significance.
Pediatric solid tumors are significantly different from adult tumors. Studies have revealed genomic aberrations in pediatric solid tumors, but these analyses were based on Western populations. Currently, it is not known to what extent the existing genomic findings represent differences in ethnic backgrounds. DESIGN: We retrospectively analyzed the basic clinical characteristics of the patients, including age, cancer type, and sex distribution, and further analyzed the somatic and germline mutations of cancer-related genes in a Chinese pediatric cohort. In addition, we investigated the clinical significance of genomic mutations on therapeutic, prognostic, diagnostic, and preventive actions. Our study enrolled 318 pediatric patients, including 234 patients with CNS tumors and 84 patients with non-CNS tumors. Somatic mutation analysis showed that there were significant differences in mutation types between CNS tumors and non-CNS tumors. P/LP germline variants were identified in 8.49% of patients. In total, 42.8% patients prompted diagnostic, 37.7% patients prompted prognostic, 58.2% patients prompted therapeutic, and 8.5% patients prompted tumor-predisposing and preventive, and we found that genomic findings might improve clinical management. Our study is the first large-scale study to analyze the landscape of genetic mutations in pediatric patients with solid tumors in China. Genomic findings in CNS and non-CNS solid pediatric tumors provide evidence for the clinical classification and individualized treatment of pediatric tumors, and they will facilitate improvement of clinical management. Data presented in this study should serve as a reference to guide the future design of clinical trials.


Tumor phenotype and concordance in synchronous bilateral breast cancer in young women.
Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS). The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40 years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance. Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38 years (range 18-40 years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2 years, 14 patients are alive with no recurrent disease. Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.


Predicting the MHC-peptide affinity using some interactive-type molecular descriptors and QSAR models.
The ligand-receptor interaction between some peptidomimetic inhibitors and a class II major histocompatibility complex (MHC)-peptide presenting molecule, the HLA-DR4 receptor, can be modeled using some 3D quantitative structure-activity relationship (QSAR) methods such as the comparative molecular field analysis (CoMFA) and some molecular descriptors using the Cerius2 program. The structures of these peptidomimetic inhibitors can be generated theoretically, and the conformations used in the 3D QSAR studies can be defined by aligning them against the known structure of HLA-DR4 receptor through a least-square fitting procedure. The best CoMFA models can be constructed using the aligned structures of the best fitting result. The principal components analysis (PCA) module of the Cerius2 program can be used to trim outliers of the CoMFA columns generated. Procedures for a direct QSAR analysis using the Cerius2 descriptors and regression analysis by the genetic function module are also presented


Lateral nose and perinasal defects: options in management following Mohs micrographic surgery for cutaneous carcinoma.
Primary and recurrent cutaneous carcinomas of the nose and the adjacent perinasal tissues often invade more deeply than cutaneous carcinomas in other areas. The operative defect may be large. The physician who has to close these defects is faced with a challenging problem that requires an appreciation of facial anatomy and function. There is often more than one option in the repair of these defects. Important concepts in the management of lateral nose and perinasal surgical defects are discussed.


Effective implementation of time-frequency matched filter with adapted pre and postprocessing for data-dependent detection of newborn seizures.
Neonatal EEG seizures often manifest as nonstationary and multicomponent signals, necessitating analysis in the time-frequency (TF) domain. This paper presents a novel neonatal seizure detector based on effective implementation of the TF matched filter. In the detection process, the TF signatures of EEG seizure are extracted to construct the TF templates used by the matched filter. Matching pursuit (MP) decomposition and narrowband filtering are proposed for the reduction of artifacts prior to seizure detection. Geometrical correlation is used to consolidate the multichannel detections and to reduce the number of false detections due to remnant artifacts. A data-dependent threshold is defined for the classification of EEG. Using 30 newborn EEG records with seizures, the classification process yielded an overall detection accuracy of 92.4% with good detection rate (GDR) of 84.8% and false detection rate of 0.36FD/h. Better detection performance (accuracy >95%) was recorded for relatively long EEG records with short seizure events.


The design and implementation of a study to investigate the effectiveness of community vs hospital eye service follow-up for patients with neovascular age-related macular degeneration with quiescent disease.
IntroductionStandard treatment for neovascular age-related macular degeneration (nAMD) is intravitreal injections of anti-VEGF drugs. Following multiple injections, nAMD lesions often become quiescent but there is a high risk of reactivation, and regular review by hospital ophthalmologists is the norm. The present trial examines the feasibility of community optometrists making lesion reactivation decisions.MethodsThe Effectiveness of Community vs Hospital Eye Service (ECHoES) trial is a virtual trial; lesion reactivation decisions were made about vignettes that comprised clinical data, colour fundus photographs, and optical coherence tomograms displayed on a web-based platform. Participants were either hospital ophthalmologists or community optometrists. All participants were provided with webinar training on the disease, its management, and assessment of the retinal imaging outputs. In a balanced design, 96 participants each assessed 42 vignettes; a total of 288 vignettes were assessed seven times by each professional group.The primary outcome is a participant's judgement of lesion reactivation compared with a reference standard. Secondary outcomes are the frequency of sight threatening errors; judgements about specific lesion components; participant-rated confidence in their decisions about the primary outcome; cost effectiveness of follow-up by optometrists rather than ophthalmologists.DiscussionThis trial addresses an important question for the NHS, namely whether, with appropriate training, community optometrists can make retreatment decisions for patients with nAMD to the same standard as hospital ophthalmologists. The trial employed a novel approach as participation was entirely through a web-based application; the trial required very few resources compared with those that would have been needed for a conventional randomised controlled clinical trial.


Microsurgical access for cell injection into the mammalian cochlea.
The potential use of stem cells to repair hearing loss requires surgical access to the cochlea. Here we describe a microsurgical technique for cell injection into the mouse cochlea. Green fluorescent cells (ZsGreen-MCF10A cells) were successfully injected via a lateral wall cochleostomy into the scala media, scala tympani and scala vestibuli compartments of the cochlea. The effect of surgery on auditory function was investigated with auditory brainstem responses (ABR) to click and tone stimuli. A computerised signal-to-noise ratio detection method was developed to measure ABR thresholds in conjunction with visual inspection. Signal-to-noise ratio detection showed ABR thresholds in control mice were similar for click (33+/-7 dB) and tone stimuli (33+/-6 dB), in agreement with visual inspection (click 39+/-7 dB, tone 35+/-6 dB). The mean ABR threshold for combined click and tone stimuli was 15-45 dB greater after surgery with minimum hearing loss achieved with a small sized cochleostomy (< or =0.4mm) and by sibling matching to control mice (control 33+/-4 dB, surgery 48+/-3 dB). The microsurgical technique will provide a basis for future studies on the use of stem cells in the treatment of hearing loss.


Reduced circulating folate among older adults caused by continuous work: nested cross-sectional study conducted in a country with folic acid fortification program.
Population aging is 1 of the biggest challenges facing public health today, and cognitive dysfunction is an important concern. Cognitive impairment may be associated with high folate concentrations and low vitamin B12 concentrations; the latter is a common problem among elderly people. Therefore, we hypothesized there was a high circulating folate concentration among older people living in a country with a mandatory folic acid fortification program. We conducted a cross-sectional study to investigate nutritional status of folate and vitamin B12 among aged people. Three dietary recalls, serum folate (sfolate), erythrocyte (red blood cell) folate (RBC folate), and serum vitamin B12 and homocysteine were collected. Linear regression models were used to investigate factors associated with circulating vitamins. We interviewed 169 participants. Half reported inadequate consumption of folate. However, RBC folate deficiency was observed in 27%, 13% in the serum, and a 10% excess of sfolate. One-quarter reported inadequate consumption of B12, but only 5% had deficiency. Factors negatively associated with circulating folate were continuous work and smoking, and positively associated with polyunsaturated fatty acid. Factor negatively associated with the circulating B12 were use of a dental prosthesis and intake of saturated fatty acid. Permanent investigation of excess of sfolate and B12 deficiency, especially among older adults living in countries exposed to a mandatory folic acid fortification program, is important because of the possible relation to the cognitive function.


Diabetes prevention: perspectives and actions of one company.
Diabetes, particularly type 2 diabetes mellitus (T2DM), has reached epidemic proportions in the U.S. and globally, highlighting the need for major improvements in treatment strategies for detecting, preventing, and slowing disease progression. Despite escalating treatment costs, diabetes care remains largely substandard, with hospitalizations for late-stage complications in particular placing a major burden on the healthcare system. Although considerable advances have been made in identifying the risk factors of diabetes and developing treatments, goals targeting prevention have remained elusive. Although there is currently no consensus regarding terminology among public health practitioners, the concept of prevention in terms of diabetes care runs the gamut from interventions used to avoid disease in individuals without risk factors (primordial prevention) to prevention of the consequences of established complications (quaternary prevention). Given the worldwide prevalence of diabetes, it is crucial to improve the quality of care for those diagnosed with overt diabetes, as well as those who have been identified as at risk for developing the disease. Earlier screening enables undiagnosed, asymptomatic individuals with diabetes to be identified sooner, managed more effectively, and where necessary, treated with the appropriate pharmacotherapeutic options in a timely manner. All stakeholders (including government, industry, professional, and patient groups) must partner in concert to address these vital issues so that treatment goals ultimately may be realized.


Synthesis, spectral characterization and antimicrobial studies of novel s-triazine derivatives.
A series of fifteen novel triazinyl derivatives, with various natural nucleobases by mono, di and tri substitution in cyanuric chloride at the 2,4- and/or 6-positions was synthesized. Target molecules were synthesized by stoichiometric addition of various nucleophiles to cyanuric chloride in the presence of suitable base. The structural characterizations of all the compounds were made by spectral and analytical techniques, IR, (1)H NMR, (13)C NMR, and 2D NMR (HSQC, HMBC), mass spectral and elemental analysis. All the synthesized compounds were screened for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains using Streptomycin and Amphotericin B as standards. The minimum inhibition concentration (MIC) results revealed that most of the purine (1a-2a, 1b-2b, and 1c-2c) compounds exhibit excellent activity against selected bacterial and fungal strains.


COVID-19-related anosmia.
On average, 47% of patients with COVID-19 self-report an olfactory disorder, although the inaccuracy of self-reporting means this figure may be higher.


Cardiovascular magnetic resonance findings in non-hospitalized paediatric patients after recovery from COVID-19.
Our study aimed to investigate the cardiac involvement with sensitive tissue characterization in non-hospitalized children with coronavirus disease 2019 (COVID-19) infection using cardiovascular magnetic resonance (CMR) imaging. We prospectively enrolled children who recovered from mildly symptomatic COVID-19 infection between November 2020 and January 2021. Patients underwent CMR at 1.5 T (Achieva, Philips Healthcare, Best, the Netherlands) including cine images, native T1 and T2 mapping. Healthy children and paediatric patients with biopsy-proven myocarditis served as control groups. We performed CMR in 18 children with a median (25th-75th percentile) age of 12 (10-15) years, 38 (24-47) days after positive PCR test, and compared them with 7 healthy controls [15 (10-19) years] and 9 patients with myocarditis [10 (4-16) years]. The COVID-19 patients reported no cardiac symptoms. None of the COVID-19 patients showed CMR findings consistent with a myocarditis. Three patients (17%) from the COVID-19 cohort presented with minimal pericardial effusion. CMR parameters of COVID-19 patients, including volumetric and strain values as well as T1 and T2 times, were not significantly different from healthy controls, but from myocarditis patients. These had significantly reduced left ventricular (LV) ejection fraction (P = 0.035), LV global longitudinal strain, and left atrial strain values as well as elevated native T1 values compared with COVID-19 patients (P < 0.001, respectively). There was no evidence of myocardial inflammation, fibrosis, or functional cardiac impairment in the studied cohort of children recently. CMR findings were comparable with those of healthy controls. Pericardial effusion suggests a mild pericarditis in a small subgroup. This is pointing to a minor clinical relevance of myocardial involvement in children after mildly symptomatic COVID-19 infections.


Endometriotic cells exhibit metaplastic change and oxidative DNA damage as well as decreased function, compared to normal endometrium.
A widely accepted theory of the etiology of endometriosis is that it originates from the implantation and invasion of cells from retrograde menstruation to various sites in the body particularly the pelvic peritoneal cavity. Little is known of the function of these cells in ectopic sites. Normal endometrium was compared with endometriotic tissue using an antibody to Placental Cadherin (P Cadherin), a recently studied cadherin that is implicated in metaplasia and early neoplasia and also 8-hydroxyguanine, an indicator of oxidative DNA damage. Comparisons of endometrial tissue function were made using expression of transforming growth factor beta-1 (TGFbeta-1) and insulin-like growth factor-I (IGF-I). There was no labelling for anti-P Cadherin or anti-8-hydroxydeoxyguanosine in normal endometrium but marked labelling for both on the apical surface of the endometriotic epithelium. Studies of markers of normal endometrial function were all de-expressed in endometriosis. This study indicates that endometriosis cells are abnormal and exhibit oxidative DNA damage, metaplasia and markedly reduced function compared to normal endometrium.


Frequent visits to various anvils during tool use by the graphic tuskfish Choerodon graphicus (Labridae).
This study investigated tool use by the graphic tuskfish Choerodon graphicus in New Caledonia. Anvils included rocks, a conical shell, flat dead corals and a concrete mooring. Sixteen tool-use events were observed in 10 h. A tool-use event often involved more than one anvil (44%). On average, C. graphicus struck prey six times and spent 84 s at an anvil. The only prey items brought to anvils were bivalve and gastropod molluscs. These results provide a foundation for future research on tool use in fishes.


Outcome of primary orbital lymphoma treated with induction chemotherapy followed by conformal radiotherapy.
To analyze the clinical outcome of primary orbital lymphoma (POL) patients treated with a combined modality approach with local radiotherapy after induction chemotherapy. We retrospectively retrieved demographic, treatment and outcome data of patients treated for POL from 2000 to 2010. The charts were reviewed and the data were tabulated in a predesigned pro-forma. 23 patients of POL were found evaluable. Median age was 55 years (range 24-70 years). Of 23 patients, 15 were male and 8 female, making the male:female ratio approximately 1.9:1. Patients were thoroughly evaluated and staged. All but one patient received multi agent chemotherapy. Radiotherapy was delivered for all cases. Radiation was delivered by 3DCRT technique. Median dose of radiation was 45Gy (range 20-45Gy). Median follow up was 26.8 months. None of the patients had any evidence of local failure or systemic progression. A combined modality therapy with a combination of CHOP/COP based chemotherapy and moderate dose of radiotherapy imparts excellent long term local and systemic disease control.


Biomolecular characterization of placental tissues in gestational diabetes mellitus using Fourier transform infrared microspectroscopy.
Gestational diabetes mellitus (GDM) is a common complication during pregnancy. It could cause severe side-effect on the mother's and newborn's heath in the short- and long-term. Prevalence has been increasing over time, likely due to increases in mean maternal age and body weight. However, how GDM affects the placenta structure and function are still unclear. Fourier transform infrared microspectroscopy is well suited to study biological samples, such as tissues and cells. Biomolecules of human tissues have characteristic absorptions in mid-infrared range. In this study, Fourier transform infrared microspectroscopy was used to measure unfixed placental tissue sections from women with GDM and matched controls. The molecular composition of different type of placental tissue sections were further analyzed with principle component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). The major spectral characteristic of biomolecules in GDM placental tissue and control group were compared. The conformational change of lipid chains and higher level of lipid oxidation were found for placental tissues from GDM pregnancies. The increase of proteins β-sheet structures relative to the α-helix structures in the GDM placental tissues were also found. The fingerprint region showed the variances of carbohydrates, nucleic acids and phospholipids between GDM and control group placental tissues. These findings are helpful for understanding how GDM affects placenta's biochemical composition and how GDM causes maternal and fetal metabolism changes. This study also provides a new approach to investigating biomolecular composition of samples from GDM pregnancy through spectroscopic method.


Adsorption and environmental behavior of mercury on suspended particulate matter from the Yellow River and Xiaoqing River estuaries.
Estuaries control the amount of Hg transported from rivers to coastal seas. The adsorption of Hg(II) on suspended particulate matter (SPM) is the key process that affects the behavior of Hg in estuaries since most riverine Hg is deposited with SPM in estuaries. In this study, the concentrations of particulate Hg (PHg) were higher than those of dissolved Hg (DHg) at the Xiaoqing River Estuary (XRE) and the Yellow River Estuary (YRE), indicating that SPM plays a crucial role in controlling the fate of Hg in estuaries. A higher partition coefficient (logKd) of Hg was observed at the YRE compared to other estuaries, indicating that Hg(II) tends to be more adsorbed on SPM in this system. The adsorption kinetics of Hg(II) on SPM at both estuaries conformed to pseudosecond-order kinetics, while the adsorption isotherms at the XRE and YRE fitted well with the Langmuir model and Freundlich model, respectively, possibly due to the difference in SPM composition and properties. The logKd was significantly positively correlated with the adsorption capacity parameter kf at the YRE, indicating that the distribution of Hg(II) at the SPM-water interface is controlled by the adsorption of Hg(II) on SPM. The results of environmental parameter correlation analysis and adsorption-desorption experiments showed that SPM and organic matter are the key factors controlling Hg distribution and partitioning at the water-solid interface in estuaries.


Effects of Cistus-tea on bacterial colonization and enzyme activities of the in situ pellicle.
Polyphenols are expected to have antibacterial properties. Cistus is a tea rich in polyphenols. The aim of the present in situ study was to investigate the effect of Cistus-tea on the pellicle and on the initial oral biofilm. For in situ pellicle formation and initial biofilm formation, bovine enamel slabs were fixed on maxillary splints and carried by four subjects at buccal sites for up to 2 h. Bacteria present in 120-min pellicles were determined with DAPI-staining and fluorescence in situ hybridization with and without a 10 min rinse with Cistus-tea performed 1 min after incorporation of the slabs. In addition, amylase, lysozyme, glucosyltransferase and peroxidase activities immobilised in the pellicle layer were measured before and after rinsing for 10 min with Cistus-tea. The amount of bacteria detected in the 120-min biofilm was reduced significantly, if a 10 min rinse with Cistus-tea was performed one min after insertion of the enamel slabs. DAPI-staining yielded 13.2+/-3.5 for controls and 6.5+/-1.1 x 10(4) bacteria/cm(2), if a rinse with Cistus-tea was applied. Lysozyme, amylase and glucosyltransferase activities immobilised in the pellicle were not affected following a rinse with Cistus-tea. However, peroxidase activity was reduced significantly. Cistus-tea may be used to reduce the initial bacterial adhesion in the oral cavity.


The association of CD4+ T-cell counts and cardiovascular risk in treated HIV disease.
HIV-infected individuals are at high risk of developing cardiovascular disease. Whether earlier initiation of HIV therapy at higher CD4 cell counts has any effect on cardiovascular risk as assessed by endothelial function is unknown. Cross-sectional study of 74 antiretroviral-treated men with undetectable plasma HIV RNA levels. Participants underwent noninvasive assessment of endothelial function using brachial artery flow-mediated dilation (FMD). The association of nadir and current CD4 T-cell count with FMD was assessed using multivariable linear regression. The median age was 47 years [interquartile range (IQR) 42-55], median current CD4 T-cell count was 659 cells/μl (IQR 542-845), and nadir CD4 cell count was 314 cells/μl (IQR 150-490). Twenty-eight percent had hypertension, and 32% hyperlipidemia. Nadir CD4 T-cell count less than 350 cells/μl was associated with lower FMD in age-adjusted and race-adjusted analyses and remained an independent predictor of FMD after adjustment for cardiovascular risk factors (hypertension, diabetes, smoking, hyperlipidemia) and HIV-related characteristics (HIV duration, HAART duration). After multivariable adjustment, individuals with nadir CD4 T-cell count less than 350 cells/μl had a 1.22% lower FMD compared with those with higher T-cell counts [95% confidence interval (CI) -2.20 to -0.19, P=0.02]. Proximal CD4 T-cell count showed little association with FMD. Among treated HIV-infected individuals, nadir CD4 T-cell count less than 350 cells/μl is independently associated with lower FMD, suggesting that delayed therapy results in sustained harm to endothelial function. Our data support future prospective studies evaluating cardiovascular effects of HAART initiation at higher CD4 cell counts.


Does hormone replacement therapy have beneficial effects on renal functions in menopausal women?
The study was carried out to evaluate the possible effects of hormone replacement therapy (HRT) on renal functions in postmenopausal women. A total of 85 postmenopausal women without a history of medical illness were enrolled in the study. They were divided into HRT users and control groups. After 30 weeks of HRT use, the changes in serum urea, creatinine, uric acid, urinary protein, urinary creatinine, urinary protein/creatinine ratio and glomerular filtration rate (GFR) (mL/min/1.73 m(2)) were evaluated. HRT was associated with statistically significant increases in glomerular filtration rate (p < 0.01), while serum urea, creatinine, uric acid, urinary protein, urinary creatinine and urinary protein/creatinine ratio did not change significantly in both groups. In our study, we suggested that usage of hormone replacement therapy appeared to affect renal functions in postmenopausal women. There were beneficial effects of HRT on GFR in our postmenopausal patients. HRT may have possible protective mechanisms for kidney against adverse effects of aging.


Cortisol inhibits apoptosis in carp neutrophilic granulocytes.
The direct effect of cortisol treatment on carp neutrophil viability was examined in vitro. Cortisol treatment caused an inhibition of neutrophil apoptosis. The effect was blocked by glucocorticoid receptor blocker RU486, showing that rescue from apoptosis was receptor mediated. Using binding studies with radioactive cortisol, a single class of glucocorticoid receptors was detected with high affinity (Kd = 2.6 nM) and low capacity (497 receptors/cell) for cortisol binding. Both in vitro and in vivo cortisol treatment did not affect neutrophil respiratory burst activity. These data indicate that cortisol can augment the supply of functional neutrophilic granulocytes in conditions of acute stress, which may be essential for survival, since phagocytes form the first line of defence against micro-organisms.


Occlusion Type, Number of Recanalization Passages and Dose Program Determine Radiation Dose in Endovascular Stroke Thrombectomy.
Identification of independent treatment factors associated with high radiation exposure during endovascular mechanical thrombectomy (EMT) in acute ischemic stroke. This retrospective analysis included all patients treated by means of EMT during the 2‑year period 2017-2018 in a comprehensive stroke center. The EMT were performed by four internal and three external certified neuroradiologists in a clinic overlapping on call system. Radiation exposure as the dependent variable (dose area product DAP, Gy ⋅ cm2) was dichotomized in < 100 Gy ⋅ cm2 and ≥ 100 Gy ⋅ cm2. Independent variables were age (< 75 years vs. ≥ 75 years), time of intervention (during vs. beyond workday), treating neuroradiologist (internal vs. external), occlusion type ("mono" vs. "tandem"), reperfusion success (TICI 0-2A vs. TICI 2B/3), recanalization attempts (≤ 2 vs. > 2) and dose protocol (normal dose in 2017 vs. low dose in 2018). The EMT treatment of 208 patients (111 female, 97 male, mean age 71.6 years) was analyzed. Median DAP was 86.6 Gy ⋅ cm2 and could be reduced from 104.8 Gy ⋅ cm2 (N = 105 in 2017) to 73.3 Gy ⋅ cm2 (N = 103 in 2018) with LD program. Univariable and multivariable binary logistic regression analysis revealed a significantly increased radiation exposure (≥ 100 Gy ⋅ cm2) in tandem occlusion type (P < 0.001), > 2 recanalization attempts (P < 0.001) and normal dose protocol (P = 0.002). Low dose programs can significantly reduce the radiation exposure in EMT. High radiation exposure is significantly associated with more than two recanalization attempts and in cases of tandem occlusions.


[Factors associated with calcium, vitamin D supplements intake and use of hormonal replacement therapy in health workers postmenopausal women].
To know the frequency and factors associated with the intake of calcium (Ca), vitamin D supplements and use of hormone replacement therapy (HRT) among postmenopausal (PM) health professionals women. During January to June 2004, health workers women of IMSS General Hospitals in Tijuana and Ensenada, Baja California, Mexico, were invited to participate. An interview and measurement of calcaneous bone mineral density (BMD) were performed. The following variables were assessed: sociodemographic, clinic and gynecologic features. We defined preventive osteoporosis (OP) treatment as the use of HRT, intake of Ca supplements (> or =1000 mg/ day) and supplements of vitamin D for a least six months. Among 739 women interviewed, 312 were PM, and 31%, 25% and 31% have been taking Ca supplements, vitamin D, and HRT respectively. Calcium, vitamin D supplements intake and use of HTR was similar during the menopause evolution. The variables significantly associated with the use of preventive OP treatment were older age, low weight, previous ooferectomy and use of corticosteroids. In the multivariate analysis, age and underweight were significantly associated with a low bone mass density, independently of the use of preventive OP treatment The frequency and length of time of Ca, vitamin D supplements intake and use of HRT was low, and 50% of PM health professional women are not under preventive OP therapy.


Vitamin E: cautionary issues.
Compared with many medications used in the patient with cardiovascular disease, vitamin E is a relatively safe supplement. There are a few populations in which caution needs to be employed, however. Patients receiving warfarin therapy should be discouraged from using vitamin E supplements and should be closely monitored if they do. Smokers should avoid vitamin E due to potential negative effects on vitamin C, and vitamin E should never be administered in conjunction with beta-carotene in this population. The rare patient requiring vitamin A therapy or having retinitis pigmentosa should also avoid vitamin E supplementation. Because of the increased risk of bleeding, vitamin E should be discontinued in the perioperative period in any patient requiring surgery.


Transcatheter aortic valve implantation with the Edwards SAPIEN versus the Medtronic CoreValve Revalving system devices: a multicenter collaborative study: the PRAGMATIC Plus Initiative (Pooled-RotterdAm-Milano-Toulouse In Collaboration).
The aim of this study was to compare outcomes after transfemoral transcatheter aortic valve implantation with the Medtronic CoreValve (MCV) versus the Edwards SAPIEN/SAPIEN XT transcatheter heart valve (ESV) for severe aortic stenosis. No large matched comparison study has been conducted so far evaluating both commercially available devices. The data from databases of 4 experienced European centers were pooled and analyzed. Due to differences in baseline clinical characteristics, propensity score matching was performed. Study objectives were Valve Academic Research Consortium outcomes at 30 days and 1 year. In total, 793 patients were included: 453 (57.1%) treated with the MCV and 340 (42.9%) with the ESV. After propensity matching, 204 patients were identified in each group. At 30 days, there were no differences in all-cause mortality (MCV, 8.8% vs. ESV, 6.4%; hazard ratio [HR]: 1.422; 95% confidence interval [CI]: 0.677 to 2.984; p = 0.352), cardiovascular mortality (MCV, 6.9% vs. ESV, 6.4%; HR: 1.083; 95% CI: 0.496 to 2.364; p = 0.842), myocardial infarction (MCV, 0.5% vs. ESV, 1.5%; HR: 0.330; 95% CI: 0.034 to 3.200; p = 0.339), stroke (MCV, 2.9% vs. ESV, 1.0%; HR: 3.061; 95% CI: 0.610 to 15.346; p = 0.174), or device success (MCV, 95.6% vs. ESV, 96.6%; HR: 0.770; 95% CI: 0.281 to 2.108; p = 0.611). Additionally, there were no differences in major vascular complications (MCV, 9.3% vs. ESV, 12.3%; HR: 0.735; 95% CI: 0.391 to 1.382; p = 0.340) or life-threatening bleeding (MCV, 13.7% vs. ESV, 8.8%; HR: 1.644; 95% CI: 0.878 to 3.077; p = 0.120). MCV was associated with more permanent pacemakers (22.5% vs. 5.9%; HR: 4.634; 95% CI: 2.373 to 9.050; p < 0.001). At 1 year, there were no differences in all-cause (MCV, 16.2% vs. ESV, 12.3%; HR: 1.374; 95% CI: 0.785 to 2.407; p = 0.266) or cardiovascular (MCV, 8.3% vs. ESV, 7.4%; HR: 1.145; 95% CI: 0.556 to 12.361; p = 0.713) mortality. No differences between the 2 commercially available transfemoral transcatheter aortic valve implantation devices were observed at the adjusted analysis in Valve Academic Research Consortium outcomes except for the need for permanent pacemakers with the MCV.


A multifunctional microporous metal-organic framework: efficient adsorption of iodine and column-chromatographic dye separation.
In this work, a multifunctional microporous metal-organic framework (MOF), [Cd(ABTC)(H2O)2(DMA)]·4DMA (JLNU-4; JLNU = Jilin Normal University; H4ABTC = 3,3',5,5'-azobenzenetetracarboxylic acid), has been synthesized based on the ligand H4ABTC under solvothermal conditions. JLNU-4 shows excellent uptake of iodine both in solution and in the vapor phase, owing to the existence of a microporous structure in JLNU-4. The adsorption kinetics during the process of iodine adsorption were analyzed via a series of qualitative and quantitative analyses, such as the Langmuir and Freündlich adsorption isotherms. In addition, according to UV/vis spectroscopy analysis and the colour variance of JLNU-4, the relatively small sized dye methylene blue (MB) could be efficiently adsorbed by JLNU-4, through size-exclusion effects. Particularly, JLNU-4 can serve as a column-chromatographic filler for the separation of dye molecules. Therefore, JLNU-4 is a multifunctional microporous MOF for iodine adsorption and column-chromatographic dye separation.


Occurrence of lymphocyte proliferative response to thyroglobulin and antithyroglobulin antibodies in normal individuals: lack of correlation with HLA.
Peripheral mononuclear cells (MNC) of patients with autoimmune thyroid disease have been shown to proliferate when cultured with human thyroglobulin (hTg). In addition, such a phenomenon is apparent in a certain number of healthy individuals. In this study we have attempted to correlate hTg-induced MNC proliferation, occurrence of anti-hTg autoantibodies and HLA phenotype (including Class II DR and DQ loci) in a population of HLA-typed normal blood donors. Fourteen out of 56 subjects showed a significant MNC proliferation to hTg. Three of them had anti-hTg autoantibodies in the serum, while none of the hTg-unresponsive subjects showed such antibodies. No correlation with HLA phenotype (including Class II DR5 specificity, referred as associated with Hashimoto's thyroiditis, and DQ alleles) was observed.


Bayesian spatio-temporal modelling and mapping of malaria and anaemia among children between 0 and 59 months in Nigeria.
A vital aspect of disease management and policy making lies in the understanding of the universal distribution of diseases. Nevertheless, due to differences all-over host groups and space-time outbreak activities, data are subject to intricacies. Herein, Bayesian spatio-temporal models were proposed to model and map malaria and anaemia risk ratio in space and time as well as to ascertain risk factors related to these diseases and the most endemic states in Nigeria. Parameter estimation was performed by employing the R-integrated nested Laplace approximation (INLA) package and Deviance Information Criteria were applied to select the best model. In malaria, model 7 which basically suggests that previous trend of an event cannot account for future trend i.e., Interaction with one random time effect (random walk) has the least deviance. On the other hand, model 6 assumes that previous event can be used to predict future event i.e., (Interaction with one random time effect (ar1)) gave the least deviance in anaemia. For malaria and anaemia, models 7 and 6 were selected to model and map these diseases in Nigeria, because these models have the capacity to receive strength from adjacent states, in a manner that neighbouring states have the same risk. Changes in risk and clustering with a high record of these diseases among states in Nigeria was observed. However, despite these changes, the total risk of malaria and anaemia for 2010 and 2015 was unaffected. Notwithstanding the methods applied, this study will be valuable to the advancement of a spatio-temporal approach for analyzing malaria and anaemia risk in Nigeria.


Simultaneous determination of steroidal and phenolic endocrine disrupting chemicals in fish by ultra-high-performance liquid chromatography-mass spectrometry/mass spectrometry.
A sensitive and reliable analytical method based on pressurized liquid extraction (PLE) and ultra-high-performance liquid chromatography equipped with tandem mass spectrometry (UHPLC-MS/MS) has been developed for simultaneously determining the steroidal and phenolic endocrine disrupting chemicals (EDCs) in fish. The most effective extraction of the target EDCs is achieved by using PLE with on-line purification and the parameters have been optimized as follows: extraction solvent - methanol-acetonitrile (1:1, v/v), on-line purification material - 5 g alumina (5% water), extraction - 3 cycles, static extraction time - 5 min and extraction temperature - 60°C. Compared to the Oasis hydrophilic-lipophilic balance (HLB) solid phase extraction (SPE), freezing-lipid filtration combined with n-hexane defatting clean-up obtains much better recoveries of the target compounds and provide cleaner extracts. The matrix effect (ME) is generally eliminated by using an internal standard method. At spiking levels of 5, 50, and 100 ng/g, the mean recoveries vary from 71.2% to 108% for the target EDCs with a relative standard deviation (RSD) less than 16%. The method limit of detection (LOD) and limit of quantitation (LOQ) are 0.04-0.08 ng/gdw and 0.07-0.27 ng/gdw, respectively. The established method has been successfully applied to fish samples from the local market to determine the target EDCs.


Deploying Kinase Inhibitors to Study Pediatric Gliomas.
Pediatric midline gliomas are a uniformly fatal disease for which there is no cure. The location of these tumors makes surgical resection impossible, and so novel therapies are urgently needed to improve outcomes. The biology of these tumors is increasingly understood, with the histone H3K27M mutation playing a critical role in the pathogenesis of these tumors. Efforts to inhibit the growth of these tumors have also focused on inhibiting the Aurora kinase and Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in order to disrupt tumor proliferation. A number of small molecule inhibitors of these kinases have shown promise in early studies. Screening and preclinical assessment of such inhibitors requires a functional assay to assess the degree of kinase inhibition. We detail here a luciferase-based reporter assay for STAT3 transcriptional activity that we have employed frequently in order to assess the efficacy of kinase inhibitors in pediatric gliomas. The assay we describe is specific to STAT3, but the overall methodology is generalizable to other downstream targets of the kinase of interest.


Histidinaemia. Part III: Impact; a prospective study.
We describe a prospective study of histidinaemia. Probands and siblings (n = 21) with typical histidinaemia in 16 families were ascertained by newborn screening; diagnosis was confirmed by appropriate investigations in each subject; none had been treated by low histidine diet. The median age of subjects with histidinaemia was 9.5 y (mean 10.0, SD 3.5, range 6-18). Age-matched sib-pairs and their mothers were studied. IQ scores (Full Scale, Verbal and Performance Scores), Visual-Motor Integration Performance (Bender Gestalt and Koppitz scores), Wide Range Achievement Test (Reading and Mathematics), school performance, and psychological history were evaluated, as well as the medical history (pregnancy, delivery, neonatal, post-natal development). Findings were correlated with biochemical phenotype. CNS development in histidinaemic subjects (mean and distribution of scores) was normal; outlier values did not correlate with degree of histidinaemia. We can conclude that histidinaemia detected by newborn screening is a non-disadaptive phenotype.


Joint K-space and Image-space Parallel Imaging (KIPI) for accelerated chemical exchange saturation transfer acquisition.
To develop an auto-calibrated technique by joint K-space and Image-space Parallel Imaging (KIPI) for accelerated CEST acquisition. The KIPI method selects a calibration frame with a low acceleration factor (AF) and auto-calibration signals (ACS) acquired, from which the coil sensitivity profiles and artifact correction maps are calculated after restoring the k-space by GRAPPA. Then the other frames with high AF and without ACS can be reconstructed by SENSE and artifact suppression. The signal leakage due to the T2 -decay filtering in k-space compromises the SENSE reconstruction, which can be corrected by the artifact suppression algorithm of KIPI. The 2D and 3D imaging experiments were done on the phantom, healthy volunteer, and brain tumor patient with a 3T scanner. The proposed KIPI method was evaluated by retrospectively undersampled data with variable AFs and compared against existing parallel imaging methods (SENSE/auto, GRAPPA, and ESPIRiT). KIPI enabled CEST frames with random AFs to achieve similar image quality, eliminated the strong aliasing artifacts, and generated significantly smaller errors than the other methods (p < 0.01). The KIPI method permitted an AF up to 12-fold in both phase-encoding and slice-encoding directions for 3D CEST source images, achieving an overall 8.2-fold speedup in scan time. KIPI is a novel auto-calibrated parallel imaging method that enables variable AFs for different CEST frames, achieves a significant reduction in scan time, and does not compromise the accuracy of CEST maps.


Seasonal Influenza Vaccine Effectiveness in Persons Aged 15-64 Years: A Systematic Review and Meta-Analysis.
Influenza is a respiratory disease caused by the influenza virus, which is highly transmissible in humans. This paper presents a systematic review and meta-analysis of randomized controlled trials (RCTs) and test-negative designs (TNDs) to assess the vaccine effectiveness (VE) of seasonal influenza vaccines (SIVs) in humans aged 15 to 64 years. An electronic search to identify all relevant studies was performed. The outcome measure of interest was VE on laboratory-confirmed influenza (any strain). Quality assessment was performed using the Cochrane risk-of-bias tool for RCTs and the ROBINS-I tool for TNDs. The search identified a total of 2993 records, but only 123 studies from 73 papers were included in the meta-analysis. Of these studies, 9 were RCTs and 116 were TNDs. The pooled VE was 48% (95% CI: 42-54) for RCTs, 55.4% (95% CI: 43.2-64.9) when there was a match between the vaccine and most prevalent circulating strains and 39.3% (95% CI: 23.5-51.9) otherwise. The TNDs' adjusted VE was equal to 39.9% (95% CI: 31-48), 45.1 (95% CI: 38.7-50.8) when there was a match and 35.1 (95% CI: 29.0-40.7) otherwise. The match between strains included in the vaccine and strains in circulation is the most important factor in the VE. It increases by more than 25% when there is a match with the most prevalent circulating strains. The laboratorial method for confirmation of influenza is a possible source of bias when estimating VE.


Cloning and characterization of the mouse tob2 gene.
Human Tob2 is a member of the Tob/BTG1 anti-proliferative family of proteins. Here, we report the molecular cloning and characterization of the mouse tob2 gene. The tob2 gene contains an open reading frame of 345 amino acids with an 89% identity to its human counterparts. The coding region of mouse tob2 is not interrupted by introns. The tob2 transcript is 4.2kb long, the size being similar to that of the human tob2 transcript, and detected ubiquitously in various tissues of adult mice. In addition, in situ hybridization shows that tob2 is ubiquitously expressed in embryo, the level of expression being especially high in skeletal muscle. Collectively, Tob2 is suggested to play roles both during embryogenesis and in adults.


Development of the stria vascularis in the common marmoset, a primate model.
Stria vascularis is a structure that generates potassium gradients in the cochlea, which is vital for hair cells to convert mechanical sound waves into electrical pulses. The precise development of the stria vascularis and subsequent generation of endocochlear potential are thus essential for hearing. Understanding the development of the stria vascularis is valuable for studying hearing loss caused by aging or genetics and designing regenerative therapy. Although inter-species differences have been reported between rodents and humans, most of our current knowledge regarding cochlear development has been obtained from rodent models because of the difficulty in using human fetal samples in this field of research. Therefore, we investigated the development of the cochlear stria vascularis in the common marmoset (Callithrix jacchus), a small monkey species native to the New World. Our study confirms that stria vascularis development in the common marmoset is similar to that in humans and is suitable for furthering our understanding of human cochlear development. The time course established in this report will aid in studying the primate-specific developmental biology of the inner ear, which could eventually lead to new treatment strategies for hearing loss in humans.


p53 isoform expression promotes a stemness phenotype and inhibits doxorubicin sensitivity in breast cancer.
In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated while those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous ∆40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. ∆40p53 and Sox2 co-localisation was also detected in breast cancer specimens. Further, in cells expressing a high ∆40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high ∆40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of ∆40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.


Lipid lowering and antioxidant effect of miglitol in triton treated hyperlipidemic and high fat diet induced obese rats.
Miglitol, an anti-diabetic drug, has been shown to reduce plasma lipids and inhibit free radical generation. The anti-hyperlipidemic and antioxidant effects of miglitol were studied in triton-induced hyperlipidemic rats and high fat diet-fed obese rats. Plasma cholesterol and triglycerides levels were significantly lowered by miglitol at 100 mg/kg body weight doses. Miglitol inhibited generation of superoxide anion and hydroxyl free radicals by 14 and 31 % in enzymatic systems and 19 and 25 % in non-enzymatic systems, respectively. The in-vitro effect of the drug on adipogenesis using 3T3-L₁ preadipocytes at 2-, 5- and 10-μM concentrations showed significant inhibition of adipogenesis (34.2 %) at 10-μM concentration. High fat diet-fed rat model was used to investigate anti-hyperlipidemic, anti-obesity and antioxidant effect of miglitol. Miglitol increased the activities of lecithin-cholesterol-acyltransferase (19 %), post heparin lipolytic activity (26 %), lipoprotein lipase (26 %) and triglyceride lipase (31 %) which result in a decrease in plasma lipid levels. The antioxidant enzymes viz., catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and thioredoxin reductase were increased by the drug in the treated animals. The antihyperlipidemic and antioxidant effect of miglitol can be correlated to its effect on different enzymes and it can be used for inhibiting the development of cardiovascular diseases.


Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation.
The development of nonalcoholic fatty liver disease (NAFLD) is associated with increased reactive oxygen species (ROS) production. Previous observations on the contradictory roles of general control nonderepressible 2 (GCN2) in regulating the hepatic redox state under different nutritional conditions prompted an investigation of the underlying mechanism by which GCN2 regulates ROS homeostasis. In the present study, GCN2 was found to interact with NRF2 and decrease NRF2 expression in a KEAP1-dependent manner. Activation of GCN2 by halofuginone treatment or leucine deprivation decreased NRF2 expression in hepatocytes by increasing GSK-3β activity. In response to oxidative stress, GCN2 repressed NRF2 transcriptional activity. Knockdown of hepatic GCN2 by tail vein injection of an AAV8-shGcn2 vector attenuated hepatic steatosis and oxidative stress in leptin-deficient (ob/ob) mice in an NRF2-dependent manner. Inhibition of GCN2 by GCN2iB also ameliorated hepatic steatosis and oxidative stress in both ob/ob mice and high fat diet-fed mice, which was associated with significant changes in lipid and amino acid metabolic pathways. Untargeted metabolomics analysis revealed that GCN2iB decreased fatty acid and sphingomyelin levels but increased aliphatic amino acid and phosphatidylcholine levels in fatty livers. Collectively, our results provided the first direct evidence that GCN2 is a novel regulator of NRF2 and that specific GCN2 inhibitors might be potential drugs for NAFLD therapy.


"Lymphocyte * Neutrophil" count decreased in SARS-CoV-2 Omicron patients in Shanghai with no significant change in CRP and SAA.
At present, there is a new variant Omicron BA.2 of SARS-CoV-2. In some previous studies, it was found that CBC, NLR, CRP, SAA, etc. in patients with SARS-CoV-2 had a series of changes, which were significantly correlated with the diagnosis and prognosis of patients. Therefore, in order to find specific diagnostic indicators, we explore the changes in these blood indicators and inflammatory indicators in patients with the SARS-CoV-2 Omicron. A total of 127 Omicron confirmed patients who had visited fever clinic was selected as the positive group, and 75 Omicron excluded patients were selected as the negative group. We collected and analyzed the CBC, CRP, SAA test data, and clinical data of all subjects for analysis and statistics. WBC, NEU, LYM, EOS, PLT, PCT, LYM * NEU count compared with the negative group were significantly lower (p < 0.05); on the contrary, CNR were significantly higher (p < 0.05); The levels of CRP and SAA were not significantly different from those of the negative group (p > 0.05); the AUC of 0.781 for the diagnosis of LYM * NEU with an optimal cutoff value of 5.79, with a sensitivity and specificity of 68% and 73%, respectively, Youden index of 0.41, giving the best diagnostic performance. The decreased LYM * NEU count can be used as the early, rapid, and accurate diagnostic indicator for Omicron. While due to the attenuated toxicity of BA.2 sublineage, CRP and SAA had no significance in the differential diagnosis of confirmed patients.


Quantitative zeptomolar imaging of miRNA cancer markers with nanoparticle assemblies.
Multiplexed detection of small noncoding RNAs responsible for posttranscriptional regulation of gene expression, known as miRNAs, is essential for understanding and controlling cell development. However, the lifetimes of miRNAs are short and their concentrations are low, which inhibits the development of miRNA-based methods, diagnostics, and treatment of many diseases. Here we show that DNA-bridged assemblies of gold nanorods with upconverting nanoparticles can simultaneously quantify two miRNA cancer markers, namely miR-21 and miR-200b. Energy upconversion in nanoparticles affords efficient excitation of fluorescent dyes via energy transfer in the superstructures with core-satellite geometry where gold nanorods are surrounded by upconverting nanoparticles. Spectral separation of the excitation beam and dye emission wavelengths enables drastic reduction of signal-to-noise ratio and the limit of detection to 3.2 zmol/ngRNA (0.11 amol or 6.5 × 104 copies) and 10.3 zmol/ngRNA (0.34 amol or 2.1 × 105 copies) for miR-21 and miR-200b, respectively. Zeptomolar sensitivity and analytical linearity with respect to miRNA concentration affords multiplexed detection and imaging of these markers, both in living cells and in vivo assays. These findings create a pathway for the creation of an miRNA toolbox for quantitative epigenetics and digital personalized medicine.


Relationship between spontaneous echo contrast in the thoracic aorta and plasma von Willebrand factor.
To clarify the relationships between spontaneous echo contrast (SEC) detected by transesophageal echocardiography (TEE) and coagulopathy, ultrasonographic findings that may correlate to biochemical coagulation markers were examined. TEE was performed on 49 consecutive patients (mean age 64 ± 14 years; 28 men, 21 women). Blood samples were taken at the same time as TEE was carried out. Aortic SEC (Ao-SEC) and left atrial SEC (LA-SEC) were classified into three grades: absent, mild and marked. Levels of von Willebrand factor (vWF), thrombin antithrombin III complex (TAT), prothrombin fragments 1+2 (F1+2) and fibrinopeptide A (FPA) were measured. Mean plasma vWF levels by Ao-SEC grade were 144 ± 39% for absent, 177 ± 55% for mild and 210 ± 73% for marked, with significantly higher levels in the Ao-SEC marked group than in the Ao-SEC absent group (P < 0.05). Mean plasma vWF levels by LA-SEC were 185 ± 73% for absent, 180 ± 49% for mild and 201 ± 62% for marked, with no significant differences apparent between groups. Moreover, no relationships were identified between Ao-SEC grade and plasma levels of coagulation indicators TAT, F1+2 and FPA. Plasma vWF levels correlated to grade of aortic SEC. Characteristics of the coagulation system differ between Ao-SEC and LA-SEC. Ao-SEC offers a clinical indicator of platelet thrombus formation.


Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT.
In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.


[The determination of the urea content in cow's milk with the help of the dry chemical system Reflotron].
The dry chemistry laboratory unit "Reflotron" (Boehringer Mannheim) is tested for its efficacy in the determination of urea in dairy milk with the test Urea. It gives reliable results. The system is easy to handle. The storage of milk is of no influence on the level of urea.


Simultaneous LC-MS/MS quantification of SGLT2 inhibitors and antipyrine in medium and tissue from human ex vivo placenta perfusions.
A liquid chromatography - tandem mass spectrometry (LC-MS/MS) method has been developed to simultaneously measure four sodium glucose co-transporter 2 (SGLT2) inhibitors and the transfer marker antipyrine (ANTI) in perfusion medium and placental tissue collected from ex vivo human placental perfusions. The four SGLT2 inhibitors were empagliflozin (EMPA), dapagliflozin (DAPA), ertugliflozin (ERTU) and canagliflozin (CANA). Chromatographic separation was achieved on an Uptisphere® C18 reversed phase column (50 mm × 4.6 mm × 5 µm) within 2.85 min, using a gradient elution with 10 mM ammonium formate in water (mobile phase A) and acetonitrile (mobile phase B) both with 0.1% formic acid. Analysis of ammonium adduct ions was performed on an AB SCIEX 6500+ triple quadrupole mass spectrometer using positive electrospray ionisation and scheduled multiple reaction monitoring (sMRM). The transitions were m/z 468.00 → 355.20 (EMPA), m/z 426.00 → 167.20 (DAPA), m/z 437.10 → 206.90 (ERTU), m/z 462.00 → 249.00 (CANA) and m/z 189.20 → 55.90 (ANTI). The method was validated according to the European Medicines Agency guidelines and was proven to be selective, linear within a concentration range of 1-1000 µg/L (DAPA, CANA, ANTI) and 1-500 µg/L (EMPA, ERTU), accurate, precise and free of carry-over, instabilities, recovery and matrix effect issues. This newly developed method is suitable to analyse perfusion medium and placenta tissue samples collected during ex vivo human placenta perfusions. It thereby enables quantification of transport across the placental barrier of the SGLT2 inhibitors EMPA, DAPA, ERTU and CANA as well as the transfer marker ANTI.


Risk Factors and Outcomes of Hospitalized Patients With Severe Coronavirus Disease 2019 (COVID-19) and Secondary Bloodstream Infections: A Multicenter Case-Control Study.
Coronavirus disease 2019 (COVID-19) has become a global pandemic. Clinical characteristics regarding secondary infections in patients with COVID-19 have been reported, but detailed microbiology, risk factors, and outcomes of secondary bloodstream infections (sBSIs) in patients with severe COVID-19 have not been well described. We performed a multicenter case-control study including all hospitalized patients diagnosed with severe COVID-19 and blood cultures drawn from 1 March 2020 to 7 May 2020 at 3 academic medical centers in New Jersey. Data collection included demographics, clinical and microbiologic variables, and patient outcomes. Risk factors and outcomes were compared between cases (sBSI) and controls (no sBSI). A total of 375 hospitalized patients were included. There were 128 sBSIs during the hospitalization. For the first set of positive blood cultures, 117 (91.4%) were bacterial and 7 (5.5%) were fungal. Those with sBSI were more likely to have altered mental status, lower mean percentage oxygen saturation on room air, have septic shock, and be admitted to the intensive care unit compared with controls. In-hospital mortality was higher in those with an sBSI versus controls (53.1% vs 32.8%, P = .0001). We observed that hospitalized adult patients with severe COVID-19 and sBSI had a more severe initial presentation, prolonged hospital course, and worse clinical outcomes. To maintain antimicrobial stewardship principles, further prospective studies are necessary to better characterize risk factors and prediction modeling to better understand when to suspect and empirically treat for sBSIs in severe COVID-19.


Hyaluronan fragments activate nitric oxide synthase and the production of nitric oxide by articular chondrocytes.
Chondrocyte CD44 receptors anchor hyaluronan to the cell surface, enabling the assembly and retention of proteoglycan aggregates in the pericellular matrix. Hyaluronan-CD44 interactions also provide signaling important for maintaining cartilage homeostasis. Disruption of chondrocyte-hyaluronan contact alters CD44 occupancy, initiating alternative signaling cascades. Treatment with hyaluronan oligosaccharides is one approach to uncouple CD44 receptors from its native ligand, hyaluronan. In bovine articular chondrocytes, treatment with hyaluronan oligosaccharides or purified hyaluronan hexasaccharides induced the production of nitric oxide that mirrored nitric oxide production following interleukin-1 treatment. In contrast, 120 and 1,260 kDa hyaluronan did not induce production of nitric oxide. Human chondrocytes responded similarly to treatment with hyaluronan or hyaluronan oligosaccharides. Nitric oxide production from chondrocytes was mediated by activation of the inducible nitric oxide synthase, as confirmed by mRNA expression and inhibition of nitric oxide production by diphenyleneiodonium. Co-treatment of chondrocytes with hyaluronan oligosaccharides and interleukin-1 did not demonstrate additive effects. Blocking interleukin-1 receptors with an antagonist did not abolish the production of nitric oxide induced by treatment with hyaluronan oligosaccharides. Moreover, only COS-7 following transfection with a pCD44, not the CD44-null parental cells, responded to treatment with hyaluronan oligosaccharides by releasing nitric oxide. This study demonstrates a novel signaling potential by hyaluronan fragments, in lieu of endogenous hyaluronan-chondrocyte interactions, resulting in the activation of inducible nitric oxide synthase.


Random forest classification to determine environmental drivers and forecast paralytic shellfish toxins in Southeast Alaska with high temporal resolution.
Paralytic shellfish poison toxins (PSTs) produced by the dinoflagellate in the genus Alexandrium are a threat to human health and subsistence lifestyles in Southeast Alaska. It is important to understand the drivers of Alexandrium blooms to inform shellfish management and aquaculture, as well as to predict trends of PST in a changing climate. In this study, we aggregate environmental data sets from multiple agencies and tribal partners to model and predict concentrations of PSTs in Southeast Alaska from 2016 to 2019. We used daily PST concentrations interpolated from regularly sampled blue mussels (Mytilus trossulus) analyzed for total PSTs using a receptor binding assay. We then created random forest models to classify shellfish above and below a threshold of toxicity (80 µg 100 g-1) and used two methods to determine variable importance. We obtained a multivariate model with key variables being sea surface temperature, salinity, freshwater discharge, and air temperature. We then used a similar model trained using lagged environmental variables to hindcast out-of-sample (OOS) shellfish toxicities during April-October in 2017, 2018, and 2019. Hindcast OOS accuracies were low (37-50%); however, we found forecasting using environmental variables may be useful in predicting the timing of early summer blooms. This study reinforces the efficacy of machine learning to determine important drivers of harmful algal blooms, although more complex models incorporating other parameters such as toxicokinetics are likely needed for accurate regional forecasts.


An anatomical investigation of visual inputs to the cat orbital cortex.
The orbital region of the cortex in the cat is known to be involved in multimodal sensory functions. Visual afferent connections of this area have been investigated using the horseradish peroxidase technique. Our results demonstrate the existence of projections from ipsilateral thalamic nuclei essentially at the suprageniculate and magnocellular medial geniculate junction, well known to have multimodal physiological properties.


Team-based multicomponent care improved and sustained glycaemic control in obese people with type 2 diabetes (T2D) in a Diabetes Centre setting: A quality improvement program with quasi-experimental design.
To evaluate the effect of a team-based multi-component intervention care (MIC) program in obese patients with type 2 diabetes (T2D) and poor glycemic control. Patients with T2D and HbA1c ≥ 8 % and body mass index (BMI) ≥ 27 kg/m2 and/or waist circumference ≥ 80 cm in women and ≥90 cm in men were recruited. The intervention in Diabetes Centre included 1) nurse-led, group-based workshops; 2) review by endocrinologists; 3) telephone reminders by healthcare assistants and 4) peer support during visits. The usual care (UC) group received consultations at outpatient clinic without workshops or peer support. The MIC group received UC after 1-year of intervention. The primary outcome was change of HbA1c from baseline at 1- and 3-year. Of 207 eligible patients [age (mean ± standard deviation): 56.9 ± 8.8 years, 47.4 % men, disease duration: 13.5 ± 8.2 years, HbA1c: 9.6 ± 1.3 %, BMI: 28.8 ± 4.3 kg/m2, waist circumference: 101.5 ± 9.9 cm (men), 95.3 ± 9.8 cm (women)], 104 received MIC and 103 received UC. 95 % patients had repeat assessments at 1- and 3-year. After adjustment for confounders, MIC had greater HbA1c reduction (β -0.51, 95 % confidence interval [CI] -1.00 to -0.01; P = 0.045) than UC at 1-year, with sustained improvement at 3-year (β -0.56, CI -1.10 to -0.02; P = 0.044). Team-based MIC for 1 year improved glycemic control in obese T2D which was sustained at 3-year.


COP1 - from plant photomorphogenesis to mammalian tumorigenesis.
The COP1 (constitutive photomorphogenic 1) protein, comprising RING finger, coiled-coil and WD40 domains, is conserved in both higher plants and vertebrates. In plants, COP1 acts as an E3 ubiquitin ligase to repress light signaling by targeting photoreceptors and downstream transcription factors for ubiquitylation and degradation. The activity of COP1 in plant cells correlates with its cytoplasmic and nuclear partitioning according to dark or light conditions. In addition, various signaling molecules have been shown to directly interact with COP1 and modulate its activity. Recently, scientists have begun to probe the function and regulation of COP1 in mammalian systems. Initial studies have pointed at possible roles for mammalian COP1 in tumorigenesis and the stress response through regulating the activities of p53 and c-Jun.


High expression of JMJD6 predicts unfavorable survival in lung adenocarcinoma.
The upregulated expression of JMJD6 was observed in various human cancers. However, little was known about JMJD6 expression and its clinicopathological significance in lung adenocarcinoma. The aim of this study was to investigate the expression and significance of JMJD6 in lung adenocarcinoma progression and prognosis. The levels of JMJD6 mRNA and protein in lung adenocarcinoma specimens and corresponding non-tumorous lung tissues were evaluated by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot. In order to investigate the correlations between JMJD6 and the clinicopathological features of lung adenocarcinoma, the expression of JMJD6 in 154 patients with lung adenocarcinoma was detected by immunohistochemistry. By qRT-PCR and Western blot, the relative expression levels of JMJD6 mRNA and protein were significantly higher in lung adenocarcinoma tissues than in corresponding non-tumorous lung tissues (P < 0.001). Immunohistochemical staining revealed that high JMJD6 expression was closely correlated with tumor size (P = 0.005), pathological grade (P = 0.003), pT status (P = 0.012), pN status (P = 0.003), and pleural invasion (P < 0.001). Moreover, the results of Kaplan-Meier analysis indicated that a high expression level of JMJD6 resulted in a significantly poor prognosis of lung adenocarcinoma patients. Multivariate analysis showed that the status of JMJD6 expression was an independent prognostic factor for lung adenocarcinoma patients. Our results showed that JMJD6 plays a key role in lung adenocarcinoma and therefore may provide an opportunity for developing a novel therapeutic target as well as a prognostic marker in lung adenocarcinoma.


Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival.
One-third of patients with Merkel cell carcinoma (MCC) present with locally advanced disease involving the regional lymph nodes, but indications for regional lymph node radiation therapy (rLN-RT) are not well established. 72 patients with locally advanced MCC were retrospectively reviewed. Regional lymph nodes were addressed with observation, lymph node dissection (LND) alone, definitive nodal radiotherapy (DnRT), or LND plus adjuvant nodal radiotherapy (AnRT). Cox regression was used to compare treatment modalities in terms of regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS) and disease-specific survival (DSS). rLN-RT, including both DnRT and AnRT, improved RRFS (Hazard ratio (HR): 0.07, 95% confidence interval (CI): 0.01-0.40, p = 0.003), DRFS (HR: 0.28, CI: 0.11-0.76, p = 0.01), DFS (HR: 0.23, CI: 0.09-0.58, p = 0.002), and DSS (HR: 0.23, CI: 0.06-0.90, p = 0.03). AnRT improved DFS and DSS in high-risk subgroups (e.g., extranodal extension (ENE), ≥ 2 positive lymph nodes, or bulkier lymph nodes). The benefit of AnRT increased with higher disease burden. After controlling for these adverse factors, AnRT significantly improved RRFS (HR: 0.04, CI: 0.01-0.37, p = 0.004), DRFS (HR: 0.14, CI: 0.04-0.50, p = 0.003), DFS (HR: 0.09, CI: 0.02-0.33, p < 0.001), and DSS (HR: 0.21, CI: 0.05-0.89, p = 0.03). rLN-RT, including both DnRT and AnRT, reduces relapse and death from MCC in patients with node-positive disease. AnRT is particularly beneficial for patients with ENE, multiple involved lymph nodes, or larger nodal foci of disease. These results argue for more liberal use of nodal RT for MCC patients who present with node-positive disease.


Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice.
A high incidence of recurrence after treatment is the most serious problem in hepatocellular carcinoma (HCC). Therefore, a new strategy for the treatment of the disease is needed. The aim of the present study was to investigate whether vitamin D binding protein-macrophage activating factor (DBP-maf) is able to inhibit the growth of HCC. The effects of DBP-maf on endothelial cells and macrophage were evaluated by WST-1 assay and phagocytosis assay, respectively. Human HCC cells (HepG2) were implanted into the dorsum of severe combined immunodeficiency (SCID) mice. These mice were divided into control and DBP-maf treatment groups (n = 10/group). The mice in the treatment group received 40 ng/kg/d of DBP-maf for 21 d. DBP-maf showed anti-proliferative activity against endothelial cells and also activated phagocytosis by macrophages. DBP-maf inhibited the growth of HCC cells (treatment group: 126 ± 18mm(3), untreated group: 1691.5 ± 546.9mm(3), P = 0.0077). Histologic examinations of the tumors revealed the microvessel density was reduced and more macrophage infiltration was demonstrated in the tumor of mice in the treatment group. DBP-maf has at least two novel functions, namely, an anti-angiogenic activity and tumor killing activity through the activation of macrophages. DBP-maf may therefore represent a new strategy for the treatment of HCC.


Episodic Migraine and Older Adults.
Migraine is and continues to be a significant medical issue in older adults. Migraine can have different characteristics in older adults and specific diagnostic and treatment considerations need to be applied when managing headache and migraine in this population, which is increasing in both size and diversity. Contrary to widely held beliefs, migraine may not improve in older women following menopause and can have new onset in older age. The purpose of this review is to give an update on the diagnosis and treatment of episodic migraine in older adults. As the population ages, migraine in older adults will become a more significant public health issue. Migraine in older adults can present with different clinical symptoms than in a younger population and is primarily a diagnosis of exclusion in older adults. Migraine treatment considerations for older adults should include comorbidities and medication interactions. Recent findings suggest there are medications that should be avoided when treating seniors with migraine. The purpose of this review is to give an update on the most important aspects regarding the diagnosis and treatment of headache and migraine in older adults. In addition, recommendations will be made concerning medications that need careful consideration when prescribing to seniors.