Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding.
MicroRNAs (miRNAs) play key roles in gene regulation, but reliable bioinformatic or experimental identification of their targets remains difficult. To provide an unbiased view of human miRNA targets, we developed a technique for ligation and sequencing of miRNA-target RNA duplexes associated with human AGO1. Here, we report data sets of more than 18,000 high-confidence miRNA-mRNA interactions. The binding of most miRNAs includes the 5' seed region, but around 60% of seed interactions are noncanonical, containing bulged or mismatched nucleotides. Moreover, seed interactions are generally accompanied by specific, nonseed base pairing. 18% of miRNA-mRNA interactions involve the miRNA 3' end, with little evidence for 5' contacts, and some of these were functionally validated. Analyses of miRNA:mRNA base pairing showed that miRNA species systematically differ in their target RNA interactions, and strongly overrepresented motifs were found in the interaction sites of several miRNAs. We speculate that these affect the response of RISC to miRNA-target binding.


Renin Angiotensin System Blocker Fetopathy: A Midwest Pediatric Nephrology Consortium Report.
Fetuses continue to be exposed to renin angiotensin system (RAS) blockers despite their known teratogenicity and a black box warning. We hypothesized that fetopathy from in utero exposure to RAS blockers has a broader spectrum of clinical manifestations than described previously and that there are a variety of clinical scenarios leading to such exposures. This was a retrospective study performed through the Midwest Pediatric Nephrology Consortium. Cases of RAS blocker fetopathy were identified, with determination of renal and extrarenal manifestations, timing of exposure, and the explanation for the fetal exposure. Twenty-four cases were identified. RAS blocker exposure after the first trimester was associated with more severe renal manifestations. Chronic dialysis or kidney transplantation was required in 8 of 17 (47%) patients with RAS blocker exposure after the first trimester and 0 of 7 patients with exposure restricted to the first trimester (P = .05). Extrarenal manifestations, some not previously noted in the literature, included central nervous system anomalies (cystic encephalomalacia, cortical blindness, sensorineural hearing loss, arachnoid cysts) and pulmonary complications (pneumothorax, pneumomediastinum). RAS blocker exposure usually was secondary to absent or poor prenatal care or undiagnosed pregnancy. RAS blocker fetopathy continues to be a cause of considerable morbidity, with more severe renal manifestations associated with exposure after the first trimester. A variety of significant extrarenal manifestations occur in these patients. Clinicians should emphasize the risk of fetopathy when prescribing RAS blockers to women of childbearing age.


Show Your Work: Responsible Model Reporting in Health Care Artificial Intelligence.
Standardized and thorough model reporting is an integral component in the development and deployment of machine learning models in health care. Model reporting includes sharing multiple model performance metrics and incorporating metadata to provide the necessary context for model evaluation. Thorough model reporting addresses common concerns about artificial intelligence in health care including model explainability, transparency, fairness, and generalizability. All stages in the model development lifecycle, from initial design to data capture to model deployment, can be communicated openly to stakeholders with responsible model reporting. Physician involvement throughout these processes can ensure clinical concerns and potential consequences are considered.


Effect of prolonged hypoxia on food consumption, respiration, growth and reproduction in marine scavenging gastropod Nassarius festivus.
The effects of prolonged exposure to reduced oxygen levels (3.0 and 1.5 mg O(2)l(-1)) on marine scavenging gastropods Nassarius festivus were studied for 8 weeks. The percentages of individuals engaged in feeding and amount of food consumed were reduced as oxygen level decreased; absorption efficiency, however, did not vary significantly with oxygen level. Oxygen consumption rates and specific oxygen consumption rates were lower at reduced oxygen levels. Reproduction occurred at all oxygen levels with less egg capsules being produced at lower oxygen levels. Egg size and number of eggs per capsule, however, were not significantly affected by oxygen level. The increase in shell length was 12%, 6% and 5% at 6.0 mgO(2)l(-1) (normoxia), 3.0 mgO(2)l(-1) and 1.5 mgO(2)l(-1), respectively. At the end of the experiment, the amount of energy allocated to growth and reproduction decreased at reduced oxygen levels with values obtained at 3.0 mgO(2)l(-1) and 1.5 mgO(2)l(-1) being 48% and 70% lower than those at 6.0 mgO(2)l(-1). At all oxygen levels, most of the accumulated energy was allocated to shell growth and reproduction, and the amount allocated to somatic growth was relatively insignificant. The reduction in energy allocated to reproduction was greater than that to shell growth as the oxygen level was reduced, indicating a strategic energy allocation of marine scavengers under stressful conditions to enhance survival.


Development of a heterogeneous catalytic cracking reactor utilizing online mass spectrometry analysis.
A laboratory system has been designed, constructed, and validated that reduces the complexity, time required, and data variability associated with catalytic microreactors that require post reaction steps prior to product analysis. In this work, a Varian (Walnut Creek, CA, USA) 3600 GC (gas chromatography) system coupled with a Saturn quadrupole ion trap mass spectrometer was used to perform mass spectral analysis in real-time catalytic cracking reactions. As this was an integrated reactor/analyzer, the GC column was exposed to temperatures beyond the degradation point of the column, and so selective ion storage RF waveform was used to remove the siloxane masses from the spectra. This produced lower detection limits and full scan data for identification. Mass/charge segmentation of the mass spectrometer allowed the complete product identification for electron impact spectra. Hexane was reacted over H-ZSM-5 catalyst for instrument validation. This produced a series of alkanes, alkenes, and aromatics with distributions consistent with that reported for the cracking of hexane.


Effects and mechanism of moderate aerobic exercise on impaired fasting glucose improvement.
Exercise is beneficial for blood glucose metabolism. However, whether moderate aerobic exercise could improve impaired fasting glucose is unknown. And the mechanism is also needed to investigate. A cross-sectional research was performed and 120 participants with impaired fasting glucose (IFG) were randomly assigned into active and controlled groups. Briefly, participants in active group were required to take moderate aerobic exercise at least 30 min for five times per week, whereas in controlled group, participants were also advised to take exercise but not mandatorily required the same degree as that of active group. At baseline and 3 month's follow-up, laboratory and demographic variables were compared. At baseline, no significant between-group differences were observed. Generally, leukocyte ROCK2 activity in the active and controlled groups were 58.7 ± 6.0 mg/mL and 60.2 ± 7.3 mg/mL, and daily average exercise time at baseline in both groups was extremely little, with 5.2 ± 3.8 min and 5.9 ± 3.5 min, respectively. After 3 months' follow-up, 52 and 56 participants in the active and controlled groups completed the whole program. Compared to baseline, leukocyte ROCK2 activity and daily average exercise time were improved in both groups. Nonetheless, compared to the controlled group, leukocyte ROCK2 activity was reduced more profoundly and the daily average exercise time was longer in the active group (37.5 ± 6.3 min versus 18.3 ± 7.2 min, p < 0.05). Moreover, the percentage of IFG in the active group was decreased more prominently than the controlled group (76.9% versus 82.1%, p < 0.05). Multivariate regression analyses revealed that exercise time and leukocyte ROCK2 activity was significantly associated with IFG, with OR of 0.836 (active group versus controlled group, 95% CI 0.825-0.852, p < 0.05) in exercise time, and 1.043 (controlled group versus active group, 95% CI 1.021-1.069, p < 0.05) in leukocyte ROCK2 activity. In addition, exercise time was significantly associated with leukocyte ROCK2 activity, with OR of 0.822 (active group versus controlled group, 95% CI 0.818-0.843, p < 0.05). In subjects with IFG, increased daily average exercise time is beneficial for improving fasting blood glucose metabolism, and the mechanism may be associated with its effects on attenuating leukocyte ROCK2 activity.


Hospital admissions for dental treatment among children with cleft lip and/or palate born between 1997 and 2003: an analysis of Hospital Episode Statistics in England.
Children with clefts have an increased tendency for dental anomalies and caries. To determine the pattern of hospital admissions for dental treatment during primary dentition among children with clefts. Cohort study based on Hospital Episode Statistics, an administrative database of all admissions to National Health Service hospitals in England. Patients born alive between 1997 and 2003 who had both a cleft diagnosis and cleft repair were included. The number of hospital admissions for surgical removal of teeth, simple extraction of teeth, and restoration of teeth before the age of seven was examined. Eight hundred and fifty-eight hospital admissions for dental treatment among 6551 children (<7 year) with a cleft were identified. 66.4% of admissions were primarily for caries and 95.6% involved extractions. 11.4% of children had at least one admission for dental treatment. The presence of additional anomalies, having a more severe cleft type, and living in relatively deprived areas increased the risk of hospital admission. Factors increasing the risk of hospital admission among cleft children should be taken into account when planning services. Efforts to reduce the number of hospital admissions should be focused on disease prevention, particularly among those most at risk of caries.


Use of cyclosporine A and tacrolimus in treatment of vernal keratoconjunctivitis.
Vernal keratoconjunctivitis is a sight-threatening inflammatory disease of conjunctiva and cornea. It is frequently observed in young children with the onset usually occurring in the first decade of life. Mild cases of VKC tend to remit with nonspecific and supportive therapy. In contrast, severe cases are usually more protracted with remission/relapse occurring for a prolonged period of time. Although VKC is classified as an allergic eye condition, the role of allergens as an inciting factor is not clear. Pathogenesis of VKC involves roles for IgE, cytokines, chemokines, and inflammatory cells (T and B lymphocytes, mast cells, basophils, neutrophils, and eosinophils) with the release of their granular proteins, proliferation of fibroblasts, and laying down exuberant amounts of collagen fibers in the conjunctival tissue. In severe VKC cases-often of tarsal VKC-diagnostic giant papilla are classically observed on the upper tarsal plate, giving the classic 'cobble-stone' appearance. Corneal ulcer can occur from the effect of eosinophilic granular proteins on corneal epithelium and by physical trauma by intense eye rubbing. Topical corticosteroids, often required for controlling symptoms and signs in severe VKC, can lead to serious ocular complications. Immunomodulators that have been investigated for VKC treatment include topical ocular preparations of cyclosporine A and tacrolimus. Severe VKC responds promptly to topical cyclosporine A and tacrolimus, mostly within 1 month of therapy. Prolonged use of cyclosporine A and tacrolimus in VKC is safe and is tolerated by most patients without significant side effects. Recent investigations on the use of these two agents in VKC are the main purpose of this review. The use of cyclosporine A and tacrolimus are a major breakthrough in treatment for severe VKC, a debilitating allergic eye disease in children.


Hyaluronic acid/inulin-based nanocrystals with an optimized ratio of indigo and indirubin for combined ulcerative colitis therapy via immune and intestinal flora regulation.
Indigo (IND) and indirubin (INB) have demonstrated a synergistic effect in treating ulcerative colitis at a ratio of 7.5:1. However, the colon mucus layer, a critical physiological barrier against external threats, is also a biological barrier, limiting the potential for effective drug delivery to the lamina propria for regulating inflammatory cells. Inspired by the potential of Hyaluronic acid (HA), to enhance cellular uptake by inflammatory cells, and Pluronic® F127 (F127), known for overcoming the mucus barrier, this study innovatively developed INB/IND nanosuspensions by co-modifying with F127 and HA. Moreover, inulin serves a dual purpose as a spray protective agent and a regulator of intestinal flora. Therefore, it was incorporated into INB/IND nanosuspensions for subsequent spray drying, resulting in the preparation of INB/IND nanocrystals (INB/IND-NC). The mucus penetration of INB/IND-NC was 24.30 times that of the control group. Besides, INB/IND-NC exhibited enhanced cellular uptake properties proximately twice that of Raw INB/IND. Importantly, INB/IND-NC exhibited improved therapeutic efficacy in DSS-induced mice by regulating the expression of cytokines, regulating immune responses via downregulating the expression of macrophages, neutrophils, and dendritic cells and maintaining intestinal flora homeostasis. Our study provides a new perspective for applying natural products for treating inflammatory diseases.


Aldosterone-mediated Na+ transport in renal epithelia: time-course of induction of a potential regulatory component of the conductive Na+ channel.
To correlate synthesis of aldosterone-induced proteins (AIPs) with the hormone's effect on transepithelial Na+ transport, protein synthesis in two model renal epithelia was examined during the natriferic response to aldosterone. Newly synthesized epithelial cell proteins were pulse-labelled with [35S]-methionine, separated by 2D-PAGE and detected by autoradiography. In both toad urinary bladder and A6 cells, a constellation of polypeptides which are a component of the renal epithelial conductive Na+ channel first appeared prior to, or concordant with, the increase in Na+ transport. The early synthesis of these proteins taken together with the fact that they appear to be the only aldosterone induced component of the multimeric Na+ channel, is compatible with the hypothesis that they are responsible for regulating Na+ channel activity during aldosterone-stimulated epithelial Na+ transport.


Ganglioside analysis by thin-layer chromatography matrix-assisted laser desorption/ionization orthogonal time-of-flight mass spectrometry.
Metastable decomposition of ions generated in matrix-assisted laser desorption/ionization (MALDI) mass spectrometers complicates analysis of biological samples that have labile bonds. Recently, several academic laboratories and manufacturers of commercial instruments have designed instruments that introduce a cooling gas into the ion source during the MALDI event and have shown that the resulting vibrational cooling stabilizes these labile bonds. In this study, we compared stabilization and detection of desorbed gangliosides on a commercial orthogonal time-of-flight (oTOF) instrument with results we reported previously that had been obtained on a home-built Fourier transform mass spectrometer. Decoupling of the desorption/ionization from the detection steps resulted in an opportunity for desorbing thin-layer chromatography (TLC)-separated gangliosides directly from a TLC plate without compromising mass spectral accuracy and resolution of the ganglioside analysis, thus coupling TLC and oTOF mass spectrometry. The application of a declustering potential allowed control of the matrix cluster and matrix adduct formation, and, thus, enhanced the detection of the gangliosides.


Rapid Near Point-of-Care Assay for HLA-B*57:01 Genotype Associated with Severe Hypersensitivity Reaction to Abacavir.
The nucleoside reverse transcriptase inhibitor abacavir (ABC) is used commonly to treat young children with HIV infection and is a component of the fixed-dose-combination Triumeq®. ABC can trigger a severe hypersensitivity reaction in people who are homozygous or heterozygous for HLA-B*57:01. Testing for HLA-B*57:01 before ABC initiation is standard-of-care in high-resource settings, but current tests are costly or difficult to access in resource-limited settings. To address these gaps, we developed an inexpensive simple-to-use rapid assay to detect HLA-B*57:01. We designed and optimized a multiplexed polymerase chain reaction (PCR) to amplify HLA-B*57 subtypes and the human beta-globin gene; employed probes and ligation to specifically tag the HLA-B*57:01 allele with biotin. Tagged-ligated products were detected by immunocapture in an enzyme-linked immunosorbent assay plate or lateral flow strip. Cell lines with known HLA genotypes were used to optimize the assay. The optimized assay was then compared with genotypes of clinical specimens (n = 60) determined by sequencing, with specimens enriched for individuals with HLA-B*57:01. The optimized assay utilizes 40-min 35-cycle multiplex PCR for B*57 and beta-globin; 20-min ligation reaction; and 15-min detection. Evaluation of the HLA-B*57:01 oligonucleotide ligation assay using clinical specimens had a sensitivity of 100% (n = 27/27 typed as B*57:01) and specificity of 100% (n = 33/33 typed as non-B*57:01) by visual interpretation of lateral flow strips. The cost is US$5.96/specimen. This rapid and economical assay accurately detects HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping and facilitate safe same-day initiation of ABC-based treatment.


Hydroxylation of R(+)- and S(-)-omeprazole after racemic dosing are different among the CYP2C19 genotypes.
To elucidate the stereoselective pharmacokinetics of omeprazole enantiomers and their metabolites after racemic IV dosing because there is little information about the stereoselective metabolism of omeprazole in in vivo study. Seventeen subjects were classified into three CYP2C19 groups based on their genotypes: homozygous extensive metabolizers (hmEMs; n = 5), heterozygous EMs (htEMs; n = 7) and poor metabolizers (PMs; n = 5). After single IV administration of racemic omeprazole (20 mg), the mean area under the plasma concentration-time curve (AUC(0-∞)) of R(+)-omeprazole in PMs was significantly higher than that in hmEMs and htEMs, while that of S(-)-omeprazole was no significance among three genotypes because of a wide inter-individual variability. In addition, although the AUC(0-∞) of R(+)-5-hydroxyomeprazole were determined among three genotypes, the that of S(-)-5-hydroxyomeprazole was undetectable in the hmEMs and barely detectable in the htEMs. Conversly, the AUC(0-∞) of S(-)-5-hydroxyomeprazole was greater than that of R(+)-5-hydroxyomeprazole in the PMs. These data therefore suggest that, for EMs, the CYP2C19-mediated formation from R(+)-enantiomer is a 5-hydroxy-metabolite, while that from S(-)-enantiomer may be a minor metabolite. Thus, the in vivo disposition of S(-)- and R(+)-omeprazole after racemic dosing may be different among the CYP2C19 genotypes.


Impact of Large Granular Lymphocyte Leukemia on Blood DNA Methylation and Epigenetic Clock Modeling in Fischer 344 Rats.
Age-dependent differences in methylation at specific cytosine-guanine (CpG) sites have been used in "epigenetic clock" formulas to predict age. Deviations of epigenetic age from chronological age are informative of health status and are associated with adverse health outcomes, including mortality. In most cases, epigenetic clocks are performed on methylation from DNA extracted from circulating blood cells. However, the effect of neoplastic cells in the circulation on estimation and interpretation of epigenetic clocks is not well understood. Here, we explored this using Fischer 344 (F344) rats, a strain that often develops large granular lymphocyte leukemia (LGLL). We found clear histological markers of LGLL pathology in the spleens and livers of 27 out of 61 rats aged 17-27 months. We assessed DNA methylation by reduced representation bisulfite sequencing with coverage of 3 million cytosine residues. Although LGLL broadly increased DNA methylation variability, it did not change epigenetic aging. Despite this, the inclusion of rats with LGLL in clock training sets significantly altered predictor selection probability at 83 of 121 commonly utilized CpG sites. Furthermore, models trained on rat samples that included individuals with LGLL had greater absolute age error than those trained exclusively rats free of LGLL (39% increase; p < .0001). We conclude that the epigenetic signals for aging and LGLL are distinct, such that LGLL assessment is not necessary for valid measures of epigenetic age in F344 rats. The precision and architecture of constructed epigenetic clock formulas, however, can be influenced by the presence of neoplastic hematopoietic cells in training set populations.


HDAC3 inhibitor (BRD3308) modulates microglial pyroptosis and neuroinflammation through PPARγ/NLRP3/GSDMD to improve neurological function after intraventricular hemorrhage in mice.
Neuroinflammation plays a vital role in intraventricular hemorrhage (IVH). Excessive neuroinflammation after IVH can activate the inflammasome in the cell and accelerate the occurrence of pyroptosis in cells, produce more inflammatory mediators, increase cell death, and lead to neurological deficits. Previous studies have reported that BRD3308 (BRD), an inhibitor of histone deacetylation by histone deacetylase 3 (HDAC3), suppresses inflammation-induced apoptosis and exhibits anti-inflammatory properties. However, it is unclear how BRD reduces the occurrence of the inflammatory cascade. In this study, we stereotactically punctured the ventricles of male C57BL/6J mice and injected autologous blood via the tail vein to simulate ventricular hemorrhage. Magnetic resonance imaging was used to detect ventricular hemorrhage and enlargement. Our findings demonstrated that BRD treatment significantly improved neurobehavioral performance and decreased neuronal loss, microglial activation, and pyroptosis in the hippocampus after IVH. At the molecular level, this treatment upregulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited NLRP3-mediated pyroptosis and inflammatory cytokines. Therefore, we concluded that BRD reduced pyroptosis and neuroinflammation and improve nerve function in part by activating the PPARγ/NLRP3/GSDMD signaling pathway. Our findings suggest a potential preventive role for BRD in IVH.


Are you surgically current? Lessons from aviation for returning to non-urgent surgery following COVID-19.
The COVID-19 crisis has caused many issues across healthcare. In surgery, many operations have been cancelled with some surgeons losing their regular operating lists. During this time, technical expertise and decision making can deteriorate. In aviation after a prolonged period of absence from flying, this deficit in keeping skills and thinking up to date is known as being "out of currency" or "not current". Although aviation and healthcare cannot be compared, numerous human factors concepts are applicable to both. In this article, we explore the likely impact of potentially prolonged absences in operating on surgical skills and psyche, and introduce the concept of a Surgical Skills Currency Barometer. We also discuss a "task-o-meter" thought experiment, and suggest practices which could be adopted to help protect surgeon workload from exceeding surgical capability when returning to operating following a period of prolonged absence.


Models for predicting BRCA1 and BRCA2 mutations in Han Chinese familial breast and/or ovarian cancer patients.
Our aim was to find an appropriate method to estimate the likelihood that a family history of cancer was a result of a mutation in the BRCA1 or BRCA2 genes. We also compared the performance of the established method with three different methods (Couch, Sh-E and BRCApro) to identify an alternative strategy for genetic council targeted to the specified population. The family history as well as individual information of two hundred unrelated probands who had completed BRCA1 and BRCA2 mutation screening was analyzed to assess the likelihood of a pathogenic mutation. A model was developed by empirical method. The performance of this model was validated in a separate patient cohort compared with BRCApro. Several factors were associated with mutations in univariate analysis and a logistic model was devised to estimate the probability for a proband of harboring a mutation in BRCA1 and/or BRCA2. Using a greater than 10% probability threshold, the highest accuracy was achieved by the established model when compared to other three models, presenting the highest sensitivity, PPV, NPV and area under ROC curve. The empirical model showed a better ROC curve compared to BRCApro in the verification cohort. A probability model targeted to Han Chinese population should be a useful tool in the genetic counseling for the specified ethnic. Its ability to predict BRCA2 mutation carriers needs to be improved.


Exploring the mechanism of Buxue Yimu Pill on hemorrhagic anemia through molecular docking, network pharmacology and experimental validation.
Buxue Yimu Pill (BYP) is a classic gynecological medicine in China, which is composed of Angelica sinensis (Oliv.) Diels, Leonurus japonicus Houtt, Astragalus membranaceus (Fisch.) Bunge, Colla corii asini and Citrus reticulata Blanco. It has been widely used in clinical therapy with the function of enriching Blood, nourishing Qi, and removing blood stasis. The current study was designed to determine the bioactive molecules and therapeutic mechanism of BYP against hemorrhagic anemia. Herein, GC-MS and UPLC/Q-TOF-MS/MS were employed to identify the chemical compounds from BYP. The genecards database (https: //www.genecards.org/) was used to obtain the potential target proteins related to hemorrhagic anemia. Autodock/Vina was adopted to evaluate the binding ability of protein receptors and chemical ligands. Gene ontology and KEGG pathway enrichment analysis were conducted using the ClusterProfiler. As a result, a total of 62 candidate molecules were identified and 152 targets related to hemorrhagic anemia were obtained. Furthermore, 34 active molecules and 140 targets were obtained through the virtual screening experiment. The data of molecular-target (M-T), target-pathway (T-P), and molecular-target-pathway (M-T-P) network suggested that 32 active molecules enhanced hematopoiesis and activated the immune system by regulating 57 important targets. Pharmacological experiments showed that BYP significantly increased the counts of RBC, HGB, and HCT, and significantly down-regulated the expression of EPO, IL-6, CSF3, NOS2, VEGFA, PDGFRB, and TGFB1. The results also showed that leonurine, leonuriside B, leosibiricin, ononin, rutin, astragaloside I, riligustilide and levistolide A, were the active molecules closely related to enriching Blood. In conclusion, based on molecular docking, network pharmacology and validation experiment results, the enriching blood effect of BYP on hemorrhagic anemia may be associated with hematopoiesis, anti-inflammation, and immunity enhancement.


Unchained melody: revisiting the estimation of SF-6D values.
In the original SF-6D valuation study, the analytical design inherited conventions that detrimentally affected its ability to predict values on a quality-adjusted life year (QALY) scale. Our objective is to estimate UK values for SF-6D states using the original data and multi-attribute utility (MAU) regression after addressing its limitations and to compare the revised SF-6D and EQ-5D value predictions. Using the unaltered data (611 respondents, 3503 SG responses), the parameters of the original MAU model were re-estimated under three alternative error specifications, known as the instant, episodic, and angular random utility models. Value predictions on a QALY scale were compared to EQ-5D3L predictions using the 1996 Health Survey for England. Contrary to the original results, the revised SF-6D value predictions range below 0 QALYs (i.e., worse than death) and agree largely with EQ-5D predictions after adjusting for scale. Although a QALY is defined as a year in optimal health, the SF-6D sets a higher standard for optimal health than the EQ-5D-3L; therefore, it has larger units on a QALY scale by construction (20.9 % more). Much of the debate in health valuation has focused on differences between preference elicitation tasks, sampling, and instruments. After correcting errant econometric practices and adjusting for differences in QALY scale between the EQ-5D and SF-6D values, the revised predictions demonstrate convergent validity, making them more suitable for UK economic evaluations compared to original estimates.


Immunolocalization of 7-2-ribonucleoprotein in the granular component of the nucleolus.
Certain autoimmune sera contain antibodies against a nucleolar ribonucleoprotein particle associated with 7-2-RNA (R. Reddy et al. (1983) J. Biol. Chem. 258, 1383; C. Hashimoto and J. A. Steitz (1983) J. Biol. Chem. 258, 1379). In this study, we showed by immunofluorescence microscopy that antibodies reactive with 7-2-ribonucleoprotein immunolocalized in the granular regions of actinomycin D and 5,6-dichloro-1-beta-D-ribofurano-sylbenzimidazole (DRB)--segregated nucleoli from Vero cells. By electron microscopic immunocytochemistry, antigen-antibody complexes were located in the granular component of transcriptionally active nucleoli from rat liver hepatocytes and HeLa cells. Anti-7-2-RNP antibodies from two autoimmune sera immunoprecipitated a major protein of Mr 40,000 from [35S] methionine--labeled HeLa cell extract. The immunolocalization data suggest that 7-2-ribonucleoprotein may be involved in stages of ribosome biogenesis which take place in the granular component of the nucleolus, i.e., assembly, maturation, and/or transport of preribosomes.


Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: correlation with clinical features.
The growth and metastasis of tumors depend on the development of an adequate blood supply via angiogenesis. Recent studies indicate that the inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF) and the tumor suppressor p53 are fundamental play-markers of the angiogenic process. Overexpression of iNOS and VEGF has been shown to induce angiogenesis in tumors. P53 suppresses angiogenesis by down-regulating VEGF and iNOS. The correlation of expression of p53, VEGF and iNOS and clinical features in gastric carcinogenesis, however, has not been well characterized. The expression of p53, iNOS and VEGF in gastric precancerous and cancerous lesions and its relation with the clinical features was determined with immunohistochemistry (avidin-biotin-peroxidase complex method) on 55 randomly selected GC patients and 60 symptom-free subjects from the mass survey in the high-incidence area for GC in Henan, northern China. The positive immunostaining rates for p53, iNOS and VEGF in gastric carcinomas were 51%, 44% and 51%, respectively, and correlated well with TNM stages, but did not show significant difference among the groups with different degrees of gastric wall invasion depth by GC. A positive immunostaining reaction for the iNOS protein was significantly correlated with lymph node metastasis (p = 0.019; Spearman correlation coefficient). P53 protein accumulation was higher in the poorly-differentiated gastric carcinoma than in well-differentiated one. In gastric biopsies, no positive immunostaining was observed for p53, iNOS and VEGF in the histologically normal tissue and chronic superficial gastritis (CSG). However, p53, iNOS and VEGF positive immunostaining was observed in the tissues with different severities of lesions of chronic atrophic gastritis (CAG), intestinal metaplasia (IM) and dysplasia (DYS), and the positive rates increased with the lesion progression from CAG to IM to DYS. A high coincidental positive and negative immunostaining rate for p53, iNOS and VEGF was observed both in biopsy samples with CAG, IM and DYS from the symptom-free subjects and in gastric cancer tissue from the GC patients. The present results indicated that p53 protein accumulation and increased expression of iNOS and VEGF might be responsible for gastric carcinogenesis and tumor aggressiveness of gastric cancer.


Midcarpal Instability: A Historical and Etymological Review.
Although midcarpal instability was first described almost 45 years ago, this uncommon condition is still poorly understood by most clinicians today. Adding to the confusion, it is known by 2 different names: midcarpal instability and carpal instability nondissociative. In this article, we describe the history of the recognition of instability of the midcarpal joint, including its pathomechanics, classification, and treatment. We hope that a more complete understanding of the etymology and kinematics of the disorder will facilitate its future recognition and assist in appropriate treatment decision making.


Origin of sex.
The competitive advantage of sex consists in being able to use redundancy to recover lost genetic information while minimizing the cost of redundancy. We show that the major selective forces acting early in evolution lead to RNA protocells in which each protocell contains one genome, since this maximizes the growth rate. However, damages to the RNA which block replication and failure of segregation make it advantageous to fuse periodically with another protocell to restore reproductive ability. This early, simple form of genetic recovery is similar to that occurring in extant segmented single stranded RNA viruses. As duplex DNA became the predominant form of the genetic material, the mechanism of genetic recovery evolved into the more complex process of recombinational repair, found today in a range of species. We thus conclude that sexual reproduction arose early in the evolution of life and has had a continuous evolutionary history. We cite reasons to reject arguments for gaps in the evolutionary sequence of sexual reproduction based on the presumed absence of sex in the cyanobacteria. Concerning the maintenance of the sexual cycle among current organisms, we take care to distinguish between the recombinational and outbreeding aspects of the sexual cycle. We argue that recombination, whether it be in outbreeding organisms, self-fertilizing organisms or automictic parthenogens, is maintained by the advantages of recombinational repair. We also discuss the role of DNA repair in maintaining the outbreeding aspects of the sexual cycle.


Observations on the source of pregnancy-associated plasma protein A (PAPP-A).
Pregnancy-associated plasma protein A (PAPP-A) was measured in 26 women before and after hysterectomy. The PAPP-A concentration declined significantly in 24 of them. It is concluded that the uterus is a source of the protein.


Coinheritance of hemoglobin D-Punjab and β0-thalassemia 3.4 kb deletion in a Thai girl.
Hemoglobin (Hb) D. Punjab [β121(GH4) Glu→Gln; HBB: C.364G>C] and β0-thalassemia 3.4 kb deletion are very rare in the Thai population. For the first time, the coinheritance of HbD-Punjab with β0-thalassemia 3.4 kb deletion was reported in a 7-year-old Thai girl. She had mild anemia (Hb 115.0 g/L and mean corpuscular hemoglobin 18.1 pg) with red blood cell microcytosis (mean corpuscular volume 52.5 fL). By capillary electrophoresis (CE), HbD-Punjab was found at a migration position of 180 s with the value of 81.9% while the level of HbA2 was 7.3%. Based on the elevated HbA2, the molecular analysis for detection of β0-thalassemia mutations was performed. The 490 bp amplified fragments from β0-thalassemia 3.4 kb deletion was observed. Thus, the coinheritance of HbD-Punjab with β0-thalassemia can be found in the Thai population. The HbA2 measured on CE is a reliable parameter for differentiating the homozygote of HbD-Punjab and compound heterozygote of HbD-Punjab and β0-thalassemia.


Theoretical aspects of virus capsid assembly.
A virus capsid is constructed from many copies of the same protein(s). Molecular recognition is central to capsid assembly. The capsid protein must polymerize in order to create a three-dimensional protein polymer. More than structure is required to understand this self-assembly reaction: one must understand how the pieces come together in solution.


External fixation greatly improves outcomes in the surgical treatment of osteoradionecrosis of the jaws without affecting quality of life: a five-year retrospective study.
Osteoradionecrosis of the jaw can be treated using both conservative treatment and surgery. External fixation may be used to bridge large resection defects after sequestrectomy for stabilisation and before secondary mandibular reconstruction. We designed a retrospective analysis of 70 patients with osteoradionecrosis treated between the years 2014 and 2018, and found that the use of external fixation greatly improves their outcomes. Patients were grouped according to Notani's classification: those who had Notani I disease were treated surgically but without external fixation; and those with Notani II and Notani III disease were eligible for external fixation. In those with Notani II disease, there was a significant reduction in the number of pathological fractures that occurred with external fixation. In those with Notani III disease, the success rate of primary sequestrectomy was only 1:14; however, those treated with external fixation all successfully healed after their first operation. It was hypothesised that although external fixation would improve outcome, it would come at a detriment to their quality of life (QoL). However, in a subset of these patients, we showed that in addition to increasing successful healing, patients' QoL with the external fixator was no worse than when they had an active osteonecrotic lesion. The treatment of osteoradionecrosis is cumbersome and advanced stages are associated with more complications. The use of an external fixator significantly reduces the probability of pathological fractures and increases the rate of successful healing in patients after mandibular resection. It does this without greatly interfering with patients' lives, while improving their condition sufficiently to allow for subsequent mandibular reconstruction.


Cryo-electron tomography for the structural study of mitochondrial translation.
Cryo-electron tomography (cryo-ET) enables the three-dimensional (3D) structural characterization of macromolecular complexes in their physiological environment. Thus, cryo-ET is uniquely suited to study the structural basis of biomolecular processes that are extremely difficult or even impossible to reconstitute using purified components. Translation of mitochondrial genes, which occurs in the secluded interior of mitochondria, falls into this category. Here, we describe the principles of cryo-ET in the context of mitochondrial translation and outline recent developments and challenges of the method. The 3D image of a frozen-hydrated biological sample is computed from its 2D projections, which are acquired using a transmission electron microscope. In conjunction with automated detection of different copies of the molecule of interest and averaging of the corresponding subtomograms, cryo-ET enables macromolecular structure determination in the native environment (i.e. in situ) at sub-nanometer resolution. The preservation of the native environment furthermore allows the extraction of contextual information about the molecules, including the location of specific molecules with respect to membranes, their relative positioning and the spatial organization with respect to other types of macromolecules. Recent preparative developments extend the field of application of cryo-ET from isolated organelles to cultured eukaryotic cells and even tissue, making the traditional borders between molecular and cellular structural biology disappear.


Time course study of the changes in blood glutathione induced by acute ethanol intoxication in the rat.
Acute ethanol treatment of rats (5 g/kg) has a biphasic effect on the glutathione content of the erythrocyte. After 3 h of intoxication there is a diminution in total GSH equivalents, followed by a recovery to basal values 6 h after treatment. The decrease of total GSH equivalents is mainly due to a diminution of the oxidized form of the tripeptide. Concomitantly a marked increase in the plasma level of glutathione was found at 3 h, followed by a diminution to values obtained at time zero.


A new approach for determining SARS-CoV-2 epitopes using machine learning-based in silico methods.
The emergence of machine learning-based in silico tools has enabled rapid and high-quality predictions in the biomedical field. In the COVID-19 pandemic, machine learning methods have been used in many topics such as predicting the death of patients, modeling the spread of infection, determining future effects, diagnosis with medical image analysis, and forecasting the vaccination rate. However, there is a gap in the literature regarding identifying epitopes that can be used in fast, useful, and effective vaccine design using machine learning methods and bioinformatics tools. Machine learning methods can give medical biotechnologists an advantage in designing a faster and more successful vaccine. The motivation of this study is to propose a successful hybrid machine learning method for SARS-CoV-2 epitope prediction and to identify nonallergen, nontoxic, antigen peptides that can be used in vaccine design from the predicted epitopes with bioinformatics tools. The identified epitopes will be effective not only in the design of the COVID-19 vaccine but also against viruses from the SARS family that may be encountered in the future. For this purpose, epitope prediction performances of random forest, support vector machine, logistic regression, bagging with decision tree, k-nearest neighbor and decision tree methods were examined. In the SARS-CoV and B-cell datasets used for education in the study, epitope estimation was performed again after the datasets were balanced with the synthetic minority oversampling technique (SMOTE) method since the epitope class samples were in the minority compared to the nonepitope class. The experimental results obtained were compared and the most successful predictions were obtained with the random forest (RF) method. The epitope prediction performance in balanced datasets was found to be higher than that in the original datasets (94.0% AUC and 94.4% PRC for the SMOTE-SARS-CoV dataset; 95.6% AUC and 95.3% PRC for the SMOTE-B-cell dataset). In this study, 252 peptides out of 20312 peptides were determined to be epitopes with the SMOTE-RF-SVM hybrid method proposed for SARS-CoV-2 epitope prediction. Determined epitopes were analyzed with AllerTOP 2.0, VaxiJen 2.0 and ToxinPred tools, and allergic, nonantigen, and toxic epitopes were eliminated. As a result, 11 possible nonallergic, high antigen and nontoxic epitope candidates were proposed that could be used in protein-based COVID-19 vaccine design ("VGGNYNY", "VNFNFNGLTG", "RQIAPGQTGKI", "QIAPGQTGKIA", "SYECDIPIGAGI", "STFKCYGVSPTKL", "GVVFLHVTYVPAQ", "KNHTSPDVDLGDI", "NHTSPDVDLGDIS", "AGAAAYYVGYLQPR", "KKSTNLVKNKCVNF"). It is predicted that the few epitopes determined by machine learning-based in silico methods will help biotechnologists design fast and accurate vaccines by reducing the number of trials in the laboratory environment.


Subcultured human endothelial cells can function independently as fully competent antigen-presenting cells.
Recent evidence has suggested that dendritic cells, epidermal Langerhan's cells and endothelial cells (EC) as well as macrophages, fulfill the requirements of antigen-presenting cells. Despite a variety of controls, one weakness in the evidence that these latter cell types can independently serve as antigen-presenting cells is that the cell preparations may contain small numbers of contaminating macrophages or other cell types. The experiments described in this paper are directed towards providing firm evidence that human EC are independently capable of presenting antigen to T cells. EC were isolated from human umbilical veins and maintained continuously by serial subculture for periods of up to 8 months. The subcultured EC displayed classic EC morphology and uniform immunofluorescent staining for Factor VIII-related antigen. The subcultured EC (tested to the 18th subculture) presented both particulate and soluble antigens to macrophage-depleted T cells with an efficiency equivalent to freshly isolated cells. Monoclonal antibodies to HLA-DR and HLA-DS determinants inhibited antigen presentation by either autologous macrophages or EC. In addition, antigen presentation by the subcultured EC was not affected by the macrophage-specific monoclonal antibody Mac-120, which inhibited antigen presentation by autologous macrophages in the same experiments. These results are consistent with human EC being able to independently function as fully competent antigen-presenting cells.


In Situ Monitoring of the Antibacterial Activity of a Copper-Silver Alloy Using Confocal Laser Scanning Microscopy and pH Microsensors.
The antibacterial efficacy of a copper-silver alloy coating under conditions resembling build up of dry surface bacterial biofilms is successfully demonstrated according to US EPA test methods with a ≥99.9% reduction of test organisms over a 24 h period. A tailor-made confocal imaging protocol is designed to visualize in situ the killing of bacterial biofilms at the copper-silver alloy surface and monitor the kinetics for 100 min. The copper-silver alloy coating eradicates a biofilm of Gram-positive bacteria within 5 min while a biofilm of Gram-negative bacteria are killed more slowly. In situ pH monitoring indicates a 2-log units increase at the interface between the metallic surface and bacterial biofilm; however, the viability of the bacteria is not directly affected by this raise (pH 8.0-9.5) when tested in buffer. The OH- production, as a result of the interaction between the electrochemically active surface and the bacterial biofilm under environmental conditions, is thus one aspect of the contact-mediated killing of the copper-silver alloy coating and not the direct cause of the observed antibacterial efficacy. The combination of oxidation of bacterial cells, release of copper ions, and local pH raise characterizes the antibacterial activity of the copper-silver alloy-coated dry surface.


Priorities to improve cancer caregiving: report of a caregiver stakeholder workshop.
Caregivers of people with cancer represent a large, overburdened, and under-recognized part of the cancer care workforce. Research efforts to address the unmet needs of these caregivers are expanding with studies focused on caregivers' skill sets, physical and psychological health, and integration into healthcare delivery. As this field of research continues to expand, integrating caregivers' input is vital to studies to ensure that research aligns with their experiences. This is a focus group study of 15 cancer caregivers conducted during a cancer caregiving workshop at the University of Pittsburgh in February 2020. During the workshop, caregivers reviewed, critiqued, and proposed priorities to support caregivers of adults with cancer. We used a multistage consensus building approach to identify priority areas of research and clinical practice to address caregivers' experiences and needs. We used descriptive content analysis to summarize caregivers' priorities. Caregiver-identified priorities included (1) training and information about cancer and treatment, (2) caregiver integration into the patient's healthcare delivery, (3) assistance with navigating the healthcare system, (4) focus on caregiver health and well-being, and (5) policy reform to address caregiver needs. We identified ways in which these priorities can inform cancer caregiving research and practice. These recommendations should be considered by researchers, clinicians, cancer center leadership, and policymakers interested in creating caregiver-focused research protocols, interventions, and support systems.


Preoperative antithrombin III activity predicts outcome after surgical repair of acute type A aortic dissection.
Acute Stanford type A aortic dissection is associated with substantial perioperative morbidity and mortality. A sepsis-like state may lead to antithrombin (AT) III consumption and deficiency. The impact of preoperative AT III activity on outcome in patients undergoing emergency surgery is yet unknown. We measured preoperative AT III activity in 99 consecutive patients undergoing emergency aortic surgery for Stanford type A aortic dissection during a 4-year period in a retrospective study. Cardiovascular co-morbidities, risk factors and surgical data were recorded and patients were followed for 30-day mortality, and occurrence of multiple organ failure (MOF). During the first 30 days, 15 patients (15%) died, and 8 patients (8%) had MOF. Median AT III levels (IQR) in 30-day non-survivors versus survivors were 64% (52-72) versus 90% (75-97) (p<0.001), and in patients with versus without MOF were 66% (52.3-77.3) versus 88% (72-96) (p=0.018), respectively. Adjusted odds ratios for 30-day mortality and MOF for AT III activity (per % increments) were 0.92 (p=0.007), and 0.96 (p=0.012), respectively, indicating a significant inverse relationship between AT III activity and outcome. There is a strong inverse association between preoperative AT III activity and adverse outcome in patients undergoing surgical repair of acute Stanford type A aortic dissection. Larger studies are necessary to determine a cut-off value for AT III and to assess whether patients with low AT III levels benefit targeted therapeutic interventions.


Chiropractic management of dominating one-sided pelvic girdle pain in pregnant women; a randomized controlled trial.
The aim of this study was to investigate the outcome of chiropractic management for a subgroup of pregnant women with dominating one-sided pelvic girdle pain (PGP). The study population was recruited from a prospective longitudinal cohort study of pregnant women. Women reporting pelvic pain (PP), and who were diagnosed with dominating one-sided PGP after a clinical examination, were invited to participate in the intervention study. Recruitment took place either at 18 weeks, or after an SMS-tracking up to week 29. The women were randomized into a treatment group or a control group. The treatment group received chiropractic treatment individualized to each woman with regards to treatment modality and number of treatments. The control group was asked to return to conventional primary health care. The primary outcome measure was new occurrence of full time and/or graded sick leave due to PP and/or low back pain. Secondary outcome measures were self-reported PP, physical disability and general health status. Proportion of women reporting new occurrence of sick leave were compared using Chi squared tests. Differences in secondary outcome measures were estimated using linear regression analyses. Fifty-Six women were recruited, and 28 of them were randomized into the treatment group, and 28 into the control group. There was no statistically significant difference in sick leave, PP, disability or general health status between the two groups during pregnancy or after delivery. The study did not demonstrate superiority of chiropractic management over conventional care for dominating one-sided PGP during pregnancy. However, the analyses revealed wide confidence intervals containing both positive and negative clinically relevant effects. The study was registered in ClinicalTrials.gov ( NCT01098136 ; 22/03/2010).


MARCH1 promotes the growth and maintaining of stem cell-like characteristics of gastric cancer cells by activating the Wnt/β-catenin signaling pathway.
Gastric carcinoma (GC) is a malignant tumor, which is an important cause of death in all tumor deaths. The role of MARCH1 in GC has not been studied, this study aims to investigate the function of MARCH1 in GC. The expression of MARCH1 in normal tissue and tumor tissue was analyzed by TCGA-based GEPIA platform and UALCAL website and verified by RT-qPCR, Western blotting (WB), and Immunohistochemistry (IHC); CCK8 assay and crystal violet assay were separately used to detect cell viability and cell cloning ability. Cell spheroidization assay and Fluorescence-activated cell sorting (FACS) were performed to determine CD44+, CD133+ cell numbers to study the stemness characteristics of GC cells. While, WB was used to study the specific signaling pathway regulated by MARCH1. Animal model of GC was established to study the regulation of MARCH1 on GC growth in vivo. It showed that the expression of MARCH1 in GC tissues was higher than that in normal tissues; CCK8 and crystal violet assay showed that MARCH1 could promote cell viability and cloning ability of GC cells; cell spheroidization experiments and FACS showed that MARCH1 promoted the cloning ability of GC cells; WB results revealed that MARCH1 mainly regulated GC through the Wnt/β-catenin signaling pathway; In-vivo results showed that MARCH1 can promote the growth of GC. This study found that MARCH1 maintained the stemness characteristics and promoted the proliferation of GC cells by activating the Wnt/β-catenin signaling pathway.


New aspects of the kinetics of isoenzyme CK-MB during myocardial infarction: discontinuous release?
Intermittent liberation of the serum marker myoglobin is found in acute myocardial infarction, and the ST segment of the electrocardiogram also shows a phasic rise and fall. We therefore measured the serum marker CK-MB at close intervals of time and recorded an oscillation in the serum level. The peaks are not as high as in the serum myoglobin time curve, and it is not easy to decide if they represent the intermittent liberation of the serum marker. It was possible to distinguish between a "high release" and a "low release" group of patients: the former having a maximum CK-MB value of greater than 100 U/l and the latter of less than 100 U/l. Most patients showed 2-3 "initial peaks" within the first 8 h. The highest of these immediately preceded the climb to the definitive maximum value. We conclude that the small size of the peaks in the CK-MB time curve is due to a different mechanism of enzyme release.


A comparison of self-reported motor vehicle collision injuries compared with official collision data: an analysis of age and sex trends using the Canadian National Population Health Survey and Transport Canada data.
The purpose of this study was to compare the age and sex trends of motor vehicle collision injuries between a nationally representative self-report survey and official police motor vehicle collision report data. To do this, population-based estimates of motor vehicle collision injuries were established using data from the National Population Health Survey (NPHS), a prospective, population-based, longitudinal survey that was compared to Transport Canada's official motor vehicle collision report statistics. Aggregated mean data (1994-1996) were compared for seven age groups (15-19, 20-24, 25-34, 35-44, 45-54, 55-64, and 65+) from both data sets. No significant differences were found between males' and females' MVC injuries for any age category in the NPHS. A comparison of the NPHS and Transport Canada data found two small (significant) within-sex differences between the data sets, but overall, the analysis largely revealed similar trends for self-reported injury for all age categories and sex. The results indicate that the incidence of injuries based on self-report data in a nationally representative sample is similar to official sources of reporting and are thus a valid indicator or motor vehicle collision injury incidence. The results also confirm that injury trends differ from fatality trends.


Effect of continuous positive pressure ventilation on left ventricular diastolic function E/A ratio in patients with obstructive sleep apnea: a meta-analysis.
Many studies have shown that obstructive sleep apnea (OSA) is related to reduced left ventricular diastolic function. Continuous positive airway pressure (CPAP) is generally recognized as the preferred therapy for OSA. Yet, the effect of CPAP on left ventricular diastolic function in patients with OSA is inconclusive. In order to assess the influence of CPAP on left ventricular diastolic function in patients with OSA, we performed this meta-analysis of clinical experiments. PubMed, Web of Science, OVID, Embase, and Cochrane Library from the establishment of the database to July 6, 2022, were searched for clinical trial data. Inclusion criteria for this meta-analysis were: (1) Patients in the experimental group were diagnosed with OSA by polysomnography; (2) CPAP treatment course ≥ 4 weeks; (3) baseline and follow-up data of the diastolic function parameter E/A ratio were reported in the literature. Exclusion criteria were: (1) Central sleep apnea (CSA); (2) comorbid organic heart diseases such as coronary heart disease; (3) age < 18 years old; (4) conference abstracts or duplicate publications. After exclusions, 7 studies (2 RCTs and 5 prospective studies) with 473 subjects (225 in the treatment group and 248 in the matched control group) were included in the meta-analysis. Subgroup analysis indicated that after CPAP therapy, the left ventricular (LV) E/A ratio was significantly increased in patients with OSA (weighted mean difference (WMD) = 0.22, 95% CI = - 0.06-0.38; P = 0.007). Sensitivity analyses showed that the combined results were not influenced by single studies. Publication bias was not significant (Egger's test, P = 0.813). The results of this meta-analysis suggest that CPAP may improve the E/A ratio in patients with OSA patients. However, the small number of studies (n = 7) decreases confidence in the findings. Thus, carefully designed randomized controlled trials are needed to confirm the findings.


Expression of allograft inflammatory factor-1 in T lymphocytes: a role in T-lymphocyte activation and proliferative arteriopathies.
Allograft inflammatory factor (AIF)-1 is a cytoplasmic, calcium-binding protein whose expression in transplanted human hearts correlates with rejection and development of coronary artery vasculopathy (CAV). AIF-1 is constitutively expressed in monocytes/macrophages, but its expression in human lymphocytes has not been described. After immunohistochemical analysis of human coronary arteries with CAV, we identified AIF-1 expression in CD3-positive lymphocytes. AIF-1 was differentially expressed in peripheral blood mononuclear cells and in the T-lymphoblastoid MOLT-4 cell line exposed to various cytokines, suggesting a role for AIF-1 in T-lymphocyte activation. To determine AIF-1 function, MOLT-4 cells were stably transduced by AIF-1 retrovirus. Overexpression of AIF-1 in these cells led to a 238% increase in cell number compared to empty vector controls. AIF-1 polymerized nonmuscle actin and MOLT-4 cells overexpressing AIF-1 migrated 95% more rapidly than empty vector controls. Primary human vascular smooth muscle cells cultured in conditioned media from AIF-1-transduced MOLT-4 cells proliferated 99% more rapidly than vascular smooth muscle cells cultured in conditioned media from empty vector-transduced MOLT-4 cells. These data indicate that AIF-1 is expressed in activated T lymphocytes, that its expression enhances activation of lymphocytes, and that AIF-1 expression in activated lymphocytes may have important ramifications for activation of adjacent arterial vascular smooth muscle cells and development of CAV.


Fat Grafting for Treatment of Facial Burns and Burn Scars.
This article presents the authors' experience with the use of fat grafting via the Coleman technique, for the adjuvant treatment of facial burn wounds and their sequelae. It demonstrates the regenerative effects of fat injected under the wound and/or the scar as well as of fat delivered to the debrided surface of the wound and to the surface of the scar after laser treatment or microneedling.


A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP.
Rab8 is a small Ras-related GTPase that regulates polarized membrane transport to the plasma membrane. Here, we developed a high-content analysis (HCA) tool to dissect Rab8-mediated actin and focal adhesion reorganization that revealed that Rab8 activation significantly induced Rac1 and Tiam1 to mediate cortical actin polymerization and RhoA-dependent stress fibre disassembly. Rab8 activation increased Rac1 activity, whereas its depletion activated RhoA, which led to reorganization of the actin cytoskeleton. Rab8 was also associated with focal adhesions, promoting their disassembly in a microtubule-dependent manner. This Rab8 effect involved calpain, MT1-MMP (also known as MMP14) and Rho GTPases. Moreover, we demonstrate the role of Rab8 in the cell migration process. Indeed, Rab8 is required for EGF-induced cell polarization and chemotaxis, as well as for the directional persistency of intrinsic cell motility. These data reveal that Rab8 drives cell motility by mechanisms both dependent and independent of Rho GTPases, thereby regulating the establishment of cell polarity, turnover of focal adhesions and actin cytoskeleton rearrangements, thus determining the directionality of cell migration.


Procedural difficulties during successful intubation in octogenarians: A prospective observational study.
Octogenarians undergo anatomic and physiopathologic degradation, making airway management problematic, specific to intubation, bag mask ventilation, leading to desaturation and aspiration. Our study's aim was to examine the process of airway management regarding the steps involved in intubation and any deviations or delays in the tasks. An institutional review board-approved difficult airway prospective observational study in older adults was conducted. Inclusion criteria included airway features indicative of difficult airway, history of failed intubation, the planned use of specialized airway devices, and/or expected airway complications due to comorbidities. Patients 80 years and older were analyzed. Demographic data collected were age, weight, BMI, gender, ASA classification, airway indices, diagnosis, and procedures. Problems with intubation (INT) (≥3 intubation attempts), laborious assisted ventilation (VEN) (2-person and/or application of CPAP>20cmH2O), and complications with oxygenation (OXY) (SpO2<95%) were analyzed. Of the 41 patients enrolled in the study, 3 (7.3%) had all 3: problematic (INT), laborious (VEN), and desaturated (OXY); 8 (19.5%) patients experienced problematic (INT), 20 (48.8%) were described as laborious (VEN), and 14 (34.1%) experienced complications with (OXY). In octogenarians, we found a low incidence of difficulty with INT-VEN-OXY together. However, bag mask ventilation was found to be laborious with a high incidence of desaturation. Success rate of INT as a sole metric may not accurately describe the process of the intubation. We recommend alternative airway devices and techniques and the establishment of protocols for airway management in the elderly.


Extracellular MicroRNAs as Intercellular Mediators and Noninvasive Biomarkers of Cancer.
MicroRNAs (miRNAs) are released by different types of cells through highly regulated mechanisms under normal and pathological conditions. These extracellular miRNAs can be delivered into recipient cells for functional purposes, acting as cell-to-cell signaling mediators. It has been discovered that cancer cells release miRNAs into their surroundings, targeting normal cells or other cancer cells, presumably to promote tumor development and progression. These extracellular miRNAs are associated with oncogenic mechanisms and, because they can be quantified in blood and other bodily fluids, may be suitable noninvasive biomarkers for cancer detection. This review summarizes recent evidence of the role of extracellular miRNAs as intercellular mediators, with an emphasis on their role in the mechanisms of tumor development and progression and their potential value as biomarkers in solid tumors. It also highlights the biological characteristics of extracellular miRNAs that enable them to function as regulators of gene expression, such as biogenesis, gene silencing mechanisms, subcellular compartmentalization, and the functions and mechanisms of release.


Scaffolding as active learning in nursing education.
Recent changes, such as COVID-19 restrictions and advances in technology, have led to unique effects on nursing education, requiring new pedagogical thinking and strategies. Studies have shown that a more active approach to learning leads to positive gains for students. In this conceptual paper, we argue that scaffolding specifically allows instructors to break down assignments into meaningful chunks with instructional support that fall within reach of a student's ability, making the assignment both more manageable and actively engaging. This paper outlines six principles (Van Lier, 1996) to the scaffolding approach and discusses two example assignments that utilize scaffolding in nursing education to increase active engagement and improve learning outcomes. Examples include a research critique paper and an unfolding case study.


Fusion of phosphatidic acid-phosphatidylcholine mixed lipid vesicles.
Ca2+-induced transformation of phosphatidylcholine-phosphatidic acid vesicles to larger bilayer structures has been examined using nuclear magnetic resonance, electron microscopy, gel permeation and radioisotope tracer techniques. For concentrated vesicle preparations where phosphatidic acid content remains less than 50% of total lipid, transformation to larger well defined unilamellar structures can be induced. The size of the product formed is dependent on phosphatidic acid content and on Ca2+ content when Ca2+ levels are between 0.3 and 1.0 mol ratios with respect to phosphatidic acid. During transformation bilayer composition remains unchanged and internal contents are retained in the final structure. These properties are indicative of concerted two vesicle and multiple vesicle fusions. The controllable and concerted fusions make the phosphatidic acid system suitable for further mechanistic studies.


Characterization of Subvisible Particles in Biotherapeutic Prefilled Syringes: The Role of Polysorbate and Protein on the Formation of Silicone Oil and Protein Subvisible Particles After Drop Shock.
Subvisible particles (SbVPs) are a critical quality attribute for biotherapeutics. Particle content in prefilled syringes (PFSs) of a biotherapeutic can include protein particles and silicone oil particles (SiOP). Here, a real-world protein therapeutic PFS shows that although polysorbate is effective in preventing protein particle formation, it also leads to the formation of SiOP. PFSs of protein and buffer formulations in the presence and absence of polysorbate are subjected to a drop shock to generate SbVP and the effect of polysorbate and protein in generating SbVP is investigated. Particle characterization by light obscuration and flow imaging shows that polysorbate prevents protein particle formation as intended, but the presence of polysorbate substantially increases the formation of SiOP. The protein itself also acts as a surfactant and leads to increased SiOP, but to a lesser degree compared to polysorbate. In a separate companion study by Joh et al., the risk of immunogenicity was assessed using in vivo and in vitro models. Flow imaging distinguishes between SiOP and protein particles and enables risk assessment of the natures of different SbVP in PFSs.


Clinical application of tentorium cerebelli hiatus incision in treatment of severe and most severe brain injuries.
To explore the role of tentorium cerebelli hiatus incision in treating severe and most severe brain injuries complicated by tentorial herniation. From July 1994 to July 1999 tentorium cerebelli hiatus incision was done based on intracranial hematoma evacuation and bone flap craniectomy decompression in 70 cases of severe and most severe brain injuries complicated by tentorial herniation. Of the 70 cases, GCS 3-5 was in 23 and GCS 6-8 in 47; satisfactory recovery in 39 cases (55.7%), moderate disability in 12 (17.1%), severe deficit in 6 (8.6%), vegetative survival in 4 (5.7%) and 8 (11.4%) died. Tentoriun cerebelli incision is helpful in alleviating secondary brain stem injury from tentorial herniation and in reducing the disability and death rate of the patients.


Total sleep deprivation effect on disengagement of spatial attention as assessed by saccadic eye movements.
Previous research has shown that total sleep deprivation (TSD) of short duration (one night) affects performance to some cognitive tasks subserved by a fronto-parietal network. The aim of our study was to assess the effects of TSD on visuo-spatial attention, which is a cognitive task involving this network. Specifically, the disengagement of spatial attention was investigated with gap and overlap paradigms of saccadic eye movements. Ten healthy young male subjects performed the two tasks the morning after a normal night and after a TSD night. The study was conducted using a balanced, crossover design. TSD significantly increased the gap effect (difference of latency between overlap and gap). This result can be interpreted as an impaired disengagement of attention after TSD. As the peak velocity, which is an indicator of alertness, was not altered by TSD, the impairment in the disengagement of spatial attention does not result from a decrease in alertness. This study shows that saccadic eye movements enable studying alertness and disengagement of spatial attention simultaneously. The idea that specific brain areas are affected by TSD is confirmed by our results.


SCIRehab uses practice-based evidence methodology to associate patient and treatment characteristics with outcomes.
To describe the application of practice-based evidence (PBE) methodology to spinal cord injury (SCI) rehabilitation in the SCIRehab study, and to summarize associations of patient characteristics and treatment interventions to outcomes. Prospective observational study. Six SCI rehabilitation centers. Patients with traumatic SCI (N=1376) admitted for first rehabilitation. Not applicable. FIM and residence at discharge, and FIM, residence, Craig Handicap Assessment and Reporting Technique, work/school status, Patient Health Questionnaire-9, Diener Satisfaction with Life Scale, rehospitalization, and presence of pressure ulcers at 1 year postinjury. Patient demographic and injury characteristics explained significant variation in rehabilitation outcomes, particularly functional outcomes. Regression modeling also identified a large number of significant associations with outcomes when total time in each discipline was modeled and when models were developed for each discipline, examining time spent in the many specific interventions provided by each discipline. The application of PBE methodology in the SCIRehab study provided extensive information about the process of inpatient SCI rehabilitation. While patient demographic and injury characteristics explain substantial variation in rehabilitation outcomes, particularly functional outcomes, significant relations also were found between the type and quantity of treatment interventions delivered by each rehabilitation discipline and a broad range of outcomes.


Direct analysis of anticonvulsant drugs in vitreous humour by HPLC using a column switching technique.
A method is described for the rapid HPLC analysis of a number of anticonvulsant drugs in vitreous humour by injection directly onto a preconcentration column without the need for prior extraction. The conditions for optimum precision and accuracy were investigated and the method was subsequently applied to the analysis of phenytoin in a number of overdose cases. Sensitivity was 0.05 microgram/ml on a 0.5 ml vitreous sample. The mean blood/vitreous ratio for phenytoin was found to be 2.8 (range: 1.4-5.1). The relationship between blood and vitreous levels had a correlation coefficient of 0.85. Vitreous was found to be a very clean, stable sample, ideally suited to this technique.


Safety and feasibility of ultrathin probe transbronchial lung cryobiopsy without balloon blocker via robotic bronchoscopy in the evaluation of peripheral lung lesions: a retrospective pilot study.
Ultrathin probe transbronchial lung cryobiopsy (UP-TBLC) via robotic bronchoscopy can be safely performed without prophylactic balloon blockade. UP-TBLC offers incremental diagnostic yields of ultrasonographic eccentric lesions. https://bit.ly/3YUEWx4.


Detection and quantitation of circulating immune complexes in arterial blood of patients with rheumatic disease.
We developed antigen-nonspecific enzyme-linked immunoassays (ELISA) to quantitate IgG-C3- and IgM-C3-containing circulating immune complexes (CIC) in venous and arterial blood from rheumatic disease patients. Standards were diethylaminoethyl (DEAE)-purified, heat-aggregated IgG incubated with fresh human serum (for IgG-C3 CIC) and IgM rheumatoid factor-rich serum incubated with reduced, alkylated IgG and then with fresh human serum (for IgM-IgG-C3 CIC). Venous serum and plasma IgG-C3 and IgM-C3 CIC correlated closely (P less than 0.01). Rheumatoid arthritis (RA) and systemic lupus erythematous (SLE) patients had elevated levels of venous IgM-C3 CIC (P less than 0.0001) but not IgG-C3 CIC; patients with vasculitis, inflammatory rheumatic diseases, or noninflammatory rheumatic diseases had mean values similar to normal individuals. Venous IgG-C3 and IgM-C3 CIC did not correlate. Paired venous and arterial samples from 16 rheumatic disease patients averaged comparable amounts of IgG-C3 and IgM-C3 CIC, respectively; venous and arterial IgM-C3 CIC levels in patients significantly exceeded normals (P less than 0.05). Venous and arterial IgG-C3 CIC levels correlated closely (P less than 0.01) as did venous and arterial IgM-C3 levels (P less than 0.05). Thus, arterial CIC offered no advantage over venous determinations for rheumatic disease patients. IgM-C3 CIC were elevated in patients with RA and SLE when IgG-C3 CIC were not. Ig isotype-specific CIC quantitation may be useful for certain rheumatic diseases.


A New Concept for Primary Reconstruction of Skull Defects with 3D-Molded PEEK Patch Assisted by Navigation Based on Animal Study.
To perform an accurate primary repair of temporal bone defects. The temporal bone defect models were performed in beagles. Extended estimated patches of the defects were predesigned by 3D reconstruction software and molded from polyether ether ketone (PEEK) using a lathe. The precise trimming of the extended PEEK patches was established via coordinate transformation of the patches between the navigation system and the reconstruction software, and in real-time tracing via intraoperative navigation. Trimmed PEEK patches were embedded onto the defects. Blood tests and image examinations were conducted postoperatively. The extended PEEK patches were prepared precisely according to the predesign. Real-time tracing of the actual skull defect profile was performed quickly and accurately. Trimmed skull patches perfectly matched the shape of the defects. No signs of infection, absorption, or translocation of the patches occurred postoperatively, and little epidural effusion was found. With the assistance of navigation and 3D reconstruction technology, customized molded PEEK patches can be used for accurate primary repair of temporal bone defects.


Association between serum 25-hydroxyvitamin D and the effects of Angiotensin II receptor blocker on renal function among African Americans: A post hoc analysis of a randomized placebo-controlled trial.
We tested the hypothesis that vitamin D status may modify the effect of Angiotensin II receptor blocker (ARB) on renal function among African Americans. Sixty-four participants were included in this ancillary study from a randomized, double-blind, placebo-controlled, crossover trial among normotensive African Americans to test the effect of ARB on stress response of blood pressure and renal sodium handling. The participants were randomly assigned to receive either ARB or placebo for one week, washed out for one week and then cross-overed to receive the other intervention for one week. On the final day of each intervention, the participant underwent a mental stress test. Baseline serum 25-hydroxyvitamin D [25(OH)D] level was measured in this ancillary study. Sixty-four participants were included, aged 26.5 ± 10.2 years and 47% were female. Among the participants with the serum 25(OH)D concentrations in the low tertile, ARB treatment was associated with 2.58 mg/dL higher blood urea nitrogen (BUN) (P < .001) and was not associated with serum creatinine (SCr) or estimated glomerular filtration rate (eGFR) (Ps > .05). Among the participants in the high 25(OH)D tertile, ARB was associated with 1.59 mg/dL lower BUN (P < .001), 0.08 mg/dL lower SCr (P = .001), and 8.59 mL/min/1.73 m2 higher eGFR (P = .001). The interactions between vitamin D and ARB on renal function were more significant during stress and recovery than at rest. The effects of ARB treatment on renal function are modified by the vitamin D status among African Americans. ARB may improve renal function only among the ones with optimal vitamin D status.


Visual acuity increased by stellate ganglion block. Case reports.
After stellate ganglion blocks 5 patients with marked decreased visual acuity showed a pronounced increase of same, verified either by Snellens types or automated perimetry.


Evolving Otolaryngology Resident Roles and Concerns at the Peak of the US COVID-19 Pandemic.
The roles of US otolaryngology residents have changed in response to the coronavirus disease 2019 (COVID-19) pandemic. As the pandemic peaked in the United States, we characterized resident activities and concerns. A cross-sectional study of US otolaryngology residents between April 20, 2020 and May 2, 2020. A total of 219 residents at 65/118 (55%) institutions responded. Thirty (14%) residents had been redeployed. Residents reported greatest concerns regarding education (P < .00001). Assuming adequate protective equipment, 55% desired active participation in high-risk procedures on COVID-19-positive patients. Redeployed residents had greater concern for burnout and reduced in-hospital well-being (P < .05). Resident satisfaction correlated with comfort communicating concerns to their department (odds ratio [OR] = 4.9, 95% confidence interval [CI] 1.4-17.3, P = .01) and inversely correlated with low perceived meaning in work (OR = 3.1, CI 1.1-9.1, P = .03). Otolaryngology resident concerns have evolved as the pandemic progressed. Residency programs should prioritize resident education, well-being in redeployed residents, and open communication as they transition toward recovery.


Effects on mood of a life-styles program for the rehabilitation of injured workers.
This study reports an examination into the effects on daily mood of participation in a life-styles program by injured workers. In the current prospective study, 14 participants completed the Memorial University Mood Scale (MUMS) prior to starting the program, at 1 month, 2 months, and at 3 months. They also completed the Memorial University Scale of Happiness (MUNSH) prior to entry and after three months. There were significant improvements on the MUMS subscales of positive mood and vigor as well as overall mood. There were no changes in negative mood. Neither the positive nor the negative dispositional subscales of the MUNSH revealed any change. The results were interpreted as indicating strong psychologic benefits of the life-styles program for injured workers and are also consistent with a recently proposed two-factor state/trait model of well-being.


Cardiovascular Modulating Effects of Magnolol and Honokiol, Two Polyphenolic Compounds from Traditional Chinese Medicine-Magnolia Officinalis.
Honokiol and its isomer magnolol are poly-phenolic compounds isolated from the Magnolia officinalis that exert cardiovascular modulating effects via a variety of mechanisms. They are used as blood-quickening and stasis-dispelling agents in Traditional Chinese Medicine and confirmed to have therapeutic potential in atherosclerosis, thrombosis, hypertension, and cardiac hypertrophy. This comprehensive review summarizes the current data regarding the cardioprotective mechanisms of those compounds and identifies areas for further research.


Early failure of quadricuspid aortic valve tricuspidization due to dehiscence of approximating coronary cusps.
A 48-year-old woman diagnosed with aortic regurgitation showing a quadricuspid aortic valve (QAV) underwent repair with tricuspidization. Two non-coronary cusps (NCC) with fenestrations were detected intraoperatively. Tricuspidization of QAV was performed by approximating the two NCCs via interrupted sutures. The aortic annulus was plicated by subcommissural annuloplasty. The residual aortic regurgitation was mild, with a vena contracta of 2.1 mm. On postoperative day 5, echocardiography demonstrated a new regurgitation from the middle of the neo-NCC, and increased central regurgitation. Intraoperative findings showed the dehiscence of approximating sutures of the neo-NCC. Mechanical valve replacement was performed uneventfully.


Mechanism of lead adsorption from aqueous solutions using an adsorbent synthesized from natural condensed tannin.
Adsorption is a method for removing lead from wastewater. The adsorption of lead on a new adsorbent synthesized from natural condensed tannin has been investigated using a series of batch adsorption experiments. The study on the adsorption mechanism indicates that the adsorbent performed in aqueous solutions as an ionic exchanger whose end group was sodium ion (Na(+)). One lead (II) ion (Pb(2+)) was adsorbed onto the adsorbent by taking the place of two Na(+) ions. The maximum exchangeable Na(+) present on the adsorbent was measured with the proton titration experiments and it was up to 1.0 mmol x Na(+)g(-1) dry adsorbent. To a significant extent, pH influenced the extraction of lead from aqueous solutions. The lead removal efficiency was up to 71%, 87% and 91% with initial solution pH at 3.0, 3.6 and 4.2, respectively. The Langmuir equation fitted the adsorption isotherm data well. The maximum adsorption capacity of lead calculated was 57.5, 76.9 and 114.9 mg lead g(-1) dry adsorbent at initial solution pH of 3.0, 3.6 and 4.2, respectively. Therefore, the adsorbent does offer favorable characteristics in lead removal from acidic wastewater.


Formal Models of Biological Systems.
Recent biomedical research studies are focused in the mechanisms by which misfolded proteins lead to the generation of oxidative stress in the form of reactive oxygen species (ROS), often implicated in neurodegenerative diseases and aging. Moreover, biological experiments are designed to investigate how proteostasis depends on the balance between the folding capacity of chaperone networks and the continuous flux of potentially nonnative proteins. Nevertheless, biological experimental methods can examine the protein folding quality control mechanisms only in individual cells, but not in a multicellular level. Formal models offer a dynamic form of modelling, which allows to explore various parameter values in an integrated time-dependent system. This paper aims to present a formal approach of a mathematical descriptive model using as example a representation of a known molecular chaperone system and its relation to diseases associated to protein misfolding and neurodegeneration.


Nerve density: a new parameter to evaluate peripheral nerve pathology on ultrasound. Preliminary study.
The possibility to realize a quantitative evaluation of nerve density on ultrasound is clinically important to enhance the evaluation of peripheral nerve disorders. We developed software that quantifies the ratio between the hypoechoic and hyperechoic areas of peripheral nerves on ultrasound. Nerve density was defined as (hypoechoic pixels)/(total pixels) and the purpose of our study was to asses if nerve density can be used to differentiate pathologic conditions affecting peripheral nerves. Ultrasound images of peripheral nerves were obtained with a high-frequency probe (17-5 MHz, 288 elements). Sixty-five different patients and (n = 65) controls (age range, 35-81 years; mean 55 years) were prospectively evaluated. Thirty-five patients had carpal tunnel syndrome and 30 patients had neurofibromas. Three radiologists performed a semiautomated evaluation with intra and interobserver agreement. A complete automatic evaluation was performed with no need of intra and interobserver evaluation. With the semiautomated evaluation, mean intraobserver agreement was good (K = 0.85). Interobserver agreements was good as well (reader 1 vs reader 2: k = 0.72; reader 2 vs reader 3: k = 0.80; reader 3 vs reader 1: k = 0.72). Differences among value of nerve density in normal nerves, CTS and neurofibromas were statistically significant (p < 0.0001). There were no statistically significant differences between the results obtained using the automatic or the semiautomatic method. Nerve density is capable of discriminating between normal and pathologic nerves of patients affected by carpal tunnel syndrome or neurofibromas. Moreover, nerve density measure is useful to discriminate between patients with mild and severe CTS.


Nitric oxide-induced blockade of NMDA receptors.
We studied the effects of nitric oxide (NO)-producing agents on N-methyl-D-aspartate (NMDA) receptor activation in cultured neurons. 3-Morpholino-sydnonimine (SIN-1) blocked both NMDA-induced currents and the associated increase in intracellular Ca2+. The actions of SIN-1 were reversible and suppressed by hemoglobin. A degraded SIN-1 solution that did not release NO was unable to block NMDA receptors. This showed that the SIN-1 effects were due to NO and not to another breakdown product. Similar results were obtained with 1-nitrosopyrrolidine (an NO-containing drug) and with NO released from NaNO2. Pretreatment with hemoglobin potentiated NMDA-induced effects, demonstrating that endogenous NO modulates NMDA receptors. Since NMDA receptor activation induces NO synthesis, these results suggest a feedback inhibition of NMDA receptors by NO under physiological condition.


A Network Meta-Analysis of Efficacy of Different Interventions in the Prevention of Postoperative Intrauterine Adhesions.
This network meta-analysis was conducted to compare the efficacy of six interventions, including anti-blocking agents, intrauterine contraceptive devices (IUDs), estrogens, intrauterine balloon, Foley catheter, and amnion graft for the prevention of intrauterine adhesions (IUAs). We searched PubMed, Embase, and Cochrane Library from inception to December 2016. Cohort studies meeting these six interventions in the prevention of IUAs were included. The combination of direct and indirect evidence was conducted to assess the odds ratio (OR) or weighted mean differences and surface under the cumulative ranking curves of the six interventions in the prevention of postoperative IUAs. Finally, 12 eligible cohort studies were included in this network meta-analysis. The results of this network meta-analysis demonstrated that during 1 to 2 months after operation, compared with the surgical group, anti-blocking agent, and estrogens presented with relatively low ratios of postoperative IUAs (OR = 0.30 95% confidence interval (CI) = 0.10-0.67; OR = 0.12, 95% CI = 0.01-0.78, respectively). Compared with IUDs, estrogens exerted comparatively low ratio of postoperative IUAs (OR = 0.10, 95% CI = 0.01-0.90), which indicated that anti-blocking agent and estrogens had relatively better prevention efficacy. The cluster analysis showed that estrogens had relatively better efficacy in the prevention postoperative IUAs. Overall, our findings support that estrogens had relatively better efficacy in the prevention of postoperative IUAs.


Synthesis and structure-activity relationship study of phenoxybenzylpiperazine analogues as CCR8 agonists.
CCR8 agonists hold promise for the treatment of various auto-immune diseases. Despite the fact that phenoxybenzylpiperazine derivatives are known to be endowed with CCR8 agonistic activity, systematic structure-activity relationship studies have not been reported. In this study, ZK756326, a previously disclosed CCR8 agonist, was divided in various fragments and each subunit was subjected to structural modifications. All newly synthesized analogues were evaluated in a CCR8 calcium mobilization assay, revealing that only limited structural variation was tolerated in both phenyl rings and at the benzylic position. In contrast, various linkers gave analogues with good CCR8 agonistic potency. In addition, the presence of small substituents on the piperazinyl moiety or the exchange of the piperazinyl for a piperidinyl group afforded compounds with promising CCR8 agonism, with the most potent congener being 10-fold more potent than ZK756326.


Prescriber Attitudes Toward Implementation of Pharmacogenomic Testing in a Family Medicine Residency Program.
Few qualitative studies have explored the attitude of prescribers towards the implementation of pharmacogenomic testing in the family medicine (FM) setting, and none among FM residents. The purpose of this study was to describe the level of engagement and interest in the implementation of pharmacogenomic education and testing in an FM clinic within a residency program. A qualitative study utilizing semistructured interviews was conducted among prescribers within the FM clinic at The Brooklyn Hospital Center (TBHC). Voluntary prescribers included FM residents and attendings. No prescribers were excluded. Prior to the interview, informational sheets about pharmacogenomics were provided to standardize participant knowledge base. The research team created an interview guide of specific open-ended questions. Interviews were audio recorded and transcribed until a point of saturation was achieved. Transcripts of interviews served as data for analysis. Coding and analysis were performed to develop a hypothesis. No formal statistical analysis was required. Of the total 28 providers eligible for participation, 15 were recruited and interviewed (53% response rate). Based on analysis of interview data, four key conceptual concerns emerged regarding benefits and risks of testing, feasibility, accessibility, and modification of FM residency training curricula. Positive attitudes and perceptions provide support for pharmacogenomic education and testing to be incorporated into FM residency curricula. Addressing practical barriers, such as curricular education and training, will allow for expansion of such initiatives in the future.


Association of the visceral adiposity index with arterial stiffness in elderly Chinese population.
The visceral adiposity index (VAI) is a new marker of adipose dysfunction and related with cardiometabolic risk. The aim of this study is to investigate the association of VAI with arterial stiffness in elderly Chinese population. A total of 1,707 elderly individuals over 60 years of age were recruited for this cross-sectional study. We measured body composition, anthropometrics, blood pressure, and lipid parameters. The arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV) and defined as baPWV ≥ 1400 cm/s. VAI was calculated based on body mass index, waist circumference, triglyceride and high-density lipoprotein cholesterol. Multivariable regression analysis was performed to evaluate the association between VAI and baPWV. There were significant differences in VAI tertiles between low-baPWV and high-baPWV group (p = 0.008). Univariate analysis demonstrated that age, history of hypertension, SBP, DBP, total cholesterol, fasting glucose, the higher VAI tertiles were correlated with the existence of high-baPWV (p < 0.05). Participants in the higher VAI tertiles had higher OR (1.0 ≤ VAI < 1.74: OR= 2.89, 95% CI [1.44, 5.80]; VAI ≥ 1.75: OR = 4.23, 95% CI [1.45, 12.37], p for trend: 0.004) comparing with the lowest VAI tertile. Non-linear relationship was detected between VAI and baPWV. VAI was positively correlated with baPWV when VAI < 2.10. This study demonstrates that VAI is independently associated with the risk of arterial stiffness in elderly population.


Ethanol affects context memory and long-term habituation in the crab Chasmagnathus.
A shadow moving overhead acts as a danger stimulus and elicits an escape response in the crab Chasmagnathus granulatus that habituates promptly and for a long period. The effect of acute ethanol treatment on this long-term memory was analyzed. A single injection of 0.01, 0.05, or 0.1 micrograms ethanol (ET)/g given 30 min before iterated presentation of a visual danger stimulus failed to affect short-term habituation. Posttraining ethanol (0.01 to 0.1 microgram/g) produces a dose-dependent impairment of long-term habituation, but pretraining ethanol had no amnestic effect. However, a retention deficit confined to context memory was disclosed with both pre- and posttraining ethanol. Results from experiments with double injection (posttraining and pretesting injections) account for the retention impairment in terms of true amnesia (failure to acquire memory) but not due to state-dependence or retrieval deficit. The nonamnestic effect of pretraining ethanol upon long-term habituation is explained by a nonespecific depressing effect caused by interaction between iterative presentation of the danger stimulus and drug-induced internal state during training.


Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics.
Polo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, frequent loss of chromosome 5q11-35 which includes PLK2 is observed in basal-like breast cancer. In this study, we found that PLK2 was tumor suppressive in breast cancer, preferentially in basal-like and triple-negative breast cancer (TNBC) subtypes. Knockdown of PLK1 rescued phenotypes induced by PLK2-loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase through the kinase but not the polo-box domains of PLK2, suggesting PLK2 functioned at least partially through the interaction with PLK1. Furthermore, an improved treatment response was seen in both Plk2-deleted/low mouse preclinical and PDX TNBC models using the PLK1 inhibitor volasertib alone or in combination with carboplatin. Re-expression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. In summary, this study delineates the effects of chromosome 5q loss in TNBC that includes PLK2, the relationship between PLK2 and PLK1, and how this may render PLK2-deleted/low tumors more sensitive to PLK1 inhibition in combination with chemotherapy.


Immunopathology of early and advanced epididymis lesions caused by Brucella ovis in rams.
Ovine brucellosis is an infectious disease that causes alterations in the reproductive tract in ram and abortion in ewes. Their negative economic impact in ovine production warrants a thorough understanding the interactions between B. ovis and the host. Here, epididymis lesions of rams infected by B. ovis were histopathologically staged into early and advanced. Expression by immunohistochemistry of Brucella antigens, inflammatory cell markers (CD3, CD79αcy) and cytokines (IFN-γ, TNF-α, TGF-β1) was assessed in both stages. Early lesions were characterized by epithelial changes, interstitial inflammation, and mild fibrosis; whereas advanced lesions displayed caseous granulomas containing numerous macrophages, multinucleated giant cells, lymphocytes, and plasma cells. Expression of Brucella antigens were observed in both stages. The cellular response in B. ovis lesions were predominantly of T-cells (CD3+) whereas low numbers of B-cells and plasma cells (CD79αcy+) were present in both early and advanced lesions. IFN-γ was expressed by lymphocytes in early lesions suggesting that the adaptive immune response against B. ovis is initiated by Th1 cells, this response was also preserved in advanced stages. Expression of TNF-α was observed in neutrophils of epithelial microabscesses and intraepithelial T-cells of early lesions suggesting a promotion of neutrophil phagocytosis triggered by TNF-α. On the other hand, advanced lesions showed a reduction of TNF-α expression which may permit B. ovis persistence in granulomas. Lastly, TGF-β1 expression (fibroblast, macrophages and less in lymphocytes) were increased with time, suggesting that B. ovis promotes TGF-β1 secretion promoting chronicity of the lesions.