11C-acetate PET imaging of lung cancer: comparison with 18F-FDG PET and 99mTc-MIBI SPET.
Recently carbon-11 acetate (AC) positron emission tomography (PET) has been reported to be of clinical value for the diagnosis of cancer that is negative on fluorine-18 fluorodeoxyglucoce (FDG) PET. We investigated the uptake of AC in lung cancer to determine whether this tracer is of potential value for tumour detection and characterisation, and to compare AC PET imaging with FDG PET and technetium-99m sestamibi (MIBI) single-photon emission tomography (SPET). Twenty-three patients with 25 lung cancers underwent AC and FDG PET. Twenty of 23 patients were also investigated with MIBI SPET. Dynamic images were acquired for 26 min after the injection of 555 MBq of AC. Standardised uptake values (SUVs) and/or tumour to non-tumour activity ratios (T/N) for each tumour were investigated at 10-20 min after AC administration, 40-60 min after administration of 185 MBq FDG and 15-45 min after administration of 555 MBq MIBI. Twenty lung cancers were resected surgically, and the degree of tracer uptake in the primary lesion was correlated with histopathological features (cell dedifferentiation and aggressiveness) and prognosis. Rapid uptake of AC followed by extremely slow clearance was observed. For the purpose of tumour identification, AC PET was inferior to FDG PET in 8 of 25 (32%) lung cancers, and the T/N of AC was lower than that of FDG. However, AC PET was superior to FDG PET in the identification of a slow-growing tumour (bronchiolo-alveolar carcinoma). There was a positive correlation between AC uptake (T/N) and MIBI uptake (T/N) (r=0.799, P<0.0001). A positive correlation was not observed between either AC or MIBI uptake and the degree of cell dedifferentiation in lung adenocarcinomas, whereas FDG uptake did correlate with the degree of cell dedifferentiation. In lung adenocarcinoma, there was a weak correlation between aggressiveness and FDG uptake, but no correlation was evident for AC and MIBI. In addition, a positive correlation was not observed between AC or MIBI uptake and postoperative recurrence in lung adenocarcinoma, whereas FDG uptake did correlate with postoperative recurrence. Thus, the greater the FDG uptake, the higher the malignant grade. In conclusion, for the purpose of tumour identification, AC PET was inferior to FDG PET but superior to MIBI SPET. Neither AC nor MIBI uptake reflects the malignant grade in lung adenocarcinoma, whereas FDG uptake does. AC PET is less diagnostically informative than FDG PET in patients with lung cancer. However, AC PET may play a complementary role in the identification of low-grade malignancies that are not FDG avid.


Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: results of a Phase Ib/IIa study.
NeuGcGM3 ganglioside is especially attractive because it is expressed on melanoma cells but it is minimally or not expressed at all on most normal human tissues. A Phase Ib/IIa clinical trial was carried out in patients with advanced cutaneous and ocular malignant melanomas, to evaluate immunogenicity and toxicity of an intramuscularly administered cancer vaccine and composed by NeuGcGM3 in a proteoliposome of Neisseria meningitides with Montanide ISA 51 as adjuvant. Twenty two patients were included, twelve at dose level of 200 microg and 10 at 400 microg. The first five doses were administered every other week and then monthly until 9 doses. 12 patients received additional immunizations. Vaccination induced specific anti-NeuGcGM3 IgM, IgG and IgA antibodies responses. Titers of IgM were greater for the highest vaccine doses. Vaccination also elicited DTH response in 45.5% of patients in the lower doses and 77.8% in the higher doses. Toxicities were mostly grade 1 or 2, according CTC-NCI criteria. Interestingly, 3 patients developed vitiligo at the lower dose (none in the highest dose) although the nominal antigen NeuGcGM3 is not present in melanocytes. Survival analysis was not the goal of this Phase I trial; nevertheless, the fact that seven patients are alive for more than 2 years after inclusion is noteworthy. Safety and immunogenicity with NeuGcGM3 vaccine treatment in advanced melanoma patients were established. The prognostic value of autoimmunity and the possibilities of dissociating anti-tumor immunity from autoimmunity deserve further research.


Probabilistic cross-link analysis and experiment planning for high-throughput elucidation of protein structure.
Emerging high-throughput techniques for the characterization of protein and protein-complex structures yield noisy data with sparse information content, placing a significant burden on computation to properly interpret the experimental data. One such technique uses cross-linking (chemical or by cysteine oxidation) to confirm or select among proposed structural models (e.g., from fold recognition, ab initio prediction, or docking) by testing the consistency between cross-linking data and model geometry. This paper develops a probabilistic framework for analyzing the information content in cross-linking experiments, accounting for anticipated experimental error. This framework supports a mechanism for planning experiments to optimize the information gained. We evaluate potential experiment plans using explicit trade-offs among key properties of practical importance: discriminability, coverage, balance, ambiguity, and cost. We devise a greedy algorithm that considers those properties and, from a large number of combinatorial possibilities, rapidly selects sets of experiments expected to discriminate pairs of models efficiently. In an application to residue-specific chemical cross-linking, we demonstrate the ability of our approach to plan experiments effectively involving combinations of cross-linkers and introduced mutations. We also describe an experiment plan for the bacteriophage lambda Tfa chaperone protein in which we plan dicysteine mutants for discriminating threading models by disulfide formation. Preliminary results from a subset of the planned experiments are consistent and demonstrate the practicality of planning. Our methods provide the experimenter with a valuable tool (available from the authors) for understanding and optimizing cross-linking experiments.


Machine learning-based prediction of future breast cancer using algorithmically measured background parenchymal enhancement on high-risk screening MRI.
Preliminary work has demonstrated that background parenchymal enhancement (BPE) assessed by radiologists is predictive of future breast cancer in women undergoing high-risk screening MRI. Algorithmically assessed measures of BPE offer a more precise and reproducible means of measuring BPE than human readers and thus might improve the predictive performance of future cancer development. To determine if algorithmically extracted imaging features of BPE on screening breast MRI in high-risk women are associated with subsequent development of cancer. Case-control study. In all, 133 women at high risk for developing breast cancer; 46 of these patients developed breast cancer subsequently over a follow-up period of 2 years. 5 T or 3.0 T T1 -weighted precontrast fat-saturated and nonfat-saturated sequences and postcontrast nonfat-saturated sequences. Automatic features of BPE were extracted with a computer algorithm. Subjective BPE scores from five breast radiologists (blinded to clinical outcomes) were also available. Leave-one-out crossvalidation for a multivariate logistic regression model developed using the automatic features and receiver operating characteristic (ROC) analysis were performed to calculate the area under the curve (AUC). Comparison of automatic features and subjective features was performed using a generalized regression model and the P-value was obtained. Odds ratios for automatic and subjective features were compared. The multivariate model discriminated patients who developed cancer from the patients who did not, with an AUC of 0.70 (95% confidence interval: 0.60-0.79, P < 0.001). The imaging features remained independently predictive of subsequent development of cancer (P < 0.003) when compared with the subjective BPE assessment of the readers. Automatically extracted BPE measurements may potentially be used to further stratify risk in patients undergoing high-risk screening MRI. 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;50:456-464.


Physician Assessment of Pretest Probability of Malignancy and Adherence With Guidelines for Pulmonary Nodule Evaluation.
The annual incidence of pulmonary nodules is estimated at 1.57 million. Guidelines recommend using an initial assessment of nodule probability of malignancy (pCA). A previous study found that despite this recommendation, physicians did not follow guidelines. Physician assessments (N = 337) and two previously validated risk model assessments of pretest probability of cancer were evaluated for performance in 337 patients with pulmonary nodules based on final diagnosis and compared. Physician-assessed pCA was categorized into low, intermediate, and high risk, and the next test ordered was evaluated. The prevalence of malignancy was 47% (n = 158) at 1 year. Physician-assessed pCA performed better than nodule prediction calculators (area under the curve, 0.85 vs 0.75; P < .001 and .78; P = .0001). Physicians did not follow indicated guidelines when selecting the next test in 61% of cases (n = 205). Despite recommendations for serial CT imaging in those with low pCA, 52% (n = 13) were managed more aggressively with PET imaging or biopsy; 12% (n = 3) underwent biopsy procedures for benign disease. Alternatively, in the high-risk category, the majority (n = 103 [75%]) were managed more conservatively. Stratified by diagnosis, 92% (n = 22) with benign disease underwent more conservative management with CT imaging (20%), PET scanning (15%), or biopsy (8%), although three had surgery (8%). Physician assessment as a means for predicting malignancy in pulmonary nodules is more accurate than previously validated nodule prediction calculators. Despite the accuracy of clinical intuition, physicians did not follow guideline-based recommendations when selecting the next diagnostic test. To provide optimal patient care, focus in the areas of guideline refinement, implementation, and dissemination is needed.


Budget impact analysis of pneumococcal conjugate vaccines in Colombia.
Objective: Pneumococcal diseases including invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM) impose a substantial public health burden. This study performed a budget impact analysis of the use of pneumococcal conjugate vaccines (PCVs) in the National Immunization Program (NIP) in Colombia.Methods: We compared the direct medical cost of the scenario without and with PCV vaccination using either pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) or 13-valent pneumococcal conjugate vaccine (PCV-13) over 5 years (2020-2024) from the health-care system perspective. Vaccine efficacy estimates were obtained from published sources and vaccine prices were taken from the Pan-American Health Organization Revolving Fund. Vaccine coverage was assumed to be 90% based on Colombia data.Results: Using PHiD-CV in the NIP in Colombia would reduce the estimated cost for treating pneumococcal disease by US$46.1 m over the 2020-2024 period (US$40.2 m using PCV-13), with a budget impact of US$100.1 m for PHiD-CV (US$121.4 m for PCV-13), and would cost US$3.1 m less per year on vaccine doses than using PCV-13.Conclusion: These findings are potentially valuable for the selection of vaccines for their national immunization programs under conditions of budgetary constraint.


Reproductive function in female mice lacking the gene for endothelial nitric oxide synthase.
Nitric oxide (NO) acts as a neuronal messenger in both the central and peripheral nervous systems and has been implicated in reproductive physiology and behavior. Pharmacological inhibition of nitric oxide synthase (NOS) with the nonspecific NOS inhibitor, l-N(G)-nitro-Arg-methyl ester (l-NAME), induced deficits in both the number of ovarian rupture sites and the number of oocytes recovered in the oviducts of mice. Female neuronal NOS knockout (nNOS-/-) mice have normal numbers of rupture sites, but reduced numbers of oocytes recovered following systemic injections of gonadotropins, suggesting that NO produced by nNOS accounts, in part, for deficits in ovulatory efficiency observed after l-NAME administration. Additionally, endothelial NOS knockout (eNOS-/-) mice have reduced numbers of ovulated oocytes after superovulation. Because endothelial NOS has been identified in ovarian follicles, and because of the noted reduced breeding efficiency of eNOS-/- mice, the present study sought to determine the role of NO from eNOS in mediating the number of rupture sites present after ovulation. Estrous cycle length and variability were consistently reduced in eNOS-/- females. The number of rupture sites was normal in eNOS-/- mice under natural conditions and after administration of exogenous GnRH. After exogenous gonadotropin administration, eNOS-/- females displayed a significant reduction in the number of ovarian rupture sites. Female eNOS-/- mice also produced fewer pups/litter compared to WT mice. These data suggest that NO from endothelial sources might play a role in mediating rodent ovulation and may be involved in regulation of the timing of the estrous cycle.


Long-term treatment of rats with haloperidol: lack of an effect on brain N-acetyl aspartate levels.
Proton magnetic resonance spectroscopy (1H-MRS) studies of schizophrenia suggest an effect of the disease or of antipsychotic medications on brain N-acetyl aspartate (NAA), a marker of neuronal viability. We studied in rat the effect of haloperidol on NAA, glutamate, and glutamine in several brain regions where metabolite reductions have been reported in chronically medicated patients with schizophrenia. Two groups of 16 rats each were treated with haloperidol depo (38 mg/kg/month) and vehicle for 6 months and were killed. Concentrations of metabolites were determined by high-resolution magic angle proton magnetic resonance spectroscopy (HR-MAS 1H-MRS) at 11.7 T in ex-vivo punch biopsies from the following brain regions: medial frontal and cingulate cortex, striatum, nucleus accumbens, dorsal and ventral hippocampus, amygdala, and temporal cortex. Factorial ANOVA of NAA concentrations revealed no significant effect of drug group (F(1,212) = 1.5; p = 0.22) or a group by brain region interaction (F(7,212) = 1.0; p = 0.43). There was a significant main effect of region (F(7,212) = 17.8; p < 0.001) with lower NAA in the striatum. A prolonged exposure to the dopamine D2 receptor blockade effects of haloperidol does not result in changes in NAA, glutamate, glutamine, and other metabolites in the proton spectrum. These results are consistent with the only other two studies of the effect of antipsychotic drugs on NAA in the rat brain. The documented lower NAA in chronically treated schizophrenia patients is most likely not a simple effect of antipsychotic medications.


Does antiretroviral treatment increase the infectiousness of smear-positive pulmonary tuberculosis?
Understanding of the effects of human immunodeficiency virus (HIV) infection and antiretroviral treatment (ART) on Mycobacterium tuberculosis transmission dynamics remains limited. We undertook a cross-sectional study among household contacts of smear-positive pulmonary tuberculosis (TB) cases to assess the effect of established ART on the infectiousness of TB. Prevalence of tuberculin skin test (TST) positivity was compared between contacts of index cases aged 2-10 years who were HIV-negative, HIV-positive but not on ART, on ART for <1 year and on ART for 1 year. Random-effects logistic regression was used to take into account clustering within households. Prevalence of M. tuberculosis infection in contacts of HIV-negative patients, HIV-positive patients on ART 1 year and HIV-positive patients not on ART/on ART <1 year index cases was respectively 44%, 21% and 22%. Compared to contacts of HIV-positive index cases not on ART or recently started on ART, the odds of TST positivity was similar in contacts of HIV-positive index cases on ART 1 year (adjusted OR [aOR] 1.0, 95%CI 0.3-3.7). The odds were 2.9 times higher in child contacts of HIV-negative index cases (aOR 2.9, 95%CI 1.0-8.2). We found no evidence that established ART increased the infectiousness of smear-positive, HIV-positive index cases.


Functional analysis of HLA-DP polymorphism: a crucial role for DPbeta residues 9, 11, 35, 55, 56, 69 and 84-87 in T cell allorecognition and peptide binding.
The information available on the specific function of HLA-DP and the structure-function relationships is very limited. Here, single amino acid substitutions of HLA-DPB1*02012 have been used to analyze the role of polymorphic residues of the DPbeta1 domain on DP-mediated T cell allorecognition and peptide binding. Using a panel of specific anti-HLA-DP mAb, we identified the HLA-DP residues involved in the recognition by these mAb, with a crucial role for DPbeta56 for most of the mAb assayed. Individual substitutions at residues 9, 11, 35, 55, 56 and 69 completely abrogated T cell recognition mediated by two different HLA-DPw2-allospecific T cell clones (8.3 and 8.9). Interestingly single changes at positions 9, 11, 35 and 55 of HLA-DPbeta also altered the binding of peptides AAII(12-27) and IIP(53-65), natural ligands of the HLA-DPB1*02012 molecule. Individual changes at residues located in pocket 1 (84, 85, 86 and 87 from HLA-DPbeta) led to a partial reduction in cytotoxic T lymphocyte-mediated lysis and also partially affected peptide binding. However, the simultaneous substitution of these positions completely abolished both T cell allorecognition and peptide binding, suggesting a major role for polymorphisms at pocket 1 in HLA-DP function. Molecular modeling, used to predict changes induced by amino acid substitutions, supported the functional data. Taken together, these results strongly suggest that polymorphic residues 84, 85, 86 and 87 at pocket 1, residues 9, 35 and 55 at pocket 9, and residues 11 and 69 at pockets 6 and 4 respectively play a key role in HLA-DP function, probably by modifying the way the peptide is bound within the groove of HLA-DP2 and determining changes in the conformation of the MHC-peptide complex recognized by the TCR.


Genetic genealogy reveals true Y haplogroup of House of Bourbon contradicting recent identification of the presumed remains of two French Kings.
Genetic analysis strongly increases the opportunity to identify skeletal remains or other biological samples from historical figures. However, validation of this identification is essential and should be done by DNA typing of living relatives. Based on the similarity of a limited set of Y-STRs, a blood sample and a head were recently identified as those belonging respectively to King Louis XVI and his paternal ancestor King Henry IV. Here, we collected DNA samples from three living males of the House of Bourbon to validate the since then controversial identification of these remains. The three living relatives revealed the Bourbon's Y-chromosomal variant on a high phylogenetic resolution for several members of the lineage between Henry IV and Louis XVI. This 'true' Bourbon's variant is different from the published Y-STR profiles of the blood as well as of the head. The earlier identifications of these samples can therefore not be validated. Moreover, matrilineal genealogical data revealed that the published mtDNA sequence of the head was also different from the one of a series of relatives. This therefore leads to the conclusion that the analyzed samples were not from the French kings. Our study once again demonstrated that in order to realize an accurate genetic identification of historical remains DNA typing of living persons, who are paternally or maternally related with the presumed donor of the samples, is required.


Tumour necrosis factor receptor gene expression and shedding in human whole lung tissue and pulmonary epithelium.
This study aimed to investigate the expression of tumour necrosis factor receptor (TNF-R) at the gene and surface level, and its shedding in human lung tissue and a pulmonary epithelial cell line, A549. Levels of gene expression of TNF-R were evaluated by Northern blot analysis. Human lung tissue expressed both type I and type II TNF-R gene, while A549 cells expressed only type I TNF-R gene. Phorbol ester upregulated and TNF-alpha down-regulated the TNF-R gene expression in A549 cells. Consistent with these modulations of TNF-R gene expression, 125I-TNF binding capacities were increased with phorbol ester stimulation and decreased with TNF stimulation after 24 h in A549 cells. The shedding of TNF-R from A549 cells was investigated using enzyme-linked immunosorbent assay (ELISA) for soluble type I TNF-R. Not only lung tissues but also A549 cells spontaneously released soluble type I TNF-R into the culture medium. Both phorbol ester and TNF stimulation accelerated the shedding of soluble TNF-R from A549 cells. These results suggest that type I TNF-R gene expression and shedding of soluble TNF-R are differentially regulated in A549 cells. We conclude that tumour necrosis factor receptor surface expression is regulated, at least in part, at the gene expression level and shedding of soluble tumour necrosis factor receptor is modulated by inflammatory mediators, such as tumour necrosis factor in A549 cells.


Methane from anaerobic fermentation.
Conventional anaerobic digestion is an established technology for wastewater stabilization, but methane production rates and net energy yields are generally too low to make the process competitive as a source of methane. Numerous improvements are being developed to make conversion of plant biomass to methane and simultaneous waste stabilization-methane production practical. Among these improvements are innovative-digester designs and process configurations. Efforts to commercialize modern anaerobic digestion technology are progressing.


Quantitation of regional ejection fractions using gated tomographic imaging with 99mTc-sestamibi.
Gated single photon emission CT (SPECT) sestamibi imaging allows the simultaneous assessment of myocardial perfusion and left ventricular function. The purpose of this study was to evaluate a technique for quantitative regional wall motion assessment using gated SPECT (99m)Tc-sestamibi imaging. Fourteen subjects without cardiac pathology and 25 patients who had experienced myocardial infarction (MI) were studied. After tomographic reconstruction of gated short-axis slices, the identification of endocardial borders was made using a standard edge-detection program in systole and diastole in each of five selected slices. Regional ejection fraction (EF) and myocardial perfusion were determined for five regions within each slice. Ten patients underwent echocardiographic regional wall-motion analysis, the results of which were compared to corresponding regional EF results. High interobserver reproducibility in the assessment of regional EFs was found, with r values ranging from 0.94 to 0.98. In patients with anterior and inferior MIs, the regional EFs were abnormal in the anterior and septal regions, and the inferior and lateral regions, respectively. The regional EFs correlated significantly with regional perfusion in the anterior walls (r = 0.71; p = 0.0001), the lateral walls (r = 0.66; p = 0.0001), and inferior walls (r = 0.54; p = 0.0004). There was a significant association between the regional EFs and the echocardiographic regional wall motion assessment at the base (p < 0.0001), mid-ventricle (p = 0.0004), and apex (p = 0.0003). Gated SPECT images obtained (99m)Tc-sestamibi can provide reproducible quantitative, segmental regional EFs for multiple left ventricular slices that are significantly associated with subjective regional wall motion assessment by echocardiography.


The Role of Gut Microbiota in Intestinal Inflammation with Respect to Diet and Extrinsic Stressors.
The gut microbiota maintains a symbiotic relationship with the host and regulates several important functions including host metabolism, immunity, and intestinal barrier function. Intestinal inflammation and inflammatory bowel disease (IBD) are commonly associated with dysbiosis of the gut microbiota. Alterations in the gut microbiota and associated changes in metabolites as well as disruptions in the intestinal barrier are evidence of the relationship between the gut microbiota and intestinal inflammation. Recent studies have found that many factors may alter the gut microbiota, with the effects of diet being commonly-studied. Extrinsic stressors, including environmental stressors, antibiotic exposure, sleep disturbance, physical activity, and psychological stress, may also play important roles in altering the composition of the gut microbiota. Herein, we discuss the roles of the gut microbiota in intestinal inflammation in relation to diet and other extrinsic stressors.


[Prospects in development of geobiophysics].
The results of the discussion about the problems of biodiversity and geobiophysics are summarised. The conclusion about the necessity of developing a new scientific branch that unites Life Sciences and Earth Sciences is drawn.


Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation.
Stem cells are thought to play a critical role in minimizing the accumulation of mutations, but it is not clear which strategies they follow to fulfill that performance objective. Slow cycling of stem cells provides a simple strategy that can minimize cell pedigree depth and thereby minimize the accumulation of replication-dependent mutations. Although the power of this strategy was recognized early on, a quantitative assessment of whether and how it is employed by biological systems is missing. Here we address this problem using a simple self-renewing organ - the C. elegans gonad - whose overall organization is shared with many self-renewing organs. Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached. This compromise is such that worm germ-line stem cells should cycle more slowly than their differentiating counterparts, but only by a modest amount. Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions. Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.


Root-knot nematode--directed expression of a plant root--specific gene.
Root-knot nematodes are obligate plant parasites that induce development of an elaborate feeding site during root infection. Feeding-site formation results from a complex interaction between the pathogen and the host plant in which the nematode alters patterns of plant gene expression within the cells destined to become the feeding site. Expression of TobRB7, a gene expressed only in tobacco roots, is induced during feeding site development. The cis-acting sequences that mediate induction by the nematode are separate from those that control normal root-specific expression. Reporter transgenes driven by the nematode-responsive promoter sequences exhibit expression exclusively in the developing feeding site.


Biologically enhanced starch bio-ink for promoting 3D cell growth.
The excellent rheological property has legitimated the suitability of starch hydrogel for extrusion-based 3D printing. However, the inability to promote cell attachment and migration has precluded the non-modified starch hydrogel from direct applications in the biomedical field. Herein, we develop a novel 3D printable nanocomposite starch hydrogel with highly enhanced biocompatibility for promoting 3D cell growth, by formulating with gelatin nanoparticles and collagen. The rheological evaluation reveals the shear-thinning and thixotropic properties of the starch-based hydrogel, as well as the combinatorial effect of collagen and gelatin nanoparticles on maintaining the printability and 3D shape fidelity. The homogeneous microporous structure with abundant collagen fibers and gelatin nanoparticles interlaced and supplies rich attachment sites for cell growth. Corroborated by the cell metabolic activity study, the multiplied proliferation rate of cells on the 3D printed nanocomposite starch hydrogel scaffold confirms the remarkable enhancement of biological function of developed starch hydrogel. Hence, the developed nanocomposite starch hydrogel serves as a highly desirable bio-ink for advancing 3D tissue engineering.


Cognitive Failures and the Role of Emotion in Dimensional Schizotypy: A Replication and Extension.
Cognitive failures are commonplace within the general population but may be particularly heightened in those with higher levels of schizotypy. This is especially salient in the context of enduring trait and momentary state negative emotion which often contributes to increases in daily impairments, leading to a more debilitating and distracted life. Particularly, individuals with elevated levels of schizotypy may be more likely to experience cognitive failures, especially in the presence of negative trait emotion such as depression, anxiety, and stress. However, little is known about the influence of state emotion and the distinct roles that state and trait emotion may have with cognitive failures and schizotypy. To replicate and extend previous findings, 306 (58% males) undergraduate students aged 18-50 years (M = 19.343; SD = 2.493) completed self-report measures of cognitive failures, trait and state emotion, and schizotypy. Mediation and moderation analyses were performed in SPSS to examine the potential effects of trait and state emotion on the relationship between schizotypy and cognitive failures. Consistent with previous findings, mood symptomology, in addition to negative affect, mediated cognitive failures in those with higher levels of schizotypy. However, in our sample, positive affect did not appear to buffer against cognitive failures. The findings of the present study suggest there may be a nuanced relationship between both negative trait and state emotions on the relationships between cognitive failures and schizotypy. Understanding the interaction of enduring versus momentary emotion on cognition as they relate to an elevated risk for developing schizophrenia-spectrum phenomena may be a point for earlier and more targeted interventions.


Young adults with juvenile arthritis in remission attain normal peak bone mass at the lumbar spine and forearm.
To assess the impact of disease activity on acquired peak bone mass and bone turnover in young adult patients with either persistent juvenile arthritis (JA) or a history of JA (JA in remission). Two hundred twenty-nine patients with JA were studied after a mean +/- SD of 15.6 +/- 2.4 years in women and 14.9 +/- 2.1 years in men since disease onset. One hundred forty-five women and 84 men were over the age of 20 at the time of examination (mean +/- SD age 24.9 +/- 2.9 years for women and 25.2 +/- 3.1 years for men). Forty-one healthy women (mean +/- SD age 27.4 +/- 3.1 years) and 55 healthy men (mean +/- SD age 25.7 +/- 3.1 years) served as a reference group. Bone mineral density (BMD) was analyzed by dual x-ray absorptiometry. Serum osteocalcin concentrations and urinary concentrations of deoxypyridium (D-Pyd) were measured. Linear regression analyses were performed to evaluate the impact of disease on BMD. Patients with persistent disease had significantly lower BMD compared with healthy subjects (P < 0.001 for women at all measured sites and for men at the femoral neck and total body; P < 0.05 for men at the radius and lumbar spine). Of the patients with a history of JA, only women had significantly lower BMD at the femoral neck and total body (P < 0.05). Patients with persistent JA had significantly more osteopenia and osteoporosis than healthy subjects, while patients with a history of JA had more frequent osteopenia only in the total body. Weight, urinary concentration of D-Pyd, and belonging to the patient group significantly affected BMD at all measured sites in the entire study population, while analysis of all patients found that only the number of months taking corticosteroids significantly affected BMD at all measured sites. However, the impact of the variables differed from site to site. Our findings imply that most young adults with JA attain the same BMD as healthy subjects if the disease goes into remission, while young adults with active disease have increased risk for osteopenia and osteoporosis.


The Vibrio cholerae vieSAB locus encodes a pathway contributing to cholera toxin production.
The genes encoding cholera toxin (CT), ctxAB, are coregulated with those for other Vibrio cholerae virulence factors by a cascade of transcriptional activators, including ToxR, TcpP, and ToxT. Additional regulators that modulate expression of ctxAB during infection were recently identified in a genetic selection. A transposon insertion in vieS, the sensor kinase of the VieSAB three-component signal transduction system, resulted in failure to induce expression of a ctxA-recombinase fusion during murine infection. To determine which components of the VieSAB system are essential for CT regulation, ctxAB transcript levels were assessed by RNase protection assay in various vieSAB in-frame deletion mutants after growth in vitro under virulence gene inducing conditions. A threefold reduction in ctxAB transcript levels was observed for the (Delta)vieSAB strain; consistent with this, the (Delta)vieSAB strain produced twofold less CT protein than the wild type, and this defect was complementable in trans. These results suggest that the VieSAB three-component system is required for full activation of the ctxAB operon during in vitro growth as well as during infection. The VieSAB system may regulate ctxAB expression indirectly by affecting production of ToxT, because decreased toxT transcript levels were observed in the (Delta)vieSAB strain.


Medical devices; immunology and microbiology devices; classification of the West Nile Virus IgM capture Elisa assay. Final rule.
The Food and Drug Administration (FDA) is classifying the West Nile Virus IgM Capture Elisa assay into class II (special controls). The agency is taking this action in response to a petition submitted under the Federal Food, Drug, and Cosmetic Act (the act) as amended by the Medical Device Amendments of 1976 (the amendments), the Safe Medical Devices Act of 1990, and the Food and Drug Administration Modernization Act of 1997 (FDAMA). The agency is classifying this device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. Elsewhere in this issue of the Federal Register, FDA is announcing the availability of a guidance document that will serve as the special control for the device.


Operations Management in Ambulatory Care in Switzerland.
Practice efficiency is influenced by its operations management. We aim at studying implementation of operations management in Swiss medical practices and we develop a dashboard that allows controlling and managing resources. To study operations management and relevant indicators in ambulant care, we distributed questionnaires by e-mail and conducted 6 interviews. In collaboration with a group practice, we collected requirements regarding a dashboard for operations management, developed a mockup and finally a prototype. This prototype was deployed and implemented in daily routine. From the assessments we learned that practice information systems (PIS) are not sufficiently supporting production planning and control. Relevant indicators include processing time per patient or waiting time for quantifying efficiency and identify potential improvements in production. Within 5 weeks of implementation of our dashboard in a group practice, we learned that calculating indicators and support of operations management by means of a dashboard is well appreciated by practice employees. Indicators are considered extremely useful for operations management.


Continuous Dopaminergic Stimulation as a Treatment for Parkinson's Disease: Current Status and Future Opportunities.
Levodopa-induced motor complications remain an important source of disability for many patients with Parkinson's disease. Substantial laboratory evidence indicates that motor complications relate to the nonphysiological restoration of brain dopamine with intermittent doses of standard oral levodopa. Dopamine levels are normally maintained at a relatively constant level, even following a dose of levodopa. However, in the Parkinsonian state, where dopamine terminals have degenerated with a loss of their buffering capacity, intermittent doses of levodopa lead to dramatic peak and trough fluctuations in striatal dopamine levels. This results in pulsatile stimulation of dopamine receptors, molecular changes in striatal neurons, physiological changes in pallidal neurons, and ultimately the development of motor complications. These observations led to the hypothesis that continuous delivery of levodopa might be associated with a reduced risk of motor complications. This concept is known as continuous dopamine stimulation (CDS). Preliminary studies in animal models and patients with Parkinson's disease supported this hypothesis, suggesting a reduced risk of both motor fluctuations and dyskinesias. The present review considers the scientific advances and the more definitive clinical trials testing this concept that have taken place during the past decade and considers ongoing experimental studies and future opportunities. © 2020 International Parkinson and Movement Disorder Society.


Human metabolism of arsenolipids present in cod liver.
We report results from the first investigation of the human metabolism of arsenic-containing lipids (arsenolipids), significant arsenic constituents of some seafood products. Two male volunteers ingested canned cod liver and the arsenic metabolites in their urine were monitored by high-performance liquid chromatography inductively coupled plasma mass spectrometry over a 66-h period. Volunteer A consumed 85 g (wet mass) of cod liver containing a total of approximately 120 microg arsenic, 77% of which was present as arsenolipids, and volunteer B consumed 85 g (wet mass) of cod liver, 25% of which was present as arsenolipids, together with 20 g of cod liver oil, containing a total of about 180 microg arsenic. The structures of the arsenolipids are currently unknown, whereas the majority of the non-lipid arsenic in the cod liver was identified as arsenobetaine, which was excreted unchanged. The arsenolipids were rapidly metabolised to water-soluble compounds and excreted in the urine; peak arsenic concentrations were recorded between 7 and 15 h (volunteer A) and between 6.5 and 15 h (volunteer B), and by the end of the experiment about 90% of the ingested arsenic had been accounted for in the urine for both volunteers. The major arsenolipid metabolite was dimethylarsinate (DMA), constituting 73% (volunteer A) or 41% (volunteer B) of the total urinary arsenic, and most of the remaining arsenolipid-derived arsenic, constituting about 10% (volunteer A) and 5% (volunteer B), comprised four novel arsenic-containing fatty acids, namely oxo-dimethylarsenopropanoic acid, thio-dimethylarsenopropanoic acid, oxo-dimethylarsenobutanoic acid, and thio-dimethylarsenobutanoic acid. Unchanged arsenobetaine (15% for volunteer A and 51% for volunteer B) made up the remaining urinary arsenic together with trace quantities of other, mostly unknown, arsenicals. In a second experiment (volunteer A only), performed with pure cod liver oil, which contains only arsenolipids, DMA and the same four arsenic fatty acids were excreted in the urine. The study shows that arsenolipids in cod liver are bioavailable, and that they are quickly biotransformed to several water-soluble arsenicals, the structures of which suggest that the native arsenolipids contain a dimethylarsine oxide moiety.


Statistical consideration for clinical biomarker research in bladder cancer.
To critically review and illustrate current methodological and statistical considerations for bladder cancer biomarker discovery and evaluation. Original, review, and methodological articles, and editorials were reviewed and summarized. Biomarkers may be useful at multiple stages of bladder cancer management: early detection, diagnosis, staging, prognosis, and treatment; however, few novel biomarkers are currently used in clinical practice. The reasons for this disjunction are many and reflect the long and difficult pathway from candidate biomarker discovery to clinical assay, and the lack of coherent and comprehensive processes (pipelines) for biomarker development. Conceptually, the development of new biomarkers should be a process that is similar to therapeutic drug evaluation-a highly regulated process with carefully regulated phases from discovery to human applications. In a further effort to address the pervasive problem of inadequacies in the design, analysis, and reporting of biomarker prognostic studies, a set of reporting recommendations are discussed. For example, biomarkers should provide unique information that adds to known clinical and pathologic information. Conventional multivariable analyses are not sufficient to demonstrate improved prediction of outcomes. Predictive models, including or excluding any new putative biomarker, need to show clinically significant improvement of performance in order to claim any real benefit. Towards this end, proper model building, avoidance of overfitting, and external validation are crucial. In addition, it is important to choose appropriate performance measures dependent on outcome and prediction type and to avoid the use of cutpoints. Biomarkers providing a continuous score provide potentially more useful information than cutpoints since risk fits a continuum model. Combination of complementary and independent biomarkers is likely to better capture the biological potential of a tumor than any single biomarker. Finally, methods that incorporate clinical consequences such as decision curve analysis are crucial to the evaluation of biomarkers. Attention to sound design and statistical practice should be delivered as early as possible and will help maximize the promise of biomarkers for patient care. Studies should include a measure of predictive accuracy and clinical decision-analysis. External validation using data from an independent cohort provides the strongest evidence that a model is valid. There is a need for adequately assessed clinical biomarkers in bladder cancer.


Patients' narratives.
Patients who suffer from inflammatory skin disease are at risk of stigmatisation and physical and psychological co-morbidities. To an extent these issues can be offset by effective coping strategies. The cumulative balance of these interactions will often lead to impairment, especially in those whose coping mechanisms are maladaptive or do not exist. When this situation arises, the detrimental effect of these various morbidities is termed 'cumulative life course impairment' (CLCI). We present 2 typical cases, one of a patient suffering from severe psoriasis and another of a patient suffering severe atopic eczema, as examples of how patients with inflammatory skin disease may be affected by CLCI. Their experiences demonstrate that the presence of inflammatory skin disease changes key life choices with resultant effect on career and relationships, amongst others. Although longitudinal evidence to support this CLCI is lacking, these patient narratives add support to the concept of CLCI.


Community-acquired Pneumonia With Pleural Effusion in Children and Municipal Human Development Index in Rio de Janeiro, Brazil.
This study evaluated admissions with severe community-acquired pneumonia (CAP) with pleural effusion (PE) in a pediatric university hospital and the impact of the increased average municipal human development index (M-HDI) in the local incidence of the disease in the last decade. This is a retrospective longitudinal study of patients (0-13 years old) with CAP. The municipal human development index (M-DHI) of the place of residence of patients was obtained. We calculate the crude odds ratios (ORs) of variables related to risk of developing PE. The variables that reached a significance level of 80% (P < 0.20) were selected for multivariate analysis. The logistic regression model was used for the selection of the parsimonious model, according to the likelihood ratio. The 465 patients' ages ranged from 1 to 174 months. The median of age (months) in children with PE was 36.00; in children without the PE was 29.00 (P < 0.011); media of variation in M-HDI in the period in patients with PE was 0.767 ± 0.002 and in patients without PE was 0.778 ± 0.002 (P < 0.001). In the logistic regression model, the absence of comorbidity (OR = 2.909) and the HDI < 0.770 (OR = 3.015) were predictive factors associated with PE. The progressive increase of the M-DHI during the study period, although to a slightly higher level, was correlated with the reduction in the number of admissions with CAP with PE.


Characterization of the replication of a baculovirus mutant lacking the DNA polymerase gene.
In a previous study, the DNA polymerase gene (dnapol) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) was identified as one of six genes required for plasmid replication in a transient replication assay (M. Kool, C. Ahrens, R.W. Goldbach, G.F. Rohrmann, J.M. Vlak, Identification of genes involved in DNA replication of the Autographa californica, Proc. Natl. Acad. Sci. U.S.A. 91, (1994) 11212-11216); however, another study based on a similar approach reported that the virally encoded polymerase was only stimulatory (A. Lu, L.K. Miller, The roles of 18 baculovirus late expression factor genes in transcription and DNA replication, J. Virol. 69, (1995) 975-982). To reconcile the conflicting data and determine if the AcMNPV DNA polymerase is required for viral DNA replication during the course of an infection, a dnapol-null virus was generated using bacmid technology. To detect viral DNA replication, a highly sensitive assay was designed based on real-time PCR and SYBR green chemistry. Our results indicate that a bacmid in which the dnapol ORF was deleted is unable to replicate its DNA when transfected into Spodoptera frugiperda (Sf-9) cells, although when the dnapol ORF was introduced into the polyhedrin (polh) locus, this repaired virus could propagate at levels similar to the control virus. These results confirm that the AcMNPV-encoded DNA polymerase is required for viral DNA replication and the host DNA polymerases cannot substitute for the viral enzyme in this process.


Intraoperative systolic blood pressure variability predicts 30-day mortality in aortocoronary bypass surgery patients.
Few data support an association between blood pressure variability and clinical outcomes during cardiac surgery. We tested the hypothesis that intraoperative systolic blood pressure variability outside a targeted blood pressure range predicts 30-day mortality in patients undergoing cardiac surgery. Electronically captured blood pressure data from 7,504 consecutive coronary bypass surgery procedures between September 1, 1996, and December 31, 2005, were divided into development and validation cohorts. Systolic blood pressure variability episodes outside a blood pressure range (e.g., higher than 135 or lower than 95 mmHg) were characterized by number of episodes, magnitude of episode, duration of episode, and magnitude x duration of excursion (i.e., area under the curve). Multiple logistic regression analysis was used to assess 30-day mortality association. The most predictive mortality risk characteristic and blood pressure range was tested in the validation cohort. A total of 3.1 million intraoperative blood pressure evaluations were analyzed. Systolic blood pressure variability was derived in 5,038 patients and validated in 2,466 patients (8% without cardiopulmonary bypass and 6% with valve procedure). Among all tested indices of blood pressure variability, mean duration of systolic excursion (outside a range of 105-130 mmHg) was most predictive of 30-day mortality (odds ratio = 1.03 per minute, 95% CI 1.02-1.39, P < 0.0001). Intraoperative blood pressure variability is associated with 30-day postoperative mortality in patients undergoing aortocoronary bypass surgery.


Single Topic Conference on Autoimmune Liver Disease from the Canadian Association for the Study of the Liver.
Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.


Indirect induction of differentiation in myeloid leukemic cells by lipid A.
Normal myeloid and MGI(+)D(+) clones of myeloid leukemic cells can be induced for Fc and complement component 3 rosettes, lysozme, and mature macrophages and granulocytes by a protein with macrophage- and granulocyte-inducing (MGI) activity, whereas MGI(+)D(-) clones can be induced by this protein for rosettes and lysozme but not mature cells. Lipopolysaccharides (LPS) from different bacteria induced the appearance of rosettes, lysozyme, and macrophages in some MGI(+)D(+) clones but did not induce any of these changes in MGI(+)D(-) clones. Lipid A gave the same results as LPS. Incubation of MGI(+)D(+) cells with LPS also induced an MGI activity detectable in the culture medium. This activity behaved like MGI in inducing (i) rosettes, lysozyme, and mature cells in MGI(+)D(+) leukemic cells including a clone resistant to LPS, (ii) rosettes and lysozyme in MGI(+)D(-) leukemic cells, and (iii) differentiation of normal myeloid cells to mature macrophages and granulocytes. This activity was induced in MGI(+)D(+) cells by LPS before the induction of rosettes or lysozyme. The results indicate that the lipid A portion of LPS indirectly induces differentiation of MGI(+)D(+) myeloid leukemic cells by inducing MGI protein. It is suggested that induction of specific regulatory proteins may be a more general mechanism for the induction of differentiation by surface-acting compounds.


Genetic diversity, genome organization, and investigation of the etiology of psychiatric diseases.
Recent advances in our understanding of the structure and organization of the human genome have strong implications for investigations of the diagnosis and etiology of psychiatric disorders. The concept of human genes as contiguous regions of DNA has been discarded and replaced by the concept of a gene split in separate pieces that must be spliced in order to make its protein products. The 'one gene - one enzyme' concept has also been modified to allow for the observation that many functional proteins are composed of multiple subunits, each coded by separate genes, whose expression is regulated by many other genetic and environmental factors. Consequently, the development of a complex phenotype cannot be predicted from knowledge of even the entire DNA sequence, and exploratory methods that rely entirely on genetic linkage analysis are unlikely to be fruitful. It is recommended that investigations reverse the natural development sequence and begin with studies at a phenotypic level, proceeding down to the genotypic level. Studies at a purely clinical level can define independent familial subtypes, which can in turn be studied at several levels of observation (social, physiological, biochemical, genetic) to identify multiple biosocial risk factors. Recent advances in genetic epidemiology now provide quantitative methods to detect major gene effects, resolve cultural inheritance from biological inheritance, and identify the influence of multiple risk factors on the development and expression of psychiatric disease.


Inhibiting RHOA Signaling in Mice Increases Glucose Tolerance and Numbers of Enteroendocrine and Other Secretory Cells in the Intestine.
Glucagon-like peptide 1 (GLP1) is produced by L cells in the intestine, and agonists of the GLP1 receptor are effective in the treatment of diabetes. Levels of GLP1 increase with numbers of L cells. Therefore, agents that increase numbers of L cell might be developed for treatment of diabetes. Ras homologue family member A (RhoA) signaling through Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) controls cell differentiation, but it is not clear whether this pathway regulates enteroendocrine differentiation in the intestinal epithelium. We investigated the effects of Y-27632, an inhibitor of ROCK1 and ROCK2, on L-cell differentiation. We collected intestinal tissues from GLU-Venus, GPR41-RFP, and Neurog3-RFP mice, in which the endocrine lineage is fluorescently labeled, for in vitro culture and histologic analysis. Small intestine organoids derived from these mice were cultured with Y-27632 and we measured percentages of L cells, expression of intestinal cell-specific markers, and secretion of GLP1 in medium. Mice were fed a normal chow or a high-fat diet and given Y-27632 or saline (control) and blood samples were collected for measurement of GLP1, insulin, and glucose. Incubation of intestinal organoids with Y-27632 increased numbers of L cells and secretion of GLP1. These increases were associated with upregulated expression of genes encoding intestinal hormones, neurogenin 3, neurogenic differentiation factor 1, forkhead box A1 and A2, and additional markers of secretory cells. Mice fed the normal chow diet and given Y-27632 had increased numbers of L cells in intestinal tissues, increased plasma levels of GLP1 and insulin, and lower blood levels of glucose compared with mice fed the normal chow diet and given saline. In mice with insulin resistance induced by the high-fat diet, administration of Y-27632 increased secretion of GLP1 and glucose tolerance compared with administration of saline. In mouse intestinal organoids, an inhibitor of RhoA signaling increased the differentiation of the secretory lineage and the development of enteroendocrine cells. Inhibitors of RhoA signaling or other strategies to increase numbers of L cells might be developed for treatment of patients with type 2 diabetes or for increasing glucose tolerance.


Comparative safety of intravenous Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia: rationale and study design of a randomized double-blind study with a focus on acute hypersensitivity reactions.
Intravenous (IV) iron is often used to treat iron deficiency anemia in patients who are unable to tolerate or are inadequately managed with oral iron. However, IV iron treatment has been associated with acute hypersensitivity reactions. The comparative risk of adverse events (AEs) with IV iron preparations has been assessed by a few randomized controlled trials, which are most often limited by small patient numbers, which lack statistical power to identify differences in low-frequency AE such as hypersensitivity reactions. Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia (FIRM) is a randomized, double-blind, international, multicenter, Phase III study designed to compare the safety of ferumoxytol and ferric carboxymaltose (FCM). The study includes adults with hemoglobin <12.0 g/dL (females) or <14.0 g/dL (males), transferrin saturation ≤20% or ferritin ≤100 ng/mL within 60 days of dosing, and a history of unsatisfactory or nontolerated oral iron therapy or in whom oral iron therapy is inappropriate. Patients are randomized (1:1) to ferumoxytol 510 mg or FCM 750 mg, each given intravenously on days 1 and 8. Primary end points are the incidence of moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. All potential hypersensitivity and hypotensive reactions will be adjudicated by a blinded, independent Clinical Events Committee. A secondary safety end point is the composite frequency of moderate-to-severe hypersensitivity reactions, including anaphylaxis, serious cardiovascular events, and death. Secondary efficacy end points include mean change in hemoglobin and mean change in hemoglobin per milligram of iron administered from baseline to week 5. Urinary excretion of phosphorus and the occurrence of hypophosphatemia after IV iron administration will be examined as well as the mechanisms of such hypophosphatemia in a substudy. FIRM will provide data on the comparative safety of ferumoxytol and FCM, two IV iron preparations with similar dosing schedules, focusing on moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. The study plans to enroll 2000 patients and is expected to complete in 2017.


A collision prevention software tool for complex three-dimensional isocentric set-ups.
During treatment planning it can be difficult to check whether a particular plan is workable, that is it avoids obstructing treatment beams with parts of the patient couch and it avoids collisions between the treatment machine head and the patient couch. To overcome this problem, the trigonometric relationships between the placement of treatment beams and the patient couch are examined. From these relationships a set of useful equations that can be generally applied is derived. The application of these equations practically as a simple (non-graphical) planning tool is described. The resulting tool enables the feasibility of a plan to be checked during treatment planning, and gives guidance as to how a patient could be repositioned to allow the use of a plan when potential beam obstructions are detected, prior to verification of the treatment on a simulator.


Design and Analysis of Multilayered Neural Network-Based Intrusion Detection System in the Internet of Things Network.
A large array of objects is networked together under the sophisticated concept known as the Internet of Things (IoT). These connected devices collect crucial information that could have a big impact on society, business, and the entire planet. In hostile settings like the internet, the IoT is particularly susceptible to multiple threats. Standard high-end security solutions are insufficient for safeguarding an IoT system due to the low processing power and storage capacity of IoT devices. This emphasizes the demand for scalable, distributed, and long-lasting smart security solutions. Deep learning excels at handling heterogeneous data of varying sizes. In this study, the transport layer of IoT networks is secured using a multilayered security approach based on deep learning. The created architecture uses the intrusion detection datasets from CIC-IDS-2018, BoT-IoT, and ToN-IoT to evaluate the suggested multi-layered approach. Finally, the new design outperformed the existing methods and obtained an accuracy of 98% based on the examined criteria.


The zona pellucida porosity: three-dimensional reconstruction of four types of mouse oocyte zona pellucida using a dual beam microscope.
In the last decade, the applicability of focus ion beam-field emission scanning electron microscopy (FIB-FESEM) in the biological field has begun to get relevance. Among the possibilities offered by FIB-FESEM, high-resolution three-dimensional (3D) reconstruction of biological structures is one of the most interesting. Using this tool, the 3D porosity of four different types of mouse oocyte zona pellucida (ZP) was analyzed. A surface analysis of the mouse oocyte ZP was first performed by SEM. Next, one oocyte per ZP type was selected, and an area of its ZP was completely milled, using the cut and view mode, in the FIB-FESEM. Through a 3D reconstruction of the milled area, a map of the distribution of the pores across the ZP was established and the number and volume of pores were quantified, thus enabling for the first time the study of the inner porosity of the mouse ZP. Differences in ZP porosity observed among the four types analyzed allowed us to outline a model to explain the changes that the ZP undergoes through immature, mature, predegenerative, and degenerative stages.


Regulation of proximal tubular cell differentiation and proliferation in primary culture by matrix stiffness and ECM components.
To explore whether matrix stiffness affects cell differentiation, proliferation, and transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) in primary cultures of mouse proximal tubular epithelial cells (mPTECs), we used a soft matrix made from monomeric collagen type I-coated polyacrylamide gel or matrigel (MG). Both kinds of soft matrix benefited primary mPTECs to retain tubular-like morphology with differentiation and growth arrest and to evade TGF-β1-induced EMT. However, the potent effect of MG on mPTEC differentiation was suppressed by glutaraldehyde-induced cross-linking and subsequently stiffening MG or by an increasing ratio of collagen in the soft mixed gel. Culture media supplemented with MG also helped mPTECs to retain tubular-like morphology and a differentiated phenotype on stiff culture dishes as soft MG did. We further found that the protein level and activity of ERK were scaled with the matrix stiffness. U-0126, a MEK inhibitor, abolished the stiff matrix-induced dedifferentiation and proliferation. These data suggest that the ERK signaling pathway plays a vital role in matrix stiffness-regulated cell growth and differentiation. Taken together, both compliant property and specific MG signals from the matrix are required for the regulation of epithelial differentiation and proliferation. This study provides a basic understanding of how physical and chemical cues derived from the extracellular matrix regulate the physiological function of proximal tubules and the pathological development of renal fibrosis.


Services provided following compensable work-related tetraplegia.
Descriptive study. To describe and compare the medical services provided following work-related tetraplegic spinal cord injury (SCI). Workers' compensation claims database. The administrative database of a workers' compensation provider was searched for work-related tetraplegia claims with dates of injury between 1 January 1989 and 31 December 1999. In total, 62 cases were identified and grouped by impairment category. Medical payment data were extracted and assigned to service categories. Although the level of services was directly related to the severity of impairment, patterns were similar across categories; for example, the largest proportions of payments were associated with durable medical equipment (DME) and attendant care in each impairment category. DME, readmissions and attendant care services varied considerably from year to year and within impairment category. Payments for physician care and medications/supplies showed the least variation within impairment categories. Workers' compensation payments were similar to National Spinal Cord Injury Database (NSCID) payments for the first year following injury; however, in subsequent years, workers' compensation figures were much higher. Differences in annual medical payment and services by impairment category appear to be primarily due to variations in DME, attendant care and readmission. Payment differences in relation to National SCI figures may be related to better capture of payments by the workers' compensation administrative database. In addition, results suggest broader coverage by workers' compensation for medical services and items related to independent living.


Alternative FIB TEM sample preparation method for cross-sections of thin metal films deposited on polymer substrates.
Transmission electron microscopy (TEM) and focused ion beam (FIB) are proven tools to produce site-specific samples in which to study devices from initial processing to causes for failure, as well as investigating the quality, defects, interface layers, etc. However, the use of polymer substrates presents new challenges, in the preparation of suitable site-specific TEM samples, which include sample warping, heating, charging, and melting. In addition to current options that address some of these problems such as cryo FIB, we add an alternative method and FIB sample geometry that address these challenges and produce viable samples suitable for TEM elemental analysis. The key feature to this approach is a larger than usual lift-out block into which small viewing windows are thinned. Significant largely unthinned regions of the block are left between and at the base of the thinned windows. These large unthinned regions supply structural support and thermal reservoirs during the thinning process. As proof-of-concept of this sample preparation method, we also present TEM elemental analysis of various thin metallic films deposited on patterned polycarbonate, lacquer, and poly-di-methyl-siloxane substrates where the pattern (from low- to high-aspect ratio) is preserved.


Forsythiaside A Activates AMP-Activated Protein Kinase and Regulates Oxidative Stress via Nrf2 Signaling.
Forsythiaside A (FA) is an active constituent isolated from Forsythia suspensa, a beneficial herb used in traditional medicine known for its antioxidant and anti-inflammatory properties. Although various studies have suggested that FA has the protective effects, its impacts on arachidonic acid (AA) plus iron in vitro models and carbon tetrachloride (CCl₄)-induced mouse liver damage in vivo have not been explored. In this study, HepG2 cells were subjected to AA + iron treatment to induce apoptosis and mitochondrial impairment and determine the molecular mechanisms. FA exhibited protective effects by inhibiting cell damage and reactive oxygen species (ROS) production induced by AA + iron, as assessed via immunoblot and flow cytometry analyses. Further molecular investigations revealed that FA resulted in the activation of extracellular-signal-related protein kinase (ERK), which subsequently triggered the activation of AMP-activated protein kinase (AMPK), a critical regulator of cellular oxidative stress. Additionally, FA modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which is a significant antioxidant transcription factor regulated by the AMPK pathway. For in vivo studies, mice were orally administered FA and then subjected to induction of CCl₄-based hepatotoxicity. The protective effect of FA was confirmed via blood biochemistry and immunohistochemical analyses. In conclusion, our findings demonstrated the protective effects of FA against oxidative stress both in vitro and in vivo, thus indicating that FA is a potential candidate for liver protection. Our study sheds light on the mechanistic pathways involved in the antioxidant effects of FA, highlighting the hepatoprotective potential of naturally occurring compounds in traditional herbs, such as FA.


Quantitative Analysis of Iron and Silicon Concentrations in Iron Ore Concentrate Using Portable X-ray Fluorescence (XRF).
As a technique capable of rapid, nondestructive, and multi-elemental analysis, portable X-ray fluorescence (pXRF) has applications to mineral exploration, environmental evaluation, and archaeological analysis. However, few applications have been conducted in the smelting industry especially when analyzing the metal concentration in ore concentrate samples. This research analyzed the effectiveness of using pXRF in determining the metal concentration in Fe concentrate. For this proof of concept study, Fe ore samples dominated by Fe and Si were collected from the Northeastern University Mineral Processing Laboratory (Shenyang, China) and directly analyzed using pXRF, laboratory-based XRF, and titration methods. The compactness (density) of the ore concentrate was found to have very little effect on pXRF readings. The pXRF readings for Fe and Si were comparative to laboratory-based XRF results. Based on the strong correlations between the pXRF and XRF results (Fe: R2 > 0.99, Si: R2 > 0.96), linear calibrations were adopted to improve the accuracy of pXRF readings. Linear regression equations derived from the relations between XRF results and pXRF results of 21 Fe ore concentrate samples were used to calibrate the pXRF, and then validation was performed on five additional samples. Results from this preliminary study suggest that ordinary least squares (OLS) regression improves the accuracy dramatically, especially for Fe with relative errors (REs) decreasing to 0.03%-3.27% from 4.26%-8.32%. Consequently, pXRF shows strong promise for rapid, quantitative analysis of Fe concentration in Fe ore concentrate. Based on the results obtained in this study, a larger, more comprehensive study is warranted to confirm the results obtained.


Perosomus elumbis in a Holstein calf infected with bovine viral diarrhea virus.
The detection of bovine viral diarrhea virus (BVDV) in a female Holstein calf presented with perosomus elumbis, a congenital anomaly, is reported here. A cow with dystocia was evaluated and an abnormal dead calf was detected during vaginal examination. The calf was retrieved via caesarean section and exhibited abnormalities characteristic of PE, such as vertebral and pelvic malformations. These abnormalities were further confirmed using radiographic and necropsy examinations. At necropsy cerebellar hypoplasia was an additional finding, which is a typical lesion associated with bovine virus diarrhea (BVD). Several tissue samples from the calf were tested for the presence of antigens of BVDV and bovine herpesvirus-1 (BHV-1) by ELISA. In addition, sera samples from the dam and calf were tested for the presence of antibodies against BVDV, BHV-1, and bluetongue disease virus (BTV) using a virus neutralization assay. Results indicated that the calf was congenitally infected with BVDV, whereas there was no evidence for the presence of BHV-1 and BTV. In the dam's serum no antibodies against BVDV, BHV-1, and BTV were detected. Even though the etiology of perosomus elumbis is unknown, BVDV, which causes fetal anomalies at early gestation in cows, may have been a contributing factor in this case.


Long QT Syndrome: Genetics and Future Perspective.
Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing.


Modification of the tremorigenic activity of physostigmine.
Drugs which reduce central catecholamine activity increased the tremorigenic action physostigmine (0.25 mg/kg) in the rat. The potentiation of physostigmine tremor induced by these neuroleptic drugs was quantitated measuring the ratio of post- to prephysostigmine motor activity; this ratio may be useful index of catecholamine/cholinergic balance. Of the compounds tested, chlorpromazine HC1 (15 mg/kg) and reserpine (10 mg/kg) had the greatest potentiating effect on the tremor-producing action of physostigmine. LDOPA (500 mg/kg) reduced the tremor induced by physostigmine in rats pre-treated with reserpine, but not in rats pre-treated with chlorpromazine.


Bioactive Interpenetrating Hydrogel Networks Based on 2-Hydroxyethyl Methacrylate and Gelatin Intertwined with Alginate and Dopped with Apatite as Scaffolding Biomaterials.
Our goal was to create bioimitated scaffolding materials for biomedical purposes. The guiding idea was that we used an interpenetrating structural hierarchy of natural extracellular matrix as a "pattern" to design hydrogel scaffolds that show favorable properties for tissue regeneration. Polymeric hydrogel scaffolds are made in a simple, environmentally friendly way without additional functionalization. Gelatin and 2-hydroxyethyl methacrylate were selected to prepare interpenetrating polymeric networks and linear alginate chains were added as an interpenetrant to study their influence on the scaffold's functionalities. Cryogelation and porogenation methods were used to obtain the designed scaffolding biomaterials. The scaffold's structural, morphological, and mechanical properties, in vitro degradation, and cell viability properties were assessed to study the effects of the preparation method and alginate loading. Apatite as an inorganic agent was incorporated into cryogelated scaffolds to perform an extensive biological assay. Cryogelated scaffolds possess superior functionalities essential for tissue regeneration: fully hydrophilicity, degradability and mechanical features (2.08-9.75 MPa), and an optimal LDH activity. Furthermore, cryogelated scaffolds loaded with apatite showed good cell adhesion capacity, biocompatibility, and non-toxic behavior. All scaffolds performed equally in terms of metabolic activity and osteoconductivity. Cryogelated scaffolds with/without HAp could represent a new advance to promote osteoconductivity and enhance hard tissue repair. The obtained series of scaffolding biomaterials described here can provide a wide range of potential applications in the area of biomedical engineering.


[Tesigraphic studies of the blood serum in psoriasis patients].
82 patients with psoriasis and 10 apparently healthy subjects (group of control) were examined. After analysis of the psoriasis patients blood serum thesigrammes in this study 3 distinct types were identified: tree-like one (49%), bush-bunch type (44%), and polymorphous type (7%). In a microscopic investigation, thesigrammes of psoriasis patients differed from those of healthy subjects in respect of morphostructural features in spite of macroscopic similarity. While studying thesigrammes during the time-related course of the illness significant differences depending on the stage of psoriasis were disclosed. The results secured permit asserting that the thesigraphic method of investigation into the blood serum can be used for the diagnosis of the condition, objectivization of control over the effectiveness of treatment and prognostication of the course of psoriasis.


Lytic action of cloned phi X174 gene E.
The phi X174 lysis gene E was placed under control of the lac promoter by cloning into the multicopy plasmid pBH20. Other phi X174 gene sequences were removed by nuclease digestion. Expression of gene E was shown to be necessary and sufficient to produce lysis phenomena exhibited by infection with intact phage. Lysis, its inhibition by MgSO4 and spermine, its progression through a spheroplasting stage, and its dependence on an early chloramphenicol-sensitive step were reproduced in clones induced for expression of the E gene product. Escherichia coli clones carrying the E gene not under lac control, and clones under lac control but only minimally induced for gene E expression, exhibited morphological aberrations consistent with the view that the mechanism by which gene E mediates cell lysis is related to host cell division processes.


Cytoplasmic APOBEC3G restricts incoming Vif-positive human immunodeficiency virus type 1 and increases two-long terminal repeat circle formation in activated T-helper-subtype cells.
Cytoplasmic APOBEC3G has been reported to block wild-type human immunodeficiency virus type 1 (HIV-1) infection in some primary cells. It is not known whether cytoplasmic APOBEC3G has residual activity in activated T cells, even though virion-packaged APOBEC3G does restrict HIV-1 in activated T cells. Because we found that APOBEC3G expression is greater in activated CD4(+) T-helper type 1 (Th1) lymphocytes than in T-helper type 2 (Th2) lymphocytes, we hypothesized that residual target cell restriction of incoming Vif-positive virions that lack APOBEC3G, if present, would be greater in Th1 than Th2 lymphocytes. Infection of activated Th1 cells with APOBEC3-negative virions did result in decreased amounts of early and late reverse transcription products and integrated virus relative to infection of activated Th2 cells. Two-long terminal repeat (2-LTR) circles, which are formed in the nucleus when reverse transcripts do not integrate, were increased after APOBEC3-negative virus infection of activated Th1 cells relative to infection of activated Th2 cells. In contrast, 2-LTR circle forms were decreased after infection of APOBEC3G-negative cells with APOBEC3G-containing virions relative to APOBEC3G-negative virions and with Th1 cell-produced virions relative to Th2 cell-produced virions. Increasing APOBEC3G in Th2 cells and decreasing APOBEC3G in Th1 cells modulated the target cell phenotypes, indicating causation by APOBEC3G. The comparison between activated Th1 and Th2 cells indicates that cytoplasmic APOBEC3G in activated Th1 cells partially restricts reverse transcription and integration of incoming Vif-positive, APOBEC3G-negative HIV-1. The differing effects of cytoplasmic and virion-packaged APOBEC3G on 2-LTR circle formation indicate a difference in their antiviral mechanisms.


Interviewer gender and self-reported sexual behavior and mental health among male military personnel.
To determine whether self-reported sexual behavior and mental health varied by interviewer gender in a population of male military personnel. Eight male and six female data collectors verbally administered structured interviews to 474 male Dominican military personnel stationed at border crossing zones in the Dominican Republic. Measurements included sexual behaviors and mental health. Respondents were less likely to report oral and vaginal sex to male interviewers, and were more likely to report sexual coercion and alcohol abuse to male interviewers. Respondents were more likely to report depression and post-traumatic stress disorder to female interviewers. Interviewer gender influenced the prevalence of sexual behaviors and mental health, which carries implications for future research in military personnel.


Cyanine fluorochrome-labeled antibodies in vivo: assessment of tumor imaging using Cy3, Cy5, Cy5.5, and Cy7.
Monoclonal antibodies to two different targetable antigens were conjugated to each of four commercially available cyanine fluorochromes. Equal amounts of all four antibodies were coinjected into tumor-bearing animals and imaged. Small, superficial tumors were adequately labeled using all four fluorochromes. Large tumors were labeled well only by Cy7, probably due to self-masking and dilution effects. Cy7 was superior to other cyanine fluorochromes for visualizing structures located deep within the animal.


Intermolecular interaction energies and molecular conformations in N-substituted 4-aryl-2-methylimidazoles with promising in vitro antifungal activity.
A convenient one-pot synthesis of 4-aryl-2-methyl-N-phenacylimidazoles (4) through a microwave-assisted pseudo-tricomponent reaction of α-bromoacetophenones (1) with acetamidine hydrochloride (2) is reported. Ketones (4) were successfully used as substrates for the preparation of the respective N-(2-hydroxyethyl)imidazoles (5) with yields up to 87%. The synthesized compounds were characterized by NMR and high-resolution mass spectrometry analyses, and several structures were confirmed and studied by single-crystal X-ray diffraction. The analysis of the whole-of-molecule interactions shows that, despite the difference in the atom-atom contacts forming the crystals, dispersion energies make the largest contribution to the formation of the solids, giving an isotropic tendency in the topology of the energy framework diagrams for pairs of molecules. In addition, the in vitro antifungal activity of both families of compounds [ketones (4) and alcohols (5)] against Candida albicans and Cryptococcus neoformans was evaluated, where the 2,4-dichlorophenyl-substituted alcohol (5f), an isomer of the drug miconazole, showed the highest activity (IC50 = 7.8 µg ml-1 against C. neoformans).


Collagenase production by smooth muscle: correlation of immunoreactive with functional enzyme in the myometrium.
A monospecific antibody to rat uterine collagenase has been produced and employed to study the cell of origin and the time course of production of this enzyme in the involuting rat uterus. The specificity of the anti-collagenase antibody was confirmed by immunoprecipitation, Western analysis, and by its ability to inhibit the activity of collagenase. Parallel measurements of functional enzyme, both latent and active, bound to tissue collagen were also made in nonpregnant, gravid, and postpartum rat uteri. Immunohistochemical staining of collagenase in sections of rat uterus showed the enzyme to be present in the perinuclear region of the smooth muscle cells only of the involuting myometrium. No detectable collagenase was present in the prepartum or nonpregnant uterus. Identity of the smooth muscle cells was confirmed using an anti-smooth muscle actin antibody. In addition, the cultured uterine cells from which the immunizing antigen was obtained were also identified as smooth muscle cells. Specificity of the tissue staining was confirmed by the ability of pure rat uterine collagenase to block the reaction of the antibody with the tissue. These observations indicate that smooth muscle cells are capable of producing collagenase and are consistent with the hypothesis that this enzyme presides over the massive collagen degradation seen in postpartum uterine involution. Furthermore, measurement of collagenase bound to uterine collagen revealed that collagenase activity could be detected only at the time that the cells could be seen to be producing the enzyme by immunolocalization. These findings support the concept that collagenase is produced only as needed and not stored, either intra- or extra-cellularly.


Impaired expression of Notch signaling genes in aged human skeletal muscle.
Notch signaling is essential for myogenesis and the regenerative potential of skeletal muscle; however, its regulation in human muscle is yet to be fully characterized. Increased expression of Notch3, Jagged1, Hes1, and Hes6 gene transcripts were observed during differentiation of cultured human skeletal muscle cells. Furthermore, significantly lower expressions of Notch1, Jagged1, Numb, and Delta-like 1 were evident in muscle biopsies from older men (60-75 years old) compared to muscle from younger men (18-25 years old). Importantly, with supervised resistance exercise training, expression of Notch1 and Hes6 genes were increased and Delta-like 1 and Numb expression were decreased. The differences in Notch expression between the age groups were no longer evident following training. These results provide further evidence to support the role of Notch in the impaired regulation of muscle mass with age and suggest that some of the benefits provided by resistance training may be mediated through the Notch signaling pathway.


Gastric cancer in women: A regional health-center seven year retrospective study.
To investigate whether regional geography influences ethnic and gender trends for the development of gastric cancer (GC). This retrospective analysis of the INVISION patient database at Louisiana State University Health Sciences Center-Shreveport (LSUHSC-S), a southern United States regional hospital, was performed from 2005-2011. Using the international statistical classification of diseases 9 (ICD-9), inpatient, day surgery outpatient, and emergency outpatient diagnosis codes entered into medical records were used to identify GC patients. For each study year, the patients were evaluated for age, ethnicity, and gender, and each patient was counted only once throughout the study. Subsequent patient encounters were counted as visits and separated by inpatient and clinic visits. Complex or severe disease may require more frequent and intensive clinical management; therefore, we evaluated annual clinic visits as "surrogate markers" of disease severity. Finally, we studied the primary diagnosis for Helicobacter pylori (H. pylori) infection (ICD-9 code 41.86) as an additional factor that might increase the risk of GC. A total of 285 patients were diagnosed with GC at LSUHSC-S between 2005 and 2011. African Americans (181 patients, 89 males and 92 females, 63.5% of total patients) had significantly higher frequencies of GC diagnosis compared with non-Hispanic whites (104 patients, 54 males and 50 females, 36.5% of total patients), at a ratio of 1.74 (P = 0.002). Within each ethnic group, men and women were diagnosed at approximately equal annual rates. Our findings differed significantly from United States national trends, which found that African American females and white females had lower risks for GC than their corresponding male counterparts. The United States national trend between 2005 and 2011 showed that African Americans males had a higher incidence of GC, with an annual mean (per 100000) of 16.31 ± 0.76 compared with white males (9 ± 0.1, P < 0.001), African American females (8.7 ± 0.34, P < 0.001) and white females (4.05 ± 0.07, P < 0.001). Among the GC patients, the number of clinic visits was highest among African American males (195.1 ± 28.1), who had significantly more clinic visits than African Americans females (123 ± 13.02, P < 0.05), white males (41.57 ± 4.74, P < 0.001) and white females (35 ± 8.9, P < 0.001). Similar trends were found for inpatient visits, with an annual mean of 11.43 ± 1.5 for African American males, followed by African American females (7.29 ± 1.36), white males (2.57 ± 0.69) and white females (1.57 ± 0.612). African American males had significantly more inpatient visits than white males (P < 0.001), and African American females had more inpatient visits than white females (P < 0.01). African American patients showed the highest frequency of H. pylori positive status, with approximately 72% vs 28% for the white patients. Increase in GC diagnoses among women at LSUHSC-S is significantly higher than United States national averages, suggesting local geographic and socioeconomic influences may alter GC disease course.


Congestive heart failure complicating non-ST segment elevation acute coronary syndrome: incidence, predictors, and clinical outcomes.
There are limited data regarding the incidence and clinical significance of congestive heart failure (CHF) in patients with non-ST segment elevation acute coronary syndromes (ACS). The objectives of this study were to examine the incidence, predictors, and clinical outcomes in patients with ACS without ST elevation who develop CHF. We studied patients with unstable angina or non-ST segment elevation myocardial infarction (NSTEMI) randomized to hirudin or unfractionated heparin in the Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) trial. The diagnosis of CHF was based on a combination of clinical and radiographic features. Patients were followed for 6 months. Of 10 141 randomized patients, 501 (4.9%) developed CHF within the first week and 643 (6.3%) during 6 months of followup. Independent predictors for the development of CHF were older age, female sex, diabetes, prior MI, prior CHF, and NSTEMI at presentation. Compared with patients who did not develop CHF, patients who developed CHF were at increased risk of death (odds ratio (OR) 3.4, 95% CI 2.7-4.3), new MI (OR 2.8, 95% CI 2.2-3.6), and the need for intra-aortic balloon pump insertion (OR 5.4, 95% CI 3.5-8.4) at 7 days and 6 months. There was no increase in use of cardiac catheterization (OR 0.8, 95% CI 0.7-1.0) or revascularization (OR 0.9, 95% CI 0.7-1.1) in patients who developed CHF. CHF is a common complication in patients presenting with non-ST segment elevation ACS and is strongly associated with adverse clinical outcomes including new MI and death. Despite this worse prognosis, patients with ACS developing CHF are less likely to be referred for invasive management.


Machine learning of biomarkers and clinical observation to predict eosinophilic chronic rhinosinusitis: a pilot study.
Subtyping chronic rhinosinusitis (CRS) by tissue eosinophilia has prognostic and therapeutic implications, and is difficult to predict using peripheral eosinophil counts or polyp status alone. The objective of this study was to test machine learning for prediction of eosinophilic CRS (eCRS). Input variables were defined as peripheral eosinophil count, urinary leukotriene E4 (uLTE4) level, and polyp status. The output was diagnosis of eCRS, defined as tissue eosinophil count >10 per high-power field. Patients undergoing surgery for CRS were retrospectively reviewed for complete datasets. Univariate analysis was performed for each input as a predictor of eCRS. Logistic regression and artificial neural network (ANN) machine learning models were developed using random and surgeon-specific training/test datasets. A total of 80 patients met inclusion criteria. In univariate analysis, area under the receiver operator characteristic curve (AUC) for peripheral eosinophil count and uLTE4 were 0.738 (95% confidence interval [CI], 0.616 to 0.840) and 0.728 (95% CI, 0.605 to 0.822), respectively. Presence of polyps was 94.1% sensitive, but 51.7% specific. Logistic regression models using random and surgeon specific datasets resulted in AUC of 0.882 (95% CI, 0.665 to 0.970) and 0.945 (95% CI, 0.755 to 0.995), respectively. ANN models resulted in AUC of 0.918 (95% CI, 0.756 to 0.975) and 0.956 (95% CI, 0.828 to 0.999) using random and surgeon-specific datasets, respectively. Model comparison of logistic regression and ANN was not statistically different. All machine learning models had AUC greater than univariate analyses (all p < 0.003). Machine learning of 3 clinical inputs has the potential to predict eCRS with high sensitivity and specificity in this patient population. Prospective investigation using larger and more diverse populations is warranted.


[Prediction of the effects of energy-stabilizing drugs in diabetes mellitus].
The authors describe a method for the prediction of the therapeutic effect of energy-stabilizing drugs, that helps rapidly select the optimal individual therapeutic policy. The method is based on measurement of the red cell ATP concentration in the course of in vitro incubation of cells in polyionic medium with the drug, and may be used in various diseases associated with energy metabolism disorders on the cellular level. The authors have used this method for the selection of a thiamine drug to be included in therapy of a diabetic in the period of the disease compensation.


Enhanced recovery after surgery for hip and knee arthroplasty: a systematic review and meta-analysis.
To collect data of randomised controlled trials (RCTs) and clinical controlled trials (CCTs) for evaluating the effects of enhanced recovery after surgery on postoperative recovery of patients who received total hip arthroplasty (THA) or total knee arthroplasty (TKA). Relevant, published studies were identified using the following key words: arthroplasty, joint replacement, enhanced recovery after surgery, fast track surgery, multi-mode analgesia, diet management, or steroid hormones. The following databases were used to identify the literature consisting of RCTs or CCTs with a date of search of 31 December 2016: PubMed, Cochrane, Web of knowledge, Ovid SpringerLink and EMBASE. All relevant data were collected from studies meeting the inclusion criteria. The outcome variables were postoperative length of stay (LOS), 30-day readmission rate, and total incidence of complications. RevMan5.2. software was adopted for the meta-analysis. A total of 10 published studies (9936 cases) met the inclusion criteria. The cumulative data included 4205 cases receiving enhanced recovery after surgery (ERAS), and 5731 cases receiving traditional recovery after surgery (non-ERAS). The meta-analysis showed that LOS was significantly lower in the ERAS group than in the control group (non-ERAS group) (p<0.01), and there were fewer incidences of complications in the ERAS group than in the control group (p=0.03). However, no significant difference was found in the 30-day readmission rate (p=0.18). ERAS significantly reduces LOS and incidence of complications in patients who have had THA or TKA. However, ERAS does not appear to significantly impact 30-day readmission rates.


Melatonin protects from ischemia/reperfusion-induced renal injury in rats: this effect is not mediated by proinflammatory cytokines.
The pathophysiologic mechanisms leading to acute ischemic renal failure are not completely understood. Melatonin, a compound with well-known antioxidant properties, reduces IR-induced renal injury. The purpose of the present study was to investigate the changes in levels of tumor necrosis factor (TNF)-alpha, IL-beta, and IL-6 in postischemic reperfused renal tissue, and to determine whether the protective effect of melatonin is related the modulation of the production of these inflammatory molecules. Male Wistar albino rats were unilaterally nephrectomized and subjected to 1 hr of renal pedicle occlusion followed by 2 hr or 24 hr of reperfusion. Melatonin (10 mg/kg, i.p.) or vehicle was administrated at 10 min prior to ischemia. After 24 hr of the reperfusion, following decapitation, kidney samples were taken both for histologic examination and for the determination of malondialdehyde (MDA), myeloperoxidase (MPO) activity, total antioxidant capacity (TAC), total oxidative stress (TOS), creatinine, and blood urea nitrogen (BUN). These were measured in serum samples. TNF-alpha, IL-beta, and IL-6 were measured in kidney samples after 2 hr of reperfusion. IR caused a significant increase in renal MDA, MPO, TOS, creatinine, and BUN while decrease TAC without any change in TNF-alpha, IL-beta, and IL-6 levels. Melatonin treatment reduced the biochemical indices without any change in the cytokine levels and ameliorated histopathologic alterations induced by IR. The protective effect of melatonin on IR-induced renal injury is related to its antioxidant properties but not to proinflammatory cytokines.