The prevalence and impact of potentially inappropriate prescribing among older persons in primary care settings: multilevel meta-analysis.
Potentially inappropriate prescribing (PIP) may not have received as much attention in primary care settings (compared to tertiary hospital and nursing home settings), due to uncertainty about its prevalence in this healthcare setting. We conducted a systematic review with meta-analysis to summarise the prevalence of PIP specific to primary care settings and computed the population attributable risk (PAR) to estimate the impact of PIP in primary care. We searched PubMed, Embase, CINAHL, Web of Science, Scopus, PsycINFO and previous review articles for studies related to 'older persons', 'primary care' and 'inappropriate prescribing'. Two reviewers selected eligible articles, extracted data and evaluated risk of bias. Multilevel meta-analysis was conducted to pool the prevalence estimates across the included studies, while meta-regression was conducted to investigate the sources of heterogeneity. Of the 4,259 articles identified, we included 67 articles with 111 prevalence estimates and a total of 5,054,975 participants. Overall, PIP had a pooled prevalence of 33.3% (95% CI 29.7-37.0%). Based on population attributable risks, PIP explained 7.7-17.3% of adverse outcomes related to older persons in primary care. If current PIP prevalence is halved, 37-79 cases of adverse outcomes may potentially be prevented (per 1,000 adverse outcomes). The findings demonstrate the relevance and potential impact of PIP specific to primary care settings. Given the increasingly central role that primary care plays in coordinating healthcare, the findings highlight the need to prioritise PIP intervention in primary care as a key strategy to reduce iatrogenic medication-related harm among older persons in current healthcare system.


An impression procedure for the neonatal patient with a cleft palate.
An impression procedure for the neonatal patient with a cleft palate is described. The procedure has been used at Beth Israel Medical Center, New York City, for the past 10 years and has been proved safe, reliable, and precise.


[On Synergism of Potassium and Magnesium in Maintenance of Myocardial Function].
systematization of studies of synergistic effect of potassium and magnesium on myocardial function. Analysis of an array of literature using methods of computer learning. Synergism of potassium and magnesium is driven by common causes of deficit (low content in diet, abnormal renal function, iatrogenic causes), by potassium sparing effects of magnesium, and by regulatory properties of magnesium in processes affecting potassium binding proteins (first of all potassium rectifier channels). Magnesium and potassium exert substantial synergism in maintenance of cardiac rhythm (in particular preventing QT prolongation) and in cardioprotection. Combination administration of organic potassium and magnesium salts was shown to be effective for urgent therapy and long term prevention both as intravenous and oral formulations.


Hypertension-related mortality in California.
Death rates in California for hypertension-related diseases during 1969-71 and 1979-81 are compared. During both periods, age-standardized rates for a composite hypertension-related mortality category are highest for blacks, followed by whites, and lowest for Asians and Pacific Islanders. Filipinos who have high prevalence rates of hypertension record low rates of hypertension-related mortality. After adjusting for the comparability ratio, the age-standardized hypertension-related death rate declined by more than 28 percent between 1969-71 and 1979-81. The decrease was greatest at age 15-44 years. Of all major hypertension-related diseases, cerebrovascular diseases registered consistently large percentage declines in mortality for all age and race groupings examined. Possible reasons for the considerable decline in hypertension-related mortality and low death rates for Asians and Pacific Islanders are discussed. The combined effects of improved population awareness, level of treatment, and control of hypertension; a greater knowledge of cardiovascular risk factors and associated modifications of behavior; and improved medical technology and care may have contributed to the decline.


Trends in maternal obesity and associated risks of adverse pregnancy outcomes in a population of Chinese women.
To assess the effect of increasing body mass index (BMI) on pregnancy outcome in a population of Chinese women. A retrospective study. A university teaching hospital. Women delivering singleton babies between 1995 and 2005 who sought antenatal care before 20 weeks of gestation. A total of 29,303 women were categorised into six BMI groups according to WHO's classification. Univariate, multivariate and logistic regression analysis were performed to compare obstetric and perinatal outcomes between BMI groups. Incidences of caesarean delivery, pre-eclampsia, gestational diabetes, preterm delivery, small for gestational age (SGA) and large for gestational age (LGA), perinatal death, and the respective odd ratios in reference to the normal group with BMI > or = 18.5 kg/m(2) and <23 kg/m(2). The median BMI increased with increasing maternal age, parity, gestation at the first visit, but decreased with year of delivery (P < 0.001). Concerning the obstetric outcomes, increasing BMI was associated with increasing incidence of caesarean section, pre-eclampsia, gestational diabetes, preterm delivery, LGA, as well as SGA according to customised growth standards (P < 0.001). The odds ratios for most of these adverse outcomes are higher than those reported in Caucasian population. Increasing BMI was not associated with the rate of stillbirth, neonatal death or shoulder dystocia. Increasing BMI is associated with increased risks of adverse obstetric outcomes. The impacts of high BMI on pre-eclampsia, gestational diabetes and preterm delivery in Chinese women might be stronger than that in Caucasian. Hence, it may be appropriate to use a lower BMI cutoff for defining overweight in Chinese.


Multiple papillomavirus-associated epidermal hamartomas and squamous cell carcinomas in situ in a dog following chronic treatment with prednisone and cyclosporine.
A 4-year-old, spayed female toy fox terrier developed multiple epidermal hamartomas and squamous cell carcinomas in situ following chronic immunosuppressive therapy with prednisone and cyclosporine for management of an immune-mediated nonregenerative anaemia. Immunohistochemical staining was positive for papillomavirus antigen within both benign (n = 19) and malignant (n = 8) cutaneous lesions that developed during a 3-year period of observation, with positive staining most often seen in keratinocytes in the granular cell layer. Treatment of the papillomavirus infection with interferon-alpha was discontinued after 2 weeks because of diarrhoea and a further increase in liver enzymes. The cutaneous lesions of this dog persisted and new lesions developed during the year following discontinuation of both cyclosporine and prednisone. This is the first reported case of papillomavirus-associated squamous cell carcinoma in situ developing in a dog following chronic administration of cyclosporine and prednisone.


G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation.
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic CNS angiogenesis; thus we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using χ(2) analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of 3 GPR124 SNPs adjacent to exon 2 and localized to a 16 kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P=0.001; rs7823249 T, P=0.014; rs12676965 C, P=0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P=0.033). Haplotype analysis revealed a significant overall association (χ(2)=12.55, 4 df, P=0.014); 2 haplotypes (ATCC, P=0.006 and GGCT, P=0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2, however genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel indel polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.


[Evaluation of a purified antigen for the diagnosis of toxocariosis].
Toxocarosis is a zoonotic disease caused by the ingestion of infective eggs of Toxocara spp. The diagnosis is based on the detection of antibodies in serum or other biological fluids. One of the current serological techniques for the diagnosis of toxocariasis is ELISA using excretory - secretory antigens of third stage larvae (ES/L3). These antigens are glycoproteins, which originate in the secretory organs of the parasite and are non species-specific. Sera from patients with other helminthiases and non- parasitic diseases were used to evaluate the specificity of ELISA using the excretory - secretory antigen (ES/L3). The reactivity of these sera was between 11 and 70%. Western blot using patients' sera revealed that the glycoprotein triplet having a molecular weight of 120 kDa was responsible for cross-reactivity. With these results, and for the purpose of purifying the antigen, ion exchange chromatography was performed. When the sera from patients with various parasitic and non-parasitic diseases were analyzed with the purified antigen ES/ L3, they were only reactive between 10 to 20%. The sensitivity of the ELISA test determined by program Epidat 3.0 for the two antigens was 100%, but the following differences in specificity were observed: 84% for the total antigen ES/L3 and 99% for purified ES/L3. Using the ES/L3 purified antigen, it can be considered that the reactive sera, with compatible symptoms correspond to patients who are or were parasitized with Toxocara canis.


[Cytochemical characteristics of nucleic acids in the peripheral blood lymphocytes of patients with multiple sclerosis].
DNA and RNA was determined with the aid of cyto-chemical methods in lymphocytes of the peripheral blood of 101 patients with disseminated sclerosis. Changes of the DNA were not found. Quite possibly, the increase of cyto-chemical indices of RNA in the lymphocytes of such patients depends upon the reactivity of the organism the degree of its sensitization and activity of the pathological process.


Immunoregulation by monoclonal sheep erythrocyte-specific IgG antibodies: suppression is correlated to level of antigen binding and not to isotype.
Six different monoclonal IgG antibodies with specificities for sheep erythrocytes (SRBC) were tested for immunosuppressive ability. Four of them, one IgG3, two IgG2a, and one IgG1, could yield suppression of more than 90% of the anti-SRBC response. The remaining two antibodies, which were both IgG2a, were found to have no significant effect. The degree of suppression correlated well with the amount of antibodies used that could bind to SRBC, as measured by an ELISA assay. High avidity for SRBC was also a factor making the monoclonal antibody more efficient as an immunosuppressor. The response against antigenic determinants on the SRBC other than those for which the monoclonals were specific, was suppressed to an equal degree. This was established by immunizing mice with SRBC using monoclonal anti-SRBC antibodies that did or did not bind to goat RBC (GRBC). The PFC responses against both SRBC and GRBC were then measured. The anti-SRBC and GRBC responses were suppressed in parallel regardless of whether or not the monoclonal reacted with GRBC. None of the tested antibodies displayed any significant ability to enhance the anti-SRBC response. Thus, IgG1 is not the only murine isotype that can efficiently suppress the immune response against SRBC, but IgG2a and IgG3 can also exert this capacity. The mechanism of IgG-mediated suppression is not one of merely blocking single epitopes but involves the immunogenicity of the entire SRBC.


Membrane potentials regulating GPCRs: insights from experiments and molecular dynamics simulations.
G-protein coupled receptors (GPCRs) form the largest class of membrane proteins in humans and the targets of most present drugs. Membrane potential is one of the defining characteristics of living cells. Recent work has shown that the membrane voltage, and changes thereof, modulates signal transduction and ligand binding in GPCRs. As it may allow differential signalling patterns depending on tissue, cell type, and the excitation status of excitable cells, GPCR voltage sensitivity could have important implications for their pharmacology. This review summarises recent experimental insights on GPCR voltage regulation and the role of molecular dynamics simulations in identifying the structural basis of GPCR voltage-sensing. We discuss the potential significance for drug design on GPCR targets from excitable and non-excitable cells.


Marathon: a life-and-death experience.
Therapists have a great need for techniques capable of provoking change in their clients. Generally, people resist change and need incentives to accomplish it. The tools to effect change are few. Therefore, the value of the theme Marathon experience is that it can be both innovative and piercing. Many clients need to have the drama of their own lives connected to a meaningful plot. The theme Marathon experience can do this. It exerts an influence on the emotional, cognitive and behavioral aspects of the participants and connects their past to the present and future, allowing them to see clearly the futility of a life of chemical dependence.


Stress ulcer prophylaxis for non-critically ill patients on a teaching service.
Doctors frequently give non-critically ill patients unjustified stress ulcer prophylaxis (SUP). It is unknown if this practice also occurs during residency training. To evaluate the pattern of SUP given to non-critically ill medical patients on the teaching service of an internal medicine residency programme. This was a retrospective cohort study of non-critically ill adults admitted to the internal medicine teaching service of a community hospital from August 2003 to July 2004. We assessed receipt of SUP, association of SUP with risk factors for stress ulcer bleeding; appropriateness of SUP according to evidence-based criteria; and incidence of stress ulcer bleeding. Of the 774 patient records reviewed, 545 were included in the study. The average age was 55.4 years. Patients were more likely to receive SUP if they had more risk factors for stress ulcer bleeding (P < 0.001). Overall, 54.9% (299 of 545) of patients received SUP. Of these 299 patients, at least 58.5% did not warrant SUP, depending on the criteria used. Of the entire cohort of 545 non-critically ill patients, 32.1% to 54.9% received unjustified SUP, depending on the criteria applied. There were no cases of stress ulcer bleeding. Many non-critically ill patients on the teaching service received unjustified SUP, suggesting the need for institutional protocols and educational interventions to promote evidence-based practice during residency training.


Selective serotonin reuptake inhibitor fluoxetine inhibits replication of human enteroviruses B and D by targeting viral protein 2C.
Although the genus Enterovirus contains many important human pathogens, there is no licensed drug for either the treatment or the prophylaxis of enterovirus infections. We report that fluoxetine (Prozac)--a selective serotonin reuptake inhibitor--inhibits the replication of human enterovirus B (HEV-B) and HEV-D but does not affect the replication of HEV-A and HEV-C or human rhinovirus A or B. We show that fluoxetine interferes with viral RNA replication, and we identified viral protein 2C as the target of this compound.


The partition matrix: exploring variable phylogenetic signals along nucleotide sequence alignments.
The partition matrix is a graphical tool for comparative analysis of nucleotide sequences following alignment. It is particularly useful for investigating the divergent phylogenies of sequence regions undergoing reticulate evolution. A partition matrix is generated by determining the consistency of the parsimoniously informative sites in a set of aligned sequences with the binary partitions inferred from the sequences. Since the linear order of sites is maintained, the matrix can be used to assess whether the distribution of sites either supporting or conflicting with particular partitions changes along the length of the alignment. The usefulness of the matrix in allowing visual identification of differences in evolutionary history among regions depends on the order in which partitions are shown; several suitable ordering schemes are proposed. We demonstrate the use of the partition matrix in interpreting the evolution of the pseudoautosomal boundary region on the sex chromosome of catarrhine primates. Its routine use should help to avoid attempts to derive single phylogenies from sequences whose evolution has been reticulate and to identify the gene conversion or recombination events underlying the reticulation. The method is relatively fast. It is exploratory, and it can form the basis for more formal analysis, which we discuss.


Clinical and Radiographic Characteristics of Vertical Root Fractures in Endodontically and Nonendodontically Treated Teeth.
A vertical root fracture (VRF) is a root fracture extending along the longitudinal axis of roots and is often noted in endodontically treated teeth. However, the clinical and radiographic characteristics of VRFs are not completely known. A total of 65 teeth with 68 vertical fractured roots in 58 Chinese patients were investigated. The clinical examination records and radiographic images were reviewed in detail. A total of 24 male (41.38%) and 34 female (58.62%) patients aged 25-90 years (average = 57 years) were included; 51 (87.93%) and 7 (12.07%) patients exhibited 1 tooth and 2 teeth with VRFs, respectively, in the dentition. VRFs occurred mainly in the mesial root (20 roots, 57.14%) of the mandibular molars (29 teeth, 44.62%). Clinically, teeth with VRFs usually presented a periodontal probing depth >5 mm (44 teeth, 91.67%, P < .001) with a prosthesis (55 teeth, 84.62%, P < .001) and a relatively intact dentition (42 patients exhibited <4 missing teeth in the dentition, 77.78%, P < .001). Most of the nonendodontically treated VRFs exhibited attrited occlusal surfaces. Radiographic characteristics of the teeth with VRFs were typically associated with prior root canal treatment (56 teeth, 86.15%, P < .001), periodontal bone loss (62 teeth, 95.38%, P < .001), apical bone loss (52 teeth, 80.00%, P < .001), and periodontal ligament widening (61 teeth, 93.85%, P < .001). The mesial roots of the mandibular molars were most susceptible to VRFs in both endodontically and nonendodontically treated teeth. These results elucidated some clinical and radiographic and diagnostic features that facilitate VRF identification.


Phenytoin binding and renal transplantation.
Limited data are available on the effect of renal transplantation on the abnormal phenytoin (PHT) binding found in uremic patients. We studied PHT binding before and after transplantation in eight patients. Return of PHT binding to normal correlated well with recovery of renal function. Correlations with serum albumin and free fatty acid levels were also studied.


Consumption of uncooked deer meat as a risk factor for hepatitis E virus infection: an age- and sex-matched case-control study.
It was reported previously food-borne transmission of hepatitis E virus (HEV) to humans from deer meat. The present study attempted to clarify whether eating uncooked deer meat is a major epidemiological risk factor for HEV infection in Kasai, a city in western Japan. In total, 45 volunteer subjects with experience of eating raw deer meat were enrolled. An equivalent number of people from the same area who had never eaten raw deer meat served as controls. The subjects and controls had comparable age and sex distributions. Serum anti-HEV IgG and anti-hepatitis A virus (HAV) IgG levels were measured in all 90 volunteers. There was no significant difference in age, overseas travel history, or rate of anti-HAV antibody positivity between the subjects and controls. Eight (17.7%) of the subjects but only one (2.2%) of the controls had measurable serum anti-HEV IgG levels (P = 0.014). Anti-HAV prevalence did not differ between the anti-HEV-positive and negative groups. The results suggest that eating uncooked deer meat is an epidemiological risk factor for HEV infection in the studied area. In countries such as Japan where deer meat is sometimes eaten raw, attention must be paid to this route of HEV infection.


A robust volumetric apparatus and method for measuring high pressure hydrogen storage properties of nanostructured materials.
A volumetric apparatus to measure hydrogen adsorption and desorption at room temperature and up to 100 atm has been constructed and studied for accuracy, reproducibility, and stability. The design principles are presented and considerable attention to detail is given to examine the effects of diurnal temperature changes in the manifold and helium adsorption by carbon-based adsorbents during free volume measurement. A heuristic for helium correction is derived from a model with a basis in literature and verified through calculation of adsorbent density. Several materials with well-known hydrogen capacities are studied to examine reproducibility. The microporous carbon AX-21 is studied to examine the effects of pressure step size and approach to equilibrium caused by gas mixing and the Joule-Thomson effect. Hydrogen spillover on a hybrid material, Pt on templated carbon, is examined for several loadings of metal. Kinetics of both physisorption and spillover are compared via the diffusion time constant (D/R(2)) estimated by fitting models for pore and surface diffusion to time-dependent adsorption profiles. No concentration dependence was found for pore diffusion; however, the surface diffusion time constant was shown to decrease with respect to increasing hydrogen concentration.


H3K36 Methylation and the Chromodomain Protein Eaf3 Are Required for Proper Cotranscriptional Spliceosome Assembly.
In the eukaryotic cell, spliceosomes assemble onto pre-mRNA cotranscriptionally. Spliceosome assembly takes place in the context of the chromatin environment, suggesting that the state of the chromatin may affect splicing. The molecular details and mechanisms through which chromatin affects splicing, however, are still unclear. Here, we show a role for the histone methyltransferase Set2 and its histone modification, H3K36 methylation, in pre-mRNA splicing through high-throughput sequencing. Moreover, the effect of H3K36 methylation on pre-mRNA splicing is mediated through the chromodomain protein Eaf3. We find that Eaf3 is recruited to intron-containing genes and that Eaf3 interacts with the splicing factor Prp45. Eaf3 acts with Prp45 and Prp19 after formation of the precatalytic B complex around the time of splicing activation, thus revealing the step in splicing that is regulated by H3K36 methylation. These studies support a model whereby H3K36 facilitates recruitment of an "adapter protein" to support efficient, constitutive splicing.


The Clinical Impact of Anti-HLA Donor Specific Antibody Detection Through First Year Screening on Stable Kidney Transplant Recipients.
Anti-HLA Donor Specific Antibody (DSA) detection post kidney transplant has been associated with adverse outcomes, though the impact of early DSA screening on stable patients remain unclear. We analyzed impact of DSA detection through screening in 1st year stable patients (n = 736) on subsequent estimated glomerular filtration rate (eGFR), death censored graft survival (DCGS), and graft failure (graft loss including return to dialysis or re-transplant, patient death, or eGFR < 20 ml/min at last follow up). Patients were grouped using 1st year screening into DSA+ (Class I, II; n = 131) or DSA- (n = 605). DSA+ group were more DR mismatched (p = 0.02), more sensitized (cPRA ≥90%, p = 0.002), less Caucasian (p = 0.04), and had less pre-emptive (p = 0.04) and more deceased donor transplants (p = 0.03). DSA+ patients had similar eGFR (54.8 vs. 53.8 ml/min/1.73 m2, p = 0.56), DCGS (91% vs. 94%, p = 0.30), and graft failure free survival (76% vs. 82%, p = 0.11). DSA timing and type did not impact survival. Among those with a protocol biopsy (n = 515), DSA detected on 1st year screening was a predictor for graft failure on multivariate analysis (1.91, 95% CI 1.03-3.55, p = 0.04). Overall, early DSA detection in stable patients was an independent risk factor for graft failure, though only among those who underwent a protocol biopsy.


Engineered calcium-precipitable restriction enzyme.
We have developed a simple system for tagging and purifying proteins. Recent experiments have demonstrated that RTX (Repeat in Toxin) motifs from the adenylate cyclase toxin gene (CyaA) of B. pertussis undergo a conformational change upon binding calcium, resulting in precipitation of fused proteins and making this method a viable alternative for bioseparation. We have designed an iGEM Biobrick comprised of an RTX tag that can be easily fused to any protein of interest. In this paper, we detail the process of creating an RTX tagged version of the restriction enzyme EcoRI and describe a method for expression and purification of the functional enzyme.


What Can We Learn from a Biomimetic Model of Nature's Oxygen-Evolving Complex?
A recently reported synthetic complex with a Mn4CaO4 core represents a remarkable structural mimic of the Mn4CaO5 cluster in the oxygen-evolving complex (OEC) of photosystem II (Zhang et al., Science 2015, 348, 690). Oxidized samples of the complex show electron paramagnetic resonance (EPR) signals at g ≈ 4.9 and 2, similar to those associated with the OEC in its S2 state (g ≈ 4.1 from an S = 5/2 form and g ≈ 2 from an S = 1/2 form), suggesting similarities in the electronic as well as geometric structure. We use quantum-chemical methods to characterize the synthetic complex in various oxidation states, to compute its magnetic and spectroscopic properties, and to establish connections with reported data. Only one energetically accessible form is found for the oxidized "S2 state" of the complex. It has a ground spin state of S = 5/2, and EPR simulations confirm it can be assigned to the g ≈ 4.9 signal. However, no valence isomer with an S = 1/2 ground state is energetically accessible, a conclusion supported by a wide range of methods, including density matrix renormalization group with full valence active space. Alternative candidates for the g ≈ 2 signal were explored, but no low-spin/low-energy structure was identified. Therefore, our results suggest that despite geometric similarities the synthetic model does not mimic the valence isomerism that is the hallmark of the OEC in its S2 state, most probably because it lacks a coordinatively flexible oxo bridge. Only one of the observed EPR signals can be explained by a structurally intact high-spin one-electron-oxidized form, while the other originates from an as-yet-unidentified rearrangement product. Nevertheless, this model provides valuable information for understanding the high-spin EPR signals of both the S1 and S2 states of the OEC in terms of the coordination number and Jahn-Teller axis orientation of the Mn ions, with important consequences for the development of magnetic spectroscopic probes to study S-state intermediates immediately prior to O-O bond formation.


Tetanus following tongue bite from repeated convulsions: a case report.
This report details a case of generalized tetanus with the added complication of tongue bite following the repeated convulsions of a six-year-old unimmunized girl. It highlights the fact that tongue bite is an unusual portal of the entry of tetanus and emphasizes the need for proper oral care of an unconscious patient and the importance of the immunization of children.


RaPiDS (GOG-3028): randomized Phase II study of balstilimab alone or in combination with zalifrelimab in cervical cancer.
Balstilimab (anti-programmed death 1) and zalifrelimab (anti-CTLA-4) are two new checkpoint inhibitors that have emerged as promising investigational agents for the treatment of cervical cancer, particularly in the setting of previously-treated, recurrent/metastatic disease. Here we describe the rationale and design of RaPiDS (NCT03894215), a two-arm Phase II study evaluating the safety, tolerability and efficacy of balstilimab administered alone or in combination with zalifrelimab in patients with advanced cervical cancer who progressed after first-line, platinum-based chemotherapy. Patients will be randomized in a 1:1 ratio. The primary end point is objective response rate, and key secondary objectives include safety, duration of response, progression-free survival, overall survival and quality of life outcomes.


[High expression of STAT2 in ovarian cancer and its effect on metastasis of ovarian cancer cells].
To investigate the expression of signal transduction and activator of transcription 2 (STAT2) in ovarian cancer and its correlation with the prognosis of ovarian cancer patients and explore the role of STAT2 inregulating metastasis of ovarian cancer cells. RT-qPCR was performed to detect the expression of STAT2 mRNA in 62 fresh frozen ovarian cancer tissues and 62 normal ovarian tissues; immunohistochemistry was used to detect STAT2 protein expressions in 95 paraffin-embedded ovarian cancer samples and 33 normal ovarian tissues. Kaplan-Meier method was used to analyze the correlation between the expression of STAT2 and the prognosis of the patients. We also examined the relationship between STAT2 and the patients' prognosis by analyzing the data in Kaplan-Meier Plotter database. Western blotting was performed to detect the expression of STAT2 in different ovarian cancer cell lines. In A2780 cells with the highest STAT2 expression, we examined the effects of STAT2 interference on cell migration and invasiveness using Transwell migration assay and on the expressions of the downstream molecule epidermal growth factor receptor (EGFR). Ovarian cancer tissues expressed significantly higher levels of STAT2 mRNA than normal ovarian tissue. A high STAT2 mRNA expression was correlated with an advanced FIGO stage. Immunohistochemistry showed that 67.4% of the ovarian cancer samples, as compared with 28.3% of normal ovarian tissues, showed high STAT2 expressions. In ovarian cancer patients, a high expression of STAT2 protein was associated with ascites volume, distant metastasis and FIGO stage (P < 0.05). Survival analysis showed that ovarian cancer patients with a high expression of STAT2 protein had poor overall survival (P=0.021) and progression-free survival (P=0.018). STAT2 was overexpressed in all the ovarian cancer cell lines tested, and A2780 cell lines showed the highest expression. Interference of STAT2 significantly suppressed the migration and invasiveness (P < 0.01) and lowered the expression level of EGFR in A2780 cells. STAT2 is overexpressed in ovarian cancer. A high expression of STAT2 is associated with a poor prognosis of ovarian cancer patients. STAT2 may promote the metastasis of ovarian cancer by enhancing the expression of EGFR.


The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.
Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.


Anal and oropharyngeal HPV distribution in HIV-negative multipartner MSM using self-sampling kits for HIV and sexually transmitted infection screening.
Men who have sex with men (MSM) are at high risk of sexually transmitted infections, among which HPV infections are particularly prominent. We took advantage of the MémoDépistages study to evaluate HPV distribution at anal and oropharyngeal sites in HIV-negative multipartner MSM. HPV DNA was detected in 82% (n = 344) of anal and 11% (n = 45) of oropharyngeal self-collected samples taken from 421 participants. Multiple HPV types were detected in 70% of anal samples, and single HPV types in 91% of oropharyngeal samples. HPV16 was the most frequent type detected in the anus, followed by HPV6, HPV51, and HPV52. HPV6, HPV16, and HPV11 were the most prevalent types in the oropharynx. HPV targeted by the nonavalent vaccine was detected in 71% and 50% of HPV-positive anal and oropharyngeal samples, respectively. The main risk factor associated with HPV detection was frequenting gay meeting places, living in large cities, and having an anal Chlamydia trachomatis/Neisseria gonorrhoeae infection. In this cohort of highly sexually active MSM, HPV detection was highly frequent and rendered them at high risk of precancerous and cancerous lesions. Universal vaccination against HPV before sexual debut is an important public health strategy to prevent HPV-associated cancers in this highly vulnerable population of HIV-negative MSM.


Management of diabetes mellitus in patients with chronic kidney disease.
Glycemic control is essential to delay or prevent the onset of diabetic kidney disease. There are a number of glucose-lowering medications available but only a fraction of them can be used safely in chronic kidney disease and many of them need an adjustment in dosing. The ideal target hemoglobin A1c is approximately 7 % but this target is adjusted based on the needs of the patient. Diabetes control should be optimized for each individual patient, with measures to reduce diabetes-related complications and minimize adverse events. Overall care of diabetes necessitates attention to multiple aspects, including reducing the risk of cardiovascular disease, and often, multidisciplinary care is needed.


Treatment of parasitic diarrhea in HIV-infected patients.
Parasitic infections responsible for diarrhea have a worldwide distribution, overlapping with AIDS in most countries. Indeed, highly active antiretroviral therapy has markedly reduced the incidence of most parasitic opportunistic infections, but parasite-related diarrhea remains frequent and probably underestimated in developing countries. In this review, we focus on the advances in molecular epidemiology, diagnosis and current treatment of the most prevalent parasitic infections in HIV-infected patients. Most of these parasites are protozoa, whose diagnosis at the laboratory requires some adapted technique and expertise. We highlight the importance of diagnosis and the skill of the laboratory of parasitology, since most parasitic infections responsible for diarrhea in AIDS patients can be treated.


Evaluation of Bioactivities of the Bovine Milk Lactoferrin-Osteopontin Complex in Infant Formulas.
Human milk contains several bioactive proteins, including lactoferrin (LF) and osteopontin (OPN). These two proteins have been shown to form a complex, which shows increased bioactivities. Bovine LF and OPN can also form such a complex. We assessed bioactivities of the bovine LF-OPN complex (at molar ratios of LF:OPN = 3:1, 5:1, or 8:1) in a formula protein matrix, including LF, OPN, bovine whey protein hydrolysate, and α-lactalbumin. Our results show that the bovine LF-OPN complex together with formula proteins is resistant to in vitro digestion, stimulates intestinal cell proliferation (by 15-50%) and differentiation (by 30-50%), increases antibacterial activity (by 25-50%), and enhances intestinal immunity. The 3:1 ratio of LF to OPN exhibits the most potent effects, as compared with the other two ratios. In conclusion, adding bovine LF and OPN to infant formulas may result in increased stability of the two components and enhanced bioactivities, possibly improving outcomes in formula-fed infants.


Effects of Cultivating Years on Survival of Culturable Escherichia coli O157:H7 in Greenhouse Soils.
The extent to how Escherichia coli O157:H7 can survive in soil and the predominant factors that determine its survival are crucial issues from a public health point of view. This study investigated the survival of E. coli O157:H7 in vegetable soils in plastic-greenhouse cultivation over 0, 1, 4, 8, and 12 years in southern China. Results showed that the survival times ( td) calculated from the Weibull model for the five tested soils ranged from 9.00 to 21.11 days. In general, E. coli O157:H7 survived longer in open-field soils than in greenhouse soils under the same incubation conditions. The td values were greater in soils with a lower level of electrical conductivity, a higher level of total nitrogen, and a higher level of sand content. Compared to other factors, electrical conductivity was the most important factor affecting the survival of E. coli O157:H7 in the tested soils. Different survival times of E. coli O157:H7 in vegetable soils under diverse cultivation patterns highlight the importance of preventing pathogenic contamination for the purpose of food safety.


Persistent trigeminal artery and associated vascular variations.
Persistent trigeminal artery (PTA) is the most frequent type of persistent primitive carotid-basilar artery anastomoses. Persistent trigeminal artery is usually associated with small or absent posterior communicating artery (Pcom). It may also be associated with hypoplastic vertebral and basilar arteries. Patients may present with symptoms related to hypo-perfusion of posterior circulation or microembolization from carotid artery to posterior circulation. We are presenting a 60-year-old who had recurrent episodes of vertigo and parasthesia, in whom MR angiography revealed a medial, Saltzman type 1 PTA on the left with absent ipsilateral Pcom, duplicated ipsilateral superior cerebellar artery, hypoplastic A1 segment of contralateral anterior cerebral artery (ACA), azygous ACA and hypoplastic ipsilateral vertebral artery.


Rapid detection and sequencing of alleles in the 3' flanking region of the interleukin-6 gene.
The 3' flanking region of the interleukin 6 gene is polymorphic due to insertions of different size. Within this region lies a sequence of approximately 500 base pairs that is AT rich. Based on flanking sequence information we have constructed oligonucleotides which prime the polymerase chain reaction (PCR) and amplify this AT rich region. The amplification products visualized by agarose gel electrophoresis gave fragment sizes for both homozygous and heterozygous individuals that were concordant with those observed by conventional genomic blotting techniques. Alleles that could not be typed by Southern analysis were resolved with this approach. These results illustrate the value of PCR for the rapid detection of length polymorphisms such as those due to variable numbers of tandem repeats. In contrast to RFLP analysis this procedure takes less than a day to perform, is cheaper, avoids the use of radioactivity and requires far less substrate DNA. Three different human alleles were sequenced, and differences were detected that were due to both large duplications and loss of one or two bases, suggesting that AT rich regions identify highly polymorphic loci. The same primers also amplified non-human primate DNA, allowing a comparison of the human sequence with that of the common chimpanzee and baboon.


Cardiomyopathy of Duchenne muscular dystrophy: pathogenesis and prospect of membrane sealants as a new therapeutic approach.
Duchenne muscular dystrophy (DMD) is a devastating progressive disease of striated muscle deterioration. This fatal X-linked disorder results from the loss of the protein dystrophin, which in turn causes striated muscle membrane instability. Cardiac dysfunction is a growing problem in patients with DMD, but relatively little is known about the pathophysiology of the dystrophic heart. At present, there is no effective treatment for DMD and the current clinical approaches are primarily supportive in nature. This review will discuss the pathogenesis of DMD in the heart and discuss how these pathogenic processes have led to a new class of agents directed specifically at restoring membrane integrity to dystrophic myocardium. The tri-block poloxamers, specifically poloxamer 188 (P188), are able to stabilize the membranes of dystrophic myocardium in animal models and may offer a new therapeutic approach for cardiac disease in DMD.


Nonsclerotic Lichen Sclerosus: Definition of a Concept and Pathologic Description.
Nonsclerotic lichen sclerosus (NSLS) refers to the clinicopathologic situation of examination findings consistent with lichen sclerosus (LS) but without dermal sclerosis on microscopy. This review aims to describe the features of NSLS and provide a classification framework. The International Society of the Study of Vulvovaginal Diseases tasked the Difficult Pathologic Diagnoses Committee with development of consensus documents for conditions with problematic histopathology. The Difficult Pathologic Diagnoses Committee reviewed the literature on NSLS and formulated descriptions and diagnostic criteria, then approved by the International Society of the Study of Vulvovaginal Diseases membership. Nonsclerotic LS may be categorized into 4 histopathologic subtypes: lichenoid dermatitis, hypertrophic lichenoid dermatitis, dermal fibrosis without acanthosis, and dermal fibrosis with acanthosis. Each has a pathologic differential diagnosis of 1 or more entities, so clinical correlation is required for final diagnosis of LS. There is no evidence to support a reliable association between absent sclerosis and clinical appearance, duration, or oncogenic potential of LS. Pathologists and clinicians should be familiar with the concept of NSLS and its implications for patient management. Use of the term "early LS" to indicate a lack of sclerosis in presumed LS should be abandoned. Clinical correlation is required to confirm LS from among the differential diagnoses.


Reasoning about the disclosure of success and failure to friends among children in the United States and China.
Children's reasoning about individuals' willingness to disclose their successes and failures was investigated among 194 6- to 11-year-olds in the United States and China. In Study 1, participants showed a valence-matching effect, in which they predicted that individuals would be more likely to disclose their performance to an audience of friends if the friends' level of achievement was similar rather than dissimilar. This effect was weaker among children from China, who were more likely to justify their responses with reference to the implications for learning together or improving future performance. Results of Study 2 suggest that for children from the United States, the disclosure of successful performance to a friend who has performed poorly is seen as implicitly conveying the message "I'm better than you," whereas for children from China the message is "I can help you to do better." Results are interpreted with reference to cultural values and expectations about helping others to learn.


Inflammatory process in murine lymphocytic choriomeningitis is maximal in H-2K or H-2D compatible interactions.
Capacity to transfer adoptively fatal lymphocytic choriomeningitis (LCM) to immunosuppressed, virus-infected recipients is a property of H-2 compatible, non-Ig-bearing virus-immune lymphocytes. Severe meningitis is recognized when donor and recipient share at least one allele at either H-2K or H-2D. Presence of unshared H-2 genes is not obviously inhibitory, and identity at the immune response (Ir) region of the H-2 gene complex is neither sufficient nor necessary. The same constraint applies to cytotoxic T cell activity in vitro; lymphocytes and virus-infected targets must be compatible for a minimum of one allele mapping at H-2K or H-2D. The present findings thus support the concept that populations of T cells, which are cytotoxic in vitro, also mediate inflammatory process in vivo and are a major, if not the only, effector population in murine LCM.


Design of a new line in treatment of experimental rheumatoid arthritis by artesunate.
This study was aimed to evaluate the therapeutic potency of a new antimalarial drug, artesunate, in an experimental model of rheumatoid arthritis. Collagen-induced arthritis (CIA) was induced in Lewis rats.The intraperitoneally administration of artesunate (ARS) and methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was intermittent. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ARS and MTX were assessed using fibrosarcoma cell line. Our results showed that i.p. injection of artesunate to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cells infiltrate in joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following ARS therapy. Moreover, our radiographic results paralleled histological findings. Cytotoxicity analysis of ARS showed greater tolerability compared with MTX. Treatment with ARS significantly diminished nitric oxide formation in treated rats compared with untreated controls. Our findings revealed the therapeutic efficacy of artesunate in experimental rheumatoid arthritis compared with a choice drug (methotrexate). This result may recommend it as a second-line drug in the treatment of rheumatoid arthritis.


Imaging state-to-state reactive scattering in the Ar+ + H2 charge transfer reaction.
The charge transfer reaction of Ar+ with H2 and D2 has been investigated in an experiment combining crossed beams with three-dimensional velocity map imaging. Angle-differential cross sections for two collision energies have been obtained for both neutral species. We find that the product ions are highly internally excited. In the reaction with H2, the spin-orbit excited Ar+ state's coupling to the "resonant" vibrationally excited product H2+ (υ = 2) dominates for both investigated energies, in line with previous investigations. The observed angular distributions, however, show significantly less back-scattering than was found previously. Furthermore, we discovered that the product ions are highly rotationally excited. In the case of Ar+ reacting with D2, the energetically closest lying vibrational levels are not strictly preferred and higher-lying vibrational levels are also populated. For both species, the backward-scattered products show higher internal excitation.


Three new endemic species of Lepanthes (Orchidaceae, Pleurothallidinae) from the highlands of Ecuador.
Three new species of Lepanthes from Ecuador are described and illustrated. These additions to the Ecuadorean flora were recorded in evergreen montane forest and páramo as part of three different research projects conducted during the last five years (2016-2021). Lepanthesoro-lojaensis was discovered in the southwest of El Oro province and is similar to L.jimburae, differing mainly in the much smaller plants, inflorescences and floral parts. Lepanthesmicroprosartima from the western slopes of Pichincha volcano in northern Ecuador resembles L.obandoi but differs in the coloration of the leaves, the inflorescence that are shorter than the leaves and the smaller floral appendix. Lepanthescaranqui, found in eastern Pichincha and Imbabura, is most similar to L.pachychila but differs from it in its much larger plants and different shape of the petals and the floral appendix. Preliminary assessments of the conservation status of the three taxonomic novelties are provided, using the IUCN Red List Categories and Criteria.


Depressive symptoms, negative urgency and substance use initiation in adolescents.
Studies show depressive symptoms are associated with substance use in adolescents, but the mechanism underlying this association is still unclear. This study investigated negative urgency - the disposition to rash action during emotional states - as a factor explaining relations between depressive symptoms and use of several substances. In this cross-sectional study, 476 adolescents (mean age 14.5 years) completed self-report surveys. Regression models and products of coefficient analyses examined the overall relation of depressive symptoms to substance use and negative urgency as a statistical mediator of this association. Depression levels associated with increased likelihood of lifetime use of cigarettes, other forms of tobacco, marijuana, alcohol, inhalants, prescription painkillers, and any substance. Relations between depression levels and lifetime use of alcohol, inhalants, and any substance were accounted for (i.e., statistically mediated) by negative urgency. In adolescents endorsing lifetime use, depression levels associated with younger age of first use of other forms of tobacco and alcohol as well as use frequency of cigarette, alcohol, and composite frequency. Negative urgency accounted for the covariance between depression level and age of first use of alcohol, but did not for other forms of tobacco or frequency of use of any substances. Depression levels are associated with lifetime use of a variety of substances in early adolescence and targeting this risk factor with preventive efforts may be useful in reducing risk. Negative urgency may be an important target for interventions aimed at alcohol and inhalant use.


Generalized Lotka-Volterra model with hierarchical interactions.
In the analysis of complex ecosystems it is common to use random interaction coefficients, which are often assumed to be such that all species are statistically equivalent. In this work we relax this assumption by imposing hierarchical interspecies interactions. These are incorporated into a generalized Lotka-Volterra dynamical system. In a hierarchical community species benefit more, on average, from interactions with species further below them in the hierarchy than from interactions with those above. Using dynamic mean-field theory, we demonstrate that a strong hierarchical structure is stabilizing, but that it reduces the number of species in the surviving community, as well as their abundances. Additionally, we show that increased heterogeneity in the variances of the interaction coefficients across positions in the hierarchy is destabilizing. We also comment on the structure of the surviving community and demonstrate that the abundance and probability of survival of a species are dependent on its position in the hierarchy.


Oral condition in children treated with bone marrow transplantation.
Oral health was studied in 49 children below 12 years of age treated with bone marrow transplantation (BMT). Dental treatment prior to BMT was required in 41% of the children. Ulceration of the mucous membranes in the mouth was observed in 37% of the patients during treatment. Those given methotrexate as prophylaxis against graft-versus-host disease (GVHD) exhibited oral ulcerations more frequently (p less than 0.05) than those given cyclosporin. One year after BMT all patients with a clinical chronic GVHD exhibited changes in the oral mucosa. During the first year after BMT 31% of the children developed carious lesions. Children treated with 10 Gy total body irradiation (TBI) had a significantly (p less than 0.05) reduced salivary secretion rate. Dental development was severely affected in children treated with TBI. These disturbances consisted of arrested root development, enamel hypoplasias and microdontia.


Sources and Implications of Maternal Accuracy About Young Adolescents' Vulnerability to Friendship Jealousy.
To assist effectively with social difficulties, parents must accurately understand the peer situations that are difficult for their child. Mothers' insight into their young adolescent's vulnerability to friendship jealousy was assessed by posing identical vignettes to 72 young adolescents and their mothers and matching their responses. Mothers and children also completed questionnaires on their relationship and the child's adjustment. Mothers as a group were poor judges of their child's jealousy, but considerable variability existed. Accuracy was greater when mother-child pairs were closer. Polynomial regression and response surface analyses indicated that maternal accuracy could dampen the friendship and aggression risks otherwise associated with being vulnerable to jealousy.


[CLINICAL OUTCOME OF ANTERIOR CERVICAL DISCECTOMY AND FUSION USING A ZERO-PROFILE INTERBODY FUSION AND FIXATION DEVICE FOR CERVICAL SPONDYLOTIC MYELOPATHY].
To analyze the clinical outcome of anterior cervical discectomy and fusion using a Zero-profile interbody fusion and fixation device (Zero-P) for cervical spondylotic myelopathy. Between April 2011 and September 2013, 26 cases of cervical spondylotic myelopathy underwent anterior cervical discectomy and fusion with the Zero-P. Of 26 cases, 12 were male and 14 were female, aged 43-82 years (mean, 58.3 years). The disease duration was from 3 months to 10 years (mean, 5.9 years). The involved segments included C3,4 in 5 cases, C4,5 in 3 cases, C5,6 in 6 cases, and C6,7 in 12 cases. The clinical outcome was evaluated using visual analogue scale (VAS) score, Japanese Orthopaedic Association (JOA) score, and Neck Disability Index (NDI) score before operation and after operation. The operations were successful and the operation time was 75-140 minutes (mean, 105 minutes); and blood loss was 20-150 mL (mean, 45 mL). There was no complications of infection, neural injury, esophageal fistula, prevertebral hematoma, or leakage of cerebrospinal. Dysphagia occurred in 1 case within 1 week after operation, and disappeared after 1 month. All patients were followed up for an average of 15.3 months (range, 12-18 months). The clinical symptoms were relieved after operation. During follow-up, no implant displacement or subsidence, screw breakage, and cervical instability were observed. At 3 and 12 months after operation, the VAS score and NDI reduced significantly (P<0.05); the JOA score increased significantly (P<0.05); and the intervertebral space height and the cervical Cobb angle improved significantly (P<0.05). But there was no significantly difference between at 3 and 12 months (P > 0.05). According to JOA evaluation, the results were excellent in 14 cases, good in 10 cases, and fair in 2 cases, with an excellent and good rate of 92.3% at last follow-up. The clinical outcome of anterior cervical discectomy and fusion using a Zero-P is satisfactory and reliable in the treatment of cervical spondylotic myelopathy. It can restore the cervical physiological curve and the intervertebral space height and decrease the incidence of postoperative dysphagia.


A comparison of the performance of the EQ-5D and the EQ-5D-Y health-related quality of life instruments in South African children.
The aim of this study was to investigate the performance of the recent EQ-5D-Y instrument compared with the standard EQ-5D in assessing the health-related quality of life of high school children in Cape Town. Either the EQ-5D or the EQ-5D-Y was given to high school children. The sample consisted of 521 respondents. The EQ-5D-Y was found to be superior in that there were statistically significant fewer missed item responses, both in the domains and the health status Visual Analogue Scale (VAS). A grade differential was noted with more missing responses in the lower grades, particularly with the EQ-5D. More children reported problems with the mobility, self-care and anxiety and depression domains when responding to the EQ-5D-Y. In addition, the mean VAS score was marginally greater using the EQ-5D-Y. The EQ-5D-Y performed better than the EQ-5D, particularly in the younger children, and should be used in early secondary school. The EQ-5D-Y generated a wider range of responses in both the domains and the VAS, and may be more responsive than the Adult version. The two seem to give different results and consequently should be considered two related but separate instruments.


Global Distribution and Evolutionary History of Enterovirus D68, with Emphasis on the 2014 Outbreak in Ontario, Canada.
Despite its first appearance in 1962, human enterovirus D68 (EV-D68) has been recognized as an emerging respiratory pathogen in the last decade when it caused outbreaks and clusters in several countries including Japan, the Philippines, and the Netherlands. The most recent and largest outbreak of EV-D68 associated with severe respiratory illness took place in North America between August 2014 and January 2015. Between September 1 and October 31 2014, EV-D68 infection was laboratory confirmed among 153/907 (16.9%) persons tested for the virus in Ontario, Canada, using real time RT-PCR and subsequent genotyping by sequencing of partial VP1 gene. In order to understand the evolutionary history of the 2014 North American EV-D68 outbreak, we conducted phylogenetic and phylodynamic analyses using available partial VP1 genes (n = 469) and NCBI available whole genome sequences (WGS) (n = 38). The global EV-D68 phylogenetic tree (n = 469) reconfirms the divergence of three distinct clades A, B, and C from the prototype EV-D68 Fermon strain as previously documented. Two sub-clades (B1 and B2) were identified, with most 2014 EV-D68 outbreak strains belonging to sub-cluster B2b2 (one of the two emerging clusters within sub-clade B2), with two signature substitutions T650A and M700V in BC and DE loops of VP1 gene, respectively. The close homology between WGS of strains from Ontario (n = 2) and USA (n = 21) in the recent EV-D68 outbreak suggests genetic relatedness and also a common source for the outbreak. The time of most recent common ancestor of EV-D68 and the 2014 EV-D68 outbreak strain suggest that the viruses possibly emerged during 1960-1961 and 2012-2013, respectively. We observed lower mean evolutionary rates of global EV-D68 using WGS data than estimated with partial VP1 gene sequences. Based on WGS data, the estimated mean rate of evolution of the EV-D68 B2b cluster was 9.75 × 10-3 substitutions/site/year (95% BCI 4.11 × 10-3 to 16 × 10-3).


Allium™ TPS--A New Prostatic Stent for the Treatment of Patients with Benign Prostatic Obstruction: The First Report.
Several prostatic stents were developed in the last three decades, none of which were able to provide a real alternative in patients unfit or unwilling to undergo classical prostatic surgeries. In this study, we report the results of the use of a newly developed prostatic stent--the Allium™ Triangular Prostatic Stent (TPS). The Allium TPS is a highly flexible, nitinol-built polymer-covered stent, which prevents tissue ingrowth and reduces encrustations. Between 2008 and 2014, at two centers (Israel and Turkey), the stent was inserted under local or regional anesthesia in 51 patients with benign prostatic obstruction (BPO) who are unwilling or unfit for surgery. Patients were followed for 12 months from surgery. The primary outcome was symptom improvement as measured by the international prostate symptom score (IPSS) and improvement in peak urinary flow. Stent insertion was successful in all patients. The mean IPSS decreased from 26.4 to 7.7 on the last follow-up. The mean peak flow increased from 5.5 mL/second before stent insertion to 16.0 mL/second 1 year thereafter. The main adverse effect was transient pain in nine patients. No stent migration or obstruction was seen. Patients reported satisfaction and improvement in quality of life. Our short-term results show that Allium TPS is safe and effective for the treatment of patients with BPO.


Fern Stomatal Responses to ABA and CO2 Depend on Species and Growth Conditions.
Changing atmospheric CO2 levels, climate, and air humidity affect plant gas exchange that is controlled by stomata, small pores on plant leaves and stems formed by guard cells. Evolution has shaped the morphology and regulatory mechanisms governing stomatal movements to correspond to the needs of various land plant groups over the past 400 million years. Stomata close in response to the plant hormone abscisic acid (ABA), elevated CO2 concentration, and reduced air humidity. Whether the active regulatory mechanisms that control stomatal closure in response to these stimuli are present already in mosses, the oldest plant group with stomata, or were acquired more recently in angiosperms remains controversial. It has been suggested that the stomata of the basal vascular plants, such as ferns and lycophytes, close solely hydropassively. On the other hand, active stomatal closure in response to ABA and CO2 was found in several moss, lycophyte, and fern species. Here, we show that the stomata of two temperate fern species respond to ABA and CO2 and that an active mechanism of stomatal regulation in response to reduced air humidity is present in some ferns. Importantly, fern stomatal responses depend on growth conditions. The data indicate that the stomatal behavior of ferns is more complex than anticipated before, and active stomatal regulation is present in some ferns and has possibly been lost in others. Further analysis that takes into account fern species, life history, evolutionary age, and growth conditions is required to gain insight into the evolution of land plant stomatal responses.


Effects of oxytocin and methacholine on cyclic nucleotide levels of rabbit myometrium.
The effects of oxytocin and methacholine on cyclic nucleotide levels in estrogen-primed rabbit myometrium were studied in the presence and absence of 1-methyl-3-isobutyl xanthine (MIX), a phosphodiesterase inhibitor. In the absence of MIX, methacholine increased guanosine 3',5'-cyclic monophosphate (cGMP) levels at a time when contraction was decreasing, but had no influence on adenosine 3',5'-cyclic monophosphate (cAMP) levels. In contrast, oxytocin did not elevate cGMP, but rapidly decreased cAMP levels. MIX (1 mM) increased both cAMP and cGMP levels. Oxytocin or methacholine further increased cGMP, indicating activation of guanylate cyclase. Oxytocin- but not methacholine-induced stimulation of guanylate cyclase was abolished in Ca2+-free solution. Oxytocin increased cAMP over the levels produced by MIX alone, whereas methacholine decreased cAMP below the MIX control values; these effects were insensitive to indomethacin. Tissue levels of cGMP and cAMP did not directly correlate with isometric tension. The results also indicate that both oxytocin and methacholine stimulate guanylate cyclase but have opposing effects on adenylate cyclase of rabbit myometrium.


Ultra-stable potassium storage and hybrid mechanism of perovskite fluoride KFeF3/rGO.
Potassium-ion batteries (PIBs) are promising for large-scale energy storage due to the abundant reserves of the element potassium yet few satisfactory cathode materials have been developed due to the limitation of the large ionic radius of the potassium ion. Cubic perovskite fluorides have three-dimensional diffusion channels and a robust structure, which are favorable for ion transfer, but their poor electronic conductivity needs to be compensated. Here, we synthesized cubic KFeF3 powder by a solvothermal procedure. After the combination with reduced graphene oxide (rGO) and carbon coating, its electronic conductivity is greatly improved. In the optimal sample KFeF3/rGO-PVA-500, KFeF3 nano-particles (smaller than 50 nm) distribute on the rGO surface evenly. Owing to the special structure, KFeF3/rGO-PVA-500 provides an excellent rate performance and cycling stability. In particular, a high capacity retention of 94% is obtained after 1000 cycles at 200 mA g-1. In addition, a hybrid reaction mechanism combining mainly solid solution and partly conversion processes is revealed by employing in situ and ex situ characterization.


One-dimensional transport equation models for sound energy propagation in long spaces: theory.
In this paper, a three-dimensional transport equation model is developed to describe the sound energy propagation in a long space. Then this model is reduced to a one-dimensional model by approximating the solution using the method of weighted residuals. The one-dimensional transport equation model directly describes the sound energy propagation in the "long" dimension and deals with the sound energy in the "short" dimensions by prescribed functions. Also, the one-dimensional model consists of a coupled set of N transport equations. Only N=1 and N=2 are discussed in this paper. For larger N, although the accuracy could be improved, the calculation time is expected to significantly increase, which diminishes the advantage of the model in terms of its computational efficiency.


Antibiotic sensitivity and resistance of gastrointestinal microflora isolated from preterm neonates.
Aim: This study aimed to isolate and identify common bacteria from 19 preterm neonates who spent their first weeks in the neonatal intensive care unit. Materials & methods: Stool samples were collected, and bacteria were isolated and purified from the samples. The isolated bacterial species were tested for antibiotic susceptibility or resistance. Results: Three common species were found in 15 stool samples: Enterobacter cloacae, Enterococcus fecalis and Klebsiella pneumoniae. Minimum inhibitory concentrations determined using antibiotic susceptibility testing showed that the minimum level of isolates was affected by the most commonly used antibiotics, with significant resistance to some of the tested antibiotics. Conclusion: The development of beneficial normal flora in preterm neonates plays a vital role in their health and well-being.


The role of emotion regulation difficulties in the connection between childhood emotional abuse and borderline personality features.
In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined the role of emotion dysregulation as a mediator between childhood abuse and borderline personality disorder (BPD) feature severity among a sample of 964 adults presenting for treatment at an outpatient clinic. A structural equation model suggested that emotional abuse relates to BPD features both directly and through difficulties with emotion regulation, whereas physical abuse showed only a weak indirect relation with BPD features. There was no link between sexual abuse and BPD feature severity in the model. Results add specificity to etiological theories of BPD and suggest that future research in treatment should focus on developing and strengthening emotion regulation strategies in clinical populations with a history of emotional abuse. Clinicians should be sure to assess the presence of childhood emotional abuse in addition to sexual and physical abuse. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Sociodemographic characteristics of indigenous population according to the 2000 and 2010 Brazilian demographic censuses: a comparative approach.
The sociodemographic profiles of different segments of the Brazilian population have been the object of multiple inter-census comparisons. This study compared the age distribution, number of household residents, formal schooling, and income of indigenous persons according to the population censuses of 2000 and 2010. There was an important decrease in the number of residents per occupied household, and slight aging of the indigenous population, except in the urban North. Meanwhile, there was a proportional increase in individuals with per capita household income up to one minimum wage, along with a reduction in the income bracket of more than two minimum wages in the country's five major geographic regions, in both urban and rural areas. Although schooling also increased, the increments differed according to geographic region and urban versus rural area; the urban Southeast showed larger gains in schooling, while the rural North and Central displayed smaller increases. The study emphasizes the need for more in-depth research focusing on specificities and backing the evaluation and implementation of public policies for the indigenous population.


First-order phase transition in the quantum adiabatic algorithm.
We simulate the quantum adiabatic algorithm (QAA) for the exact cover problem for sizes up to N=256 using quantum Monte Carlo simulations incorporating parallel tempering. At large N, we find that some instances have a discontinuous (first-order) quantum phase transition during the evolution of the QAA. This fraction increases with increasing N and may tend to 1 for N-->infinity.


Bone formation in transforming growth factor beta-I-loaded titanium fiber mesh implants.
The osteoconductive properties of porous titanium (Ti) fiber mesh with or without a calcium phosphate (Ca-P) coating and osteoinductive properties of noncoated Ti fiber mesh loaded with recombinant human Transforming Growth Factor beta-1 (rhTGF-beta1) were investigated in a rabbit non-critical size cranial defect model. Nine Ca-P-coated and 18 non-coated porous titanium implants, half of them loaded with rhTGF-beta1, were bilaterally placed in the cranium of 18 New Zealand White rabbits. At 8 weeks postoperative, the rabbits were sacrificed and the skulls with the implants were retrieved. Histological analysis demonstrated that in the TGF-beta1-loaded implants, bone had been formed throughout the implant, up to its center, whereas in the non-loaded implants only partial ingrowth of bone was observed. Bone formation had a trabecular appearance together with bone marrow-like tissue. No difference in ingrowth could be observed between the non-TGF-beta1-loaded non-coated implants and the Ca-P-coated ones. All histological findings were confirmed by image analysis: 97% ingrowth was seen in the rhTGF-beta1-loaded implants, while only 57% and 54% ingrowth was observed in the non-loaded Ca-P-coated and non-coated implants, respectively. Bone surface area and bone fill were significantly higher in the rhTGF-beta1-loaded implants (1.37 mm2 and 36%, respectively) than in the non-loaded implants (0.57 mm2 and 26%). No statistical difference was found for any parameter between the Ca-P-coated and noncoated implants. Quadruple fluorochrome labeling showed that in the Ti and Ti-CaP implants mainly bone guidance had occurred from the former defect edge, while in the Ti-TGF-beta1 implants bone formation had mainly started in the center of a pore and proceeded in a centrifugal manner. Our results show that: (1) the combination of Timesh with TGF-beta1 can induce orthotopic bone formation; (2) Ti-fiber mesh has good osteoconductive properties; (3) a thin Ca-P coating, as applied in this study, does not seem to further enhance the bone-conducting properties of a titanium scaffold material.


Central neural respiratory response to carotid sinus nerve stimulation in newborns.
During exposure to hypoxia newborns hypoventilate following a brief period of hyperventilation. Failure of integration of the afferent signals from peripheral O2 chemoreceptors due to immaturity of the central respiratory centers could explain this paradoxical respiratory response. To test this hypothesis we have utilized anesthetized, paralyzed, mechanically ventilated newborn piglets and lambs (less than 11 days) and old piglets (19-35 days). The vagus nerves were cut in each animal. Respiratory activity was quantified by integration of phrenic neural activity. A carotid sinus nerve (CSN) was isolated and electrically stimulated for periods of 1-6 min. In all three groups of animals respiratory activity was continuously elevated throughout the period of CSN stimulation. After CSN stimulation respiratory activity immediately declined about 25% from the stimulated value. Thereafter respiratory activity declined in an exponential fashion toward the initial control level of respiratory activity. The time constant of this latter decay was 84.2 s in the young piglets, 83.2 s in the old piglets, and 63.0 s in the lambs. These results indicate that the respiratory centers of newborn piglets and lambs can maintain integration of continuous afferent CSN activity. Further, the respiratory afterdischarge that follows CSN stimulus cessation is similar to that of adults. These studies indicate that, during periods of O2 sufficiency, the central respiratory centers of newborns respond in a qualitatively similar manner to CSN stimulation as do adult cats.


Under-recognized post-stroke acute kidney injury: risk factors and relevance for stroke outcome of a frequent comorbidity.
Acute kidney injury (AKI) is emerging as a predictor of poor stroke outcome, however, it is often not recognized. The aim of our study was to evaluate post-stroke AKI burden, AKI risk factors and their influence in post-stroke outcome. From 2013 to 2016, 440 individuals with stroke diagnosis admitted in Stroke Unit, Foundation IRCCS Policlinico San Matteo (Pavia, Italy), were retrospectively enrolled. AKI cases identified by KDIGO criteria through the electronic database and hospital chart review were compared with the ones reported in discharge letters or in administrative hospital data base. Mortality data were provided by Agenzia Tutela della Salute of Pavia. We included 430 patients in the analysis. Median follow-up was 19.2 months. We identified 79 AKI cases (18% of the enrolled patients, 92% classified as AKI stage 1), a fivefold higher number of cases than the ones reported at discharge. 37 patients had AKI at the admission in the hospital, while 42 developed AKI during the hospitalization. Cardioembolic (p = 0.01) and hemorrhagic (p = 0.01) stroke types were associated with higher AKI risk. Admission National Institutes of Health Stroke Scale (NIHSS, p < 0.05) and Charlson Comorbidity Index (p < 0.01) were independently associated with overall AKI, while admission NIHSS (p < 0.05) and eGFR (p < 0.005) were independently associated with AKI developed during the hospitalization. AKI was associated to longer in-hospital stay (p = 0.01), worse Rankin Neurologic Disability Score at discharge (p < 0.0001) and discharge disposition other than home (p = 0.03). AKI was also independently associated to higher in-hospital mortality (OR 3.9 95% CI 1.2-12.9 p = 0.023) but not with long-term survival. Post-stroke AKI diagnosis needs to be improved by strictly monitoring individuals with cardioembolic or hemorrhagic stroke, reduced kidney function, higher Charlson Comorbidity Index and worse NIHSS at presentation.


Amputation is not isolated: an overview of the US Army Amputee Patient Care Program and associated amputee injuries.
Rates of amputation as a percentage of all combat injuries have increased significantly since the Korean War. Following traumatic and combat-related amputation, definitive treatment and rehabilitation require a large, multidisciplinary team to provide comprehensive medical and supportive care. Associated injuries are remarkably frequent, complicating treatment and potentially delaying rehabilitation and/or limiting outcomes. Patient and family psychosocial issues also must be assessed and appropriately addressed. The US Army Amputee Patient Care Program, with the support of numerous other government and private organizations, has been developed to meet the comprehensive medical, rehabilitative, and social needs of amputees injured in the current global war on terrorism, with the goal of maximizing subsequent patient outcomes utilizing a sports medicine approach.


Evidence of infection with Toxoplasma gondii and Neospora caninum in South Australia: using wild rabbits as a sentinel species.
The aim of this study was to utilise wild rabbits (Oryctolagus cuniculus) as a sentinel species to study levels of environmental contamination with N. caninum and T. gondii in South Australia, and to examine associations with rainfall, climate and land use. Toxoplasma gondii (T. gondii), an apicomplexan parasite, causes the clinical disease toxoplasmosis, which can affect sheep as well as humans and many other animals. Neosporosis, the clinical disease caused by closely related Neospora caninum (N. caninum), causes abortions in cattle, with large economic impacts to cattle industries. Aliquots of wild rabbit (Oryctolagus cuniculus) serum were obtained from twelve sites across South Australia over a period of eighteen years, with a total of 2114 samples. An in-house Modified Agglutination Test (MAT) was developed, and samples were screened for the specific antibodies against both T.gondii and N. caninum. Overall, 9.9% of samples screened for T. gondii tested positive and 6.1% of samples screened for N. caninum tested positive. There was no difference observed in seroprevalence of T.gondii specific antibodies between samples collected throughout summer, autumn, winter or spring. By contrast, a significantly higher (p=0.030) seroprevalence of N. caninum specific antibodies was observed in spring than any other season. T. gondii and N. caninum antibodies were discovered at sites across a broad area of South Australia, indicating these environments maybe infected with both parasites. Results provide evidence that suggests N. caninum oocysts may have different survival characteristics, such as varying tolerances to low relative humidity, than T. gondii oocysts.


DL0410 Ameliorates Memory and Cognitive Impairments Induced by Scopolamine via Increasing Cholinergic Neurotransmission in Mice.
Deficiency of the cholinergic system is thought to play a vital role in cognitive impairment of dementia. DL0410 was discovered as a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinestease (BuChE), with potent efficiency in in-vitro experiments, but its in vivo effect on the cholinergic model has not been evaluated, and its action mechanism has also not been illustrated. In the present study, the capability of DL0410 in ameliorating the amnesia induced by scopolamine was investigated, and its effect on the cholinergic system in the hippocampus and its binding mode in the active site of AChE was also explored. Mice were administrated DL0410 (3 mg/kg, 10 mg/kg, and 30 mg/kg), and mice treated with donepezil were used as a positive control. The Morris water maze, escape learning task, and passive avoidance task were used as behavioral tests. The test results indicated that DL0410 could significantly improve the learning and memory impairments induced by scopolamine, with 10 mg/kg performing best. Further, DL0410 inhibited the AChE activity and increased acetylcholine (ACh) levels in a dose-dependent manner, and interacted with the active site of AChE in a similar manner as donepezil. However, no difference in the activity of BuChE was found in this study. All of the evidence indicated that its AChE inhibition is an important mechanism in the anti-amnesia effect. In conclusion, DL0410 could be an effective therapeutic drug for the treatment of dementia, especially Alzheimer's disease.


Modeling thrombus formation and growth.
The paper reviews the state-of-the-art in computational modeling of thrombus formation and growth and related phenomena including platelet margination, activation, adhesion, and embolization. Presently, there is a high degree of empiricism in the modeling of thrombus formation. Based on the experimentally observed physics, the review gives useful strategies for predicting thrombus formation and growth. These include determining blood components involved in atherosclerosis, effective blood viscosity, tissue properties, and methods proposed for boundary conditions. In addition to the guidelines, ongoing research on the effect of shear stress on platelet margination, activation and adhesion, and platelet-surface interactions are reviewed. Biotechnol. Bioeng. 2017;114: 2154-2172. © 2017 Wiley Periodicals, Inc.


Field theoretic treatment of an effective action for a model of catalyzed autoamplification.
Reaction-diffusion models can exhibit continuous phase transitions in behaviors, and their dynamics at criticality often exhibit scalings with key parameters that can be characterized by exponents. While models with only a single field that transitions between absorbing and nonabsorbing states are well characterized and typically fall in the directed percolation universality class, the effects of coupling multiple fields remain poorly understood. We recently introduced a model which has three fields: one of which relaxes exponentially, one of which displays critical behavior, and one of which has purely diffusive dynamics but exerts an influence on the critical field [Tchernookov, J. Chem. Phys. 130, 134906 (2009)]. Simulations suggested that this model is in a universality class distinct from other reaction-diffusion systems studied previously. Although the three fields give rise to interesting physics, they complicate analysis of the model with renormalization-group methods. Here, we show how to systematically simplify the action for this model such that analytical expressions for the exponents of this universality class can be obtained by standard means. We expect the approach taken here to be of general applicability in reaction-diffusion systems with coupled order parameters that display qualitatively different behaviors close to criticality.


Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases.
Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas of elderly patients and has a predilection for the limbs. Herein, we report a previously undescribed variant of MFS showing epithelioid morphology. Seventeen cases diagnosed as epithelioid MFS were retrieved from the authors' files from among 570 cases of MFS. Hematoxylin and eosin-stained sections were reexamined and immunostains for pan-keratin (15 cases), S-100 protein (15), desmin (15), and alpha-smooth muscle actin (13) were performed. Nine patients were men and 8 were women (age range 43 to 89 y; median 63.5). Fifteen patients presented with a mass, and in 2 of these there was also pain. Duration of symptoms varied from 1 to 24 months (median 3). Tumor size ranged from 2 to 15 cm (median 6.75). In 10 cases, the tumor was located in subcutaneous tissue and in 6 cases it was subfascial. The majority of the tumors were located on the limbs (8 lower extremities and 6 upper extremities) followed by neck (1), scalp (1), and trunk (1). Follow-up was available for 14 patients (range 2 to 240 mo; median 16). Twelve patients were treated by surgery followed by chemotherapy and/or radiation (8 cases). One patient received chemotherapy after an incisional biopsy and 1 patient was treated by surgery alone. Ten patients (71.4%) developed local recurrences. Seven patients (50%) developed metastases to lungs or retroperitoneum. Five patients (35.7%) have died of disease so far. Two patients were lost to follow-up. Morphologically, 14 cases were high grade, 2 were intermediate, and 1 was low grade. Tumors were characterized by a multinodular, infiltrating growth pattern with alternation of hypercellular and hypocellular myxoid areas; the latter showed prominent curvilinear vessels. Neoplastic cells were arranged singly and in small clusters in the myxoid areas or formed sheets in the hypercellular areas, where they showed epithelioid morphology with round nuclei, vesicular chromatin, prominent nucleoli, and moderate amounts of eosinophilic cytoplasm. The epithelioid areas were generally multifocal with admixed areas of conventional MFS. Immunostains were negative for all markers studied. Differential diagnosis included carcinoma, melanoma, myoepithelial carcinoma, pleomorphic liposarcoma, and pleomorphic rhabdomyosarcoma. In conclusion, epithelioid MFS is a rare variant of MFS, accounting for <3% of MFS in consultation material. Its natural history seems more aggressive than usual high-grade MFS, with approximately 70% local recurrence and 50% metastases, even within a relatively short follow-up period.


Venous Thromboembolism in Hospitalized Critical and Noncritical COVID-19 Patients: A Systematic Review and Meta-analysis.
Introduction Venous thromboembolism (VTE) has been observed as a frequent complication in patients with severe novel coronavirus disease 2019 (COVID-19) infection requiring hospital admission. Aim This study was aimed to evaluate the epidemiology of VTE in hospitalized intensive care unit (ICU) and non-ICU patients. Materials and Methods PubMed was searched up to November 13, 2020, and updated in December 12, 2020. We included studies that evaluated the epidemiology of VTE, including pulmonary embolism (PE) and/or deep vein thrombosis (DVT), in patients with COVID-19. Results A total of 91 studies reporting on 35,017 patients with COVID-19 was included. The overall frequency of VTE in all patients, ICU and non-ICU, was 12.8% (95% confidence interval [CI]: 11.103-14.605), 24.1% (95% CI: 20.070-28.280), and 7.7% (95% CI: 5.956-9.700), respectively. PE occurred in 8.5% (95% CI: 6.911-10.208), and proximal DVT occurred in 8.2% (95% CI: 6.675-9.874) of all hospitalized patients. The relative risk for VTE associated with ICU admission was 2.99 (95% CI: 2.301-3.887, p <0.001). DVT and PE estimated in studies that adopted some form of systematic screening were higher compared with studies with symptom-triggered screening. Analysis restricted to studies in the 5th quintile of sample size reported significantly lower VTE estimates. Conclusion This study confirmed a high risk of VTE in hospitalized COVID-19 patients, especially those admitted to the ICU. Nevertheless, sensitivity analysis suggests that previously reported frequencies of VTE in COVID-19 might have been overestimated.


Bone marrow stromal cells in the pathogenesis of acute myeloid leukemia.
Acute myeloid leukemia (AML) is clonal disorder affecting pluripotent stem cell and characterized by ineffective hematopoiesis. Genetic abnormalities in a progenitor cells is thought to lead to uncontrolled growth of leukemia cells. In addition, in the last years, it has been clearly recognized that the hematopoietic microenvironment (HM) plays an important role in the pathogenesis of AML. The HM can regulate hematopoiesis by interacting directly with HC and/or by secreting regulatory molecules that exert a positive or negative influence on the growth of HC. Stromal elements are important in the homing of immature HC or hematopoietic stem cells. Several studies propose that important quantitative and functional alterations are present in the BMSC of AML patients. AML may arise in the setting of an abnormal HM, resulting in the generation of multiple populations with varying initiation event. Dysfunction of HM may contribute to leukemia by supplying abundant growth factors that promote proliferation and/or inhibit apoptosis. Recent discoveries utilizing mouse models showed that genetic alteration in cells of HM can induce AML.


Infectious Bronchitis Coronavirus Limits Interferon Production by Inducing a Host Shutoff That Requires Accessory Protein 5b.
During infection of their host cells, viruses often inhibit the production of host proteins, a process that is referred to as host shutoff. By doing this, viruses limit the production of antiviral proteins and increase production capacity for viral proteins. Coronaviruses from the genera Alphacoronavirus and Betacoronavirus, such as severe acute respiratory syndrome coronavirus (SARS-CoV), establish host shutoff via their nonstructural protein 1 (nsp1). The Gammacoronavirus and Deltacoronavirus genomes, however, do not encode nsp1, and it has been suggested that these viruses do not induce host shutoff. Here, we show that the Gammacoronavirus infectious bronchitis virus (IBV) does induce host shutoff, and we find that its accessory protein 5b is indispensable for this function. Importantly, we found that 5b-null viruses, unlike wild-type viruses, induce production of high concentrations of type I interferon protein in vitro, indicating that host shutoff by IBV plays an important role in antagonizing the host's innate immune response. Altogether, we demonstrate that 5b is a functional equivalent of nsp1, thereby answering the longstanding question of whether lack of nsp1 in gammacoronaviruses is compensated for by another viral protein. As such, our study is a significant step forward in the understanding of coronavirus biology and closes a gap in the understanding of some IBV virulence strategies. Many viruses inhibit protein synthesis by their host cell to enhance virus replication and to antagonize antiviral defense mechanisms. This process is referred to as host shutoff. We studied gene expression and protein synthesis in chicken cells infected with the important poultry pathogen infectious bronchitis virus (IBV). We show that IBV inhibits synthesis of host proteins, including that of type I interferon, a key component of the antiviral response. The IBV-induced host shutoff, however, does not require degradation of host RNA. Furthermore, we demonstrate that accessory protein 5b of IBV plays a crucial role in the onset of host shutoff. Our findings suggest that inhibition of host protein synthesis is a common feature of coronaviruses and primarily serves to inhibit the antiviral response of the host.


Dermatitis Artefacta: A Practical Guide for Diagnosis and Management.
Dermatitis artefacta (DA) is a psycho-dermatologic condition based on patients' behavioral patterns, characterized by an intentional production of cutaneous lesions on their own skin. The clinical presentation can be highly variable. Patients with DA seldom seek psychological support or psychiatric consultation. More often, they seek help from their primary care physician or dermatologist. This review article aims to provide a practical guide for the diagnosis and management of AD and affected patients. A broad literature search was performed using the PubMed and Google Scholar electronic online databases, using key words "dermatitis artefacta", "diagnosis", "management", and "psychodermatology". The search was limited to English and Spanish language articles and was supplemented with themed books and book chapters. DA can occur in a variety of clinical presentations, and physicians should suspect DA in patients with a history of psychiatric disorders or extensive use of healthcare services. The ultimate goal of DA treatment may be a proper referral to mental health services. However, the prognosis is poor even when successful mental health referrals are achieved, with low recovery rates. A useful approach may include the suggestion that a mental health provider can help with the anxiety and the distress generated by the lesions: in this case in this case it will be crucial to discuss this with the mental health provider after obtaining informed consent from the patient. Considering the difficulty in promoting patients' adherence to treatment, the ideal setting for DA treatment is a psycho-dermatologic clinic, where both dermatologic and psychological interventions can be seamlessly integrated.


Evaluating Substance Use and Insulin Misuse in Adolescents With Type 1 Diabetes.
Substance use behaviors often emerge during adolescence, and adolescents with type 1 diabetes (T1D) may be at risk for engaging in traditional substance use (eg, alcohol, tobacco, and illicit substances) as well as a unique form of substance use: insulin misuse. The purpose of this exploratory study was to examine substance use and insulin misuse in adolescents with T1D. Sixty adolescents aged 12 to 20 years with T1D (n = 60) completed surveys on substance use, insulin misuse, and diabetes self-management during a routine diabetes appointment. Demographic measures were summarized by mean (SD) or percentage. Prevalence of substance use and insulin misuse was calculated and stratified by demographic and clinical characteristics. Two-sample t test (continuous variables) and chi-square analysis (categorical variables) determined statistically significant differences. The prevalence of ever using substances was 36.7%, and that for ever misusing insulin was 19%. Older participants (17.1 ± 1.8 vs 15.6 ± 1.9 years; P < .01) and those with depression (31.8% vs 7.9%; P = .02) were more likely to use substances. Disordered eating behaviors were the most frequently reported reason for insulin misuse. Self-harm intent was reported by one-third of insulin misusers. Substance use and insulin misuse were not related to glycemic control or diabetes self-management behaviors. The diabetes care team should be aware that substance use and insulin misuse are common in adolescents with T1D. Screening for these risky behaviors is critical in those who are older or have mental health disorders. Effective education, prevention, and treatment strategies targeted at these behaviors are needed to improve the overall health of this population.


Cell death upon epigenetic genome methylation: a novel function of methyl-specific deoxyribonucleases.
Alteration in epigenetic methylation can affect gene expression and other processes. In Prokaryota, DNA methyltransferase genes frequently move between genomes and present a potential threat. A methyl-specific deoxyribonuclease, McrBC, of Escherichia coli cuts invading methylated DNAs. Here we examined whether McrBC competes with genome methylation systems through host killing by chromosome cleavage. McrBC inhibited the establishment of a plasmid carrying a PvuII methyltransferase gene but lacking its recognition sites, likely through the lethal cleavage of chromosomes that became methylated. Indeed, its phage-mediated transfer caused McrBC-dependent chromosome cleavage. Its induction led to cell death accompanied by chromosome methylation, cleavage and degradation. RecA/RecBCD functions affect chromosome processing and, together with the SOS response, reduce lethality. Our evolutionary/genomic analyses of McrBC homologs revealed: a wide distribution in Prokaryota; frequent distant horizontal transfer and linkage with mobility-related genes; and diversification in the DNA binding domain. In these features, McrBCs resemble type II restriction-modification systems, which behave as selfish mobile elements, maintaining their frequency by host killing. McrBCs are frequently found linked with a methyltransferase homolog, which suggests a functional association. Our experiments indicate McrBC can respond to genome methylation systems by host killing. Combined with our evolutionary/genomic analyses, they support our hypothesis that McrBCs have evolved as mobile elements competing with specific genome methylation systems through host killing. To our knowledge, this represents the first report of a defense system against epigenetic systems through cell death.


Simple capillary electrophoretic determination of soluble oxalate and nitrate in forage grasses.
A simple capillary electrophoretic method is described for the simultaneous determination of soluble oxalate and nitrate in forage grasses. Grass samples were ground and extracted with water. The extracts were filtered and submitted to capillary electrophoresis. Electrophoresis was performed in a 75 microm x 50 cm fused silica capillary with 30 mM sodium sulfate containing an electroosmotic flow modifier under constant voltage at -8 kV. Separated oxalate and nitrate were detected with direct UV absorption at 214 nm. The present method can be used for routine monitoring of the concentration of soluble oxalate and nitrate in grasses.


Cause-specific visual impairment and mortality: results from a population-based study of older people in the United Kingdom.
To assess the association between mortality and cause-specific visual impairment in older people. Visual acuity and causes of visual impairment were collected in 13 569 participants 75 years and older participating in a randomized trial of health screening. Participants were followed up for mortality for a median of 6.1 years. Compared with those with 6/6 (or 20/20 Snellen) or better visual acuity, the age- and sex-adjusted rate ratio for visually impaired people (binocular visual acuity <6/18 or <20/60 Snellen) was 1.60 (95% confidence interval, 1.47-1.74), which was markedly attenuated (rate ratio, 1.17; 95% confidence interval, 1.07-1.27) after adjustment for confounding factors. People whose visual impairment was due to cataract or age-related macular degeneration had excess risks of all-cause and cardiovascular mortality, which disappeared after adjustment. People with refractive error remained at small risk, despite adjustment, probably owing to residual confounding from factors associated with minimal use of eye services rather than underlying eye disease. There were no associations with cancer mortality. Associations reported for visual impairment and mortality or for specific causes of visual impairment reflect confounding by comorbidities, risk factors, and other factors related to susceptibility to death rather than an independent biological association of vision problems or specific eye diseases.