Demographic and clinical factors associated with same-day discharge and unplanned readmission following shoulder arthroplasty: a retrospective cohort study.
Same-day discharge, defined as discharge from the hospital within 24 h of surgery, has been shown to be safe for joint arthroplasty. We examined demographic and clinical factors associated with same-day discharge and unplanned readmission following shoulder arthroplasty in adult patients. Utilizing data from the American College of Surgeons National Surgical Quality Improvement Program database, we extracted information of all patients that underwent shoulder arthroplasty. The primary and secondary outcome of interest was same-day discharge and 30-day unplanned readmission, respectively. We utilized multivariable logistic regression to identify covariates associated with these outcomes. There were 17,011 patients analyzed when identifying predictors for same-day discharge. There was an increase in same-day discharge from 2007 to 2016. The odds of same-day discharge were significantly better for males (P < 0.001). The odds of same-day discharge was significantly decreased for every 10-year increase in age and for patients with insulin dependent diabetes, poor functional status, chronic obstructive pulmonary disease, congestive heart failure, bleeding disorder, and comorbidity burden (all P < 0.001). There were 14,276 patients analyzed for hospital readmission. The odds of unplanned readmission were significantly higher for every 10-year increase in age and for patients with poor functional status, congestive heart failure, bleeding disorder, and higher comorbidity burden (all P < 0.001). The results of this study show that preoperative comorbidities and advanced age reduce the odds of same-day discharge. Risk stratification, preoperative optimization, and coordinated care after surgery may be helpful to optimize patients for same-day discharge.


How to use…the direct ophthalmoscope.
Ophthalmoscopy and red reflex examination are core medical skills required to identify sight-threatening and life-threatening disease. We discuss the predictive utility and limitations of findings with an ophthalmoscope and tips as to how to optimise these. We outline important considerations in three clinical scenarios: an abnormal red reflex, an abnormal optic disc and retinal haemorrhages in the context of child protection concerns.


Renal transtubular transport of mercapturic acid in vivo.
When S-benzyl-N-acetyl-L-[U-14C]cysteine, a mercapturic acid, was administered to rats intravenously, the plasma level of radioactivity decreased very rapidly with a concomitant increase in the renal level of radioactivity. The renal radioactivity reached its maximum within 2 min and then decreased rapidly with concomitant appearance of the radioactive mercapturic acid in the urine. Bilateral ligation of the ureters resulted in only a slight decrease in the rate of disappearance of mercapturic acid from the plasma, while bilateral nephrectomy caused a marked retardation of its clearance from the plasma. Intravenous administration of probenecid, a well known inhibitor of a renal transtubular transport system for organic acids, caused a significant retardation of mercapturate clearance from the plasma in both of the control and ureter-ligated animals. The renal accumulation of this mercapturic acid as well as its excretion into urine was inhibited by probenecid. All these data suggested that a mercapturic acid in the plasma was preferentially taken up by renal tubule cells from the basolateral side of plasma membranes via the probenecid-sensitive transtubular transport system and then excreted rapidly into the lumenal space. This transtubular transport of a mercapturic acid seems to constitute an important process in the hepato-renal cooperation in the mercapturic acid biosynthesis in vivo.


Design and Rationale of Cytokine Filtration in Lung Transplantation (GLUSorb): Protocol for a Multicenter Clinical Randomized Controlled Trial.
Lung transplantation (LTx) is the only treatment option for end-stage lung disease. Despite improvements, primary graft dysfunction (PGD) remains the leading cause of early mortality and precipitates chronic lung allograft dysfunction, the main factor in late mortality after LTx. PGD develops within the first 72 hours and impairs the oxygenation capacity of the lung, measured as partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2). Increasing the PaO2/FiO2 ratio is thus critical and has an impact on survival. There is a general lack of effective treatments for PGD. When a transplanted lung is not accepted by the immune system in the recipient, a systemic inflammatory response starts where cytokines play a critical role in initiating, amplifying, and maintaining the inflammation leading to PGD. Cytokine filtration can remove these cytokines from the circulation, thus reducing inflammation. In a proof-of-concept preclinical porcine model of LTx, cytokine filtration improved oxygenation and decreased PGD. In a feasibility study, we successfully treated patients undergoing LTx with cytokine filtration (ClinicalTrials.gov; NCT05242289). The purpose of this clinical trial is to demonstrate the superiority of cytokine filtration in improving LTx outcome, based on its effects on oxygenation ratio, plasma levels of inflammatory markers, PGD incidence and severity, lung function, kidney function, survival, and quality of life compared with standard treatment with no cytokine filtration. This study is a Swedish national interventional randomized controlled trial involving 116 patients. Its primary objective is to investigate the potential benefits of cytokine filtration when used in conjunction with LTx. Specifically, this study aims to determine whether the application of cytokine filtration, administered for a duration of 12 hours within the initial 24 hours following a LTx procedure, can lead to improved patient outcomes. This study seeks to assess various aspects of patient recovery and overall health to ascertain the potential positive impact of this intervention on the posttransplantation course. The process of patient recruitment for this study is scheduled to commence subsequent to a site initiation visit, which was slated to take place on August 28, 2023. The primary outcome measure that will be assessed in this research endeavor is the oxygenation ratio, a metric denoted as the highest PaO2/FiO2 ratio achieved by patients within a 72-hour timeframe following their LTx procedure. We propose that cytokine filtration could enhance the overall outcomes of LTx. Our hypothesis suggests potential improvements in LTx outcome and patient care. ClinicalTrials.gov NCT05526950; https://www.clinicaltrials.gov/study/NCT05526950. PRR1-10.2196/52553.


Can an inexperienced observer accurately plot disc contours using Heidelberg retinal Tomograph?
To examine the reliability of inexperienced observers in plotting optic disc contours on Heidelberg retinal tomography images before and after training. Observational study. One hundred eyes that were randomly selected from the Singapore Indian Eye Study. Both eyes of subjects were imaged with Heidelberg Retina Tomograph 3 (HRT-3; Heidelberg Engineering, Heidelberg, Germany). Optic disc contours were plotted on the same images by 2 new observers on 2 separate occasions, before and after 2-hour standardized training on the skills and tools available to accurately identify and delineate optic disc contours. These plottings were compared with an experienced, trained glaucoma expert (gold standard). Agreement and variability were analyzed by interclass correlation tests and Bland-Altman plots. A total of 182 images (18 excluded because of poor quality) from 89 Indian subjects were included. The mean age was 53.27 ± 7.25 years and 54.8% were male. There was moderate-to-high agreement between pretraining (both new observers) and experienced observer's results (interclass correlation values range, 0.76-0.99). The interclass correlation improved for all the HRT-3 parameters after the 2 new observers were adequately trained. Comparing the interclass correlation values before and after training, the differences for mean retinal nerve fibre layer thickness for Observer 1 and all the HRT-3 parameters for Observer 2 were statistically significant. This study shows that it is easy to train a new inexperienced observer to plot optic disc contours on HRT images, which translates into improved and acceptable interobserver variability and agreement.


The FG-repeat asymmetry of the nuclear pore complex is dispensable for bulk nucleocytoplasmic transport in vivo.
Nucleocytoplasmic transport occurs through gigantic proteinaceous channels called nuclear pore complexes (NPCs). Translocation through the NPC is exquisitely selective and is mediated by interactions between soluble transport carriers and insoluble NPC proteins that contain phenylalanine-glycine (FG) repeats. Although most FG nucleoporins (Nups) are organized symmetrically about the planar axis of the nuclear envelope, very few localize exclusively to one side of the NPC. We constructed Saccharomyces cerevisiae mutants with asymmetric FG repeats either deleted or swapped to generate NPCs with inverted FG asymmetry. The mutant Nups localize properly within the NPC and exhibit exchanged binding specificity for the export factor Xpo1. Surprisingly, we were unable to detect any defects in the Kap95, Kap121, Xpo1, or mRNA transport pathways in cells expressing the mutant FG Nups. These findings suggest that the biased distribution of FG repeats is not required for major nucleocytoplasmic trafficking events across the NPC.


Molecular mechanism of docking of dense-core vesicles to the plasma membrane in neuroendocrine cells.
Almost every cell in our organism releases proteins and other biological substances using a fundamental cellular process known as constitutive exocytosis. In contrast, in exocrine and endocrine glands, the cells are inherent in an additional and more refined release mechanism directly tuned by extracellular signals. This process, referred to as regulated exocytosis, ensures the timely delivery of molecules such as peptide hormones and digestive enzymes to the exact moment-to-moment requirements of the organism. Recent studies of the final step of hormone secretion have been shown that the monomeric GTPase Rab27 subfamily and its cell type-or tissue-specific Rab27-binding protein(s) [also called Rab27 effector(s)] exist on the hormone-containing dense-core vesicle membrane and regulate the secretion of peptide hormones in endocrine cells. Synaptotagmin-like proteins (Slps) and rabphilin contain an N-terminal Rab27-binding domain and C-terminal tandem C2 domains, and some of the Rab27-binding proteins have recently been shown to promote docking of dense-core vesicles to the plasma membrane in a variety of secretory cells. We discuss here the evidence supporting a molecular mechanism for the way that the Rab27 and Rab27 effector complex controls the docking step in the trafficking of dense-core vesicles in neuroendocrine cells.


The value of magnetic resonance imaging in investigating complex atypical hyperplasia of the endometrium.
Magnetic resonance imaging (MRI) has been recommended to rule out myometrial invasion or distant metastasis before treatment for complex atypical hyperplasia (CAH). This study aimed to evaluate whether preoperative MRI in patients diagnosed with CAH on initial biopsy will have any impact on their management. A retrospective study of women diagnosed with CAH on initial endometrial biopsy that subsequently had hysterectomies. Definitive diagnosis was established at histology of the hysterectomy specimens and compared with preoperative MRI findings. Preoperative MRI scan was performed in 33 of 106 patients and myometrial invasion was reported in 12 patients with final histology diagnosing endometrial cancer in 10 patients. Twenty-one out of 33 cases were reported as no invasion on MRI but nine patients were confirmed with endometrial cancer on histology. Of the thirty-three patients diagnosed with endometrial cancer, twenty had stage 1a cancer, eight had stage 1b and five had stage 2 cancer. Twenty-seven patients had grade 1 and six patients had grade 2 cancer with no high-grade subtypes. In our series, we found that MRI had no value in the management of CAH. Thirty-three endometrioid endometrial cancers (31%) were identified and we found no high-risk subtypes, and simple hysterectomy and bilateral salpingo-oophorectomy would be performed and the few stage 2 cases diagnosed were microscopic and would not have been diagnosed on MRI.


Potential role of Flavobacterial gliding-motility and type IX secretion system complex in root colonization and plant defense.
Members of the Flavobacterium genus are often highly abundant in the rhizosphere. Nevertheless, the physiological characteristics associated with their enhanced rhizosphere competence are currently an enigma. Flavobacteria possess a unique gliding-motility complex that is tightly associated with a recently characterized Bacteroidetes-specific type IX protein secretion system, which distinguishes them from the rest of the rhizosphere microbiome. We hypothesize that proper functionality of this complex may confer a competitive advantage in the rhizosphere. To test this hypothesis, we constructed mutant and complement root-associated flavobacterial variants with dysfunctional secretion and gliding motility, and tested them in a series of in planta experiments. These mutants demonstrated significantly lower rhizosphere persistence (approximately 10-fold), plant root colonization (approximately fivefold), and seed adhesion capacity (approximately sevenfold) than the wild-type strains. Furthermore, the biocontrol capacity of the mutant strain toward foliar-applied Clavibacter michiganensis was significantly impaired relative to the wild-type strain, suggesting a role of the gliding and secretion complex in plant protection. Collectively, these results provide an initial link between the high abundance of flavobacteria in the rhizosphere and their unique physiology, indicating that the flavobacterial gliding-motility and secretion complex may play a central role in root colonization and plant defense.


Alcohol protective behavioral strategies for young adults: a content analysis across drinking contexts and gender.
Background: Protective behavioral strategies (PBS) are specific harm reduction behaviors which mitigate alcohol-related consequences among young adults. Prior work indicates PBS utilization varies according to drinking context and gender, suggesting a need for further research assessing whether young adults employ unidentified PBS according to such factors.Objectives: This study examined alcohol PBS young adults suggest using across drinking contexts and gender to inform alcohol-related harm reduction interventions.Methods: An online survey with 514 young adult heavy drinkers (n = 269 female, Mage = 22.36 years) assessed PBS use generally, and across 12 physical and social contexts. We utilized qualitative content analysis methods to code and derive themes from open-ended responses from a prompt asking participants to state additional PBS used per context. The frequency of each theme's appearance was calculated across the overall sample, by gender, and within each context.Results: PBS endorsement varied across context and gender within each theme. Young adults who reported PBS use most frequently endorsed utilizing strategies related to drink content (18.30%), social support (12.36%), and engaging in other activities (10.34%). Participants infrequently endorsed strategies related to awareness of time (0.23%), standards of behavior (0.78%) and avoiding environments (0.87%).Conclusions: Young adults endorse utilizing additional PBS in varying frequency according to drinking context and gender. Given PBS are often a key component of alcohol harm reduction interventions, monitoring trends in young adult PBS use is crucial to ensure continued relevance and efficacy of such interventions to minimize harms associated with young adult heavy alcohol use.


Control of Culex quinquefasciatus in a storm drain system in Florida using attractive toxic sugar baits.
Attractive toxic sugar baits (ATSBs) were used to control mosquitoes in the storm drains of a residential area on the outskirts of St Augustine, Florida. The drainage system was newly constructed and no mosquitoes were breeding inside it. The area covered by the storm drains was divided in half; 10 drains served as control drains and 16 drains served as experimental drains. The baits, which consisted of a mixture of brown sugar, fruit juice, green dye marker and boric acid, were presented at the entrances of the treated drains and exit traps were positioned over the drain openings and the connecting tubes leading to retention ponds. Similar baits with orange dye and without toxin were presented at the entrances of control drains. A total of 220 pupae of Culex quinquefasciatus (Diptera: Culicidae) were released in each control and toxin-treated drain, and the numbers of recovered mosquitoes were examined to determine the effectiveness of ATSBs in the storm drain system. An average of 178.2 mosquitoes exited each drain in the control area; 87.0% of these had fed on the baits and were stained orange, whereas 13.0% were unstained. In the toxin-treated drains, 83.7% of hatched females and 86.6% of hatched males were controlled by the baits.


Lung Ultrasound in the Neonatal Intensive Care Unit: Does It Impact Clinical Care?
A neonatal point-of-care ultrasound has multiple applications, but its use has been limited in neonatal intensive care units in the Unites States. An increasing body of evidence suggests that lung ultrasound performed by the neonatologist, at the bedside, is reliable and accurate in differentiating neonatal respiratory conditions, predicting morbidity, and guiding invasive interventions. Recent research has shown that a lung ultrasound can assist the clinician in accurately identifying and managing conditions such as respiratory distress syndrome, transient tachypnea of the newborn, and bronchopulmonary dysplasia. In this review, we discuss basic lung ultrasound terminology, evidence for applications of neonatal lung ultrasound, and its use as a diagnostic and predictive tool for common neonatal respiratory pathologies.


Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions.
Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.


Patient experience of access to primary care: identification of predictors in a national patient survey.
The 2007/8 GP Access Survey in England measured experience with five dimensions of access: getting through on the phone to a practice, getting an early appointment, getting an advance appointment, making an appointment with a particular doctor, and surgery opening hours. Our aim was to identify predictors of patient satisfaction and experience with access to English primary care. 8,307 English general practices were included in the survey (of 8,403 identified). 4,922,080 patients were randomly selected and contacted by post and 1,999,523 usable questionnaires were returned, a response rate of 40.6%. We used multi-level logistic regressions to identify patient, practice and regional predictors of patient satisfaction and experience. After controlling for all other factors, younger people, and people of Asian ethnicity, working full time, or with long commuting times to work, reported the lowest levels of satisfaction and experience of access. For people in work, the ability to take time off work to visit the GP effectively eliminated the disadvantage in access. The ethnic mix of the local area had an impact on a patient's reported satisfaction and experience over and above the patient's own ethnic identity. However, area deprivation had only low associations with patient ratings. Responses from patients in small practices were more positive for all aspects of access with the exception of satisfaction with practice opening hours. Positive reports of access to care were associated with higher scores on the Quality and Outcomes Framework and with slightly lower rates of emergency admission. Respondents in London were the least satisfied and had the worst experiences on almost all dimensions of access. This study identifies a number of patient groups with lower satisfaction, and poorer experience, of gaining access to primary care. The finding that access is better in small practices is important given the increasing tendency for small practices to combine into larger units. Consideration needs to be given to ways of retaining these and other benefits of small practice size when primary care services are reconfigured. Differences between population groups (e.g. younger people, ethnic minorities) may be due to differences in actual care received or different response tendencies of different groups. Further analysis is needed to determine whether case-mix adjustment is required when comparing practices serving different populations.


Cytoadherence by Plasmodium falciparum-infected erythrocytes is correlated with the expression of a family of variable proteins on infected erythrocytes.
Plasmodium falciparum-infected erythrocytes (IRBCs) adhere specifically to venular endothelium and thereby evade spleen-dependent immune mechanisms. We have investigated the molecular basis of cytoadherence. We report here that the capacity for cytoadherence of IRBCs is correlated with the expression of a family of variable proteins on the surface of IRBCs. Essential to these studies was the use of in vitro techniques for modulating the cytoadherence phenotype of cloned parasites. In initial studies, we found culture-adapted parasites to be poorly cytoadherent or noncytoadherent. To select for cytoadherent parasites, we incubated knobbed IRBCs with C32 melanoma cells and cultured the adherent cells. Repeated rounds of selection produced parasites with increased cytoadherence. To select for noncytoadherent parasites, we cultured the cells that did not adhere to C32 melanoma cells. Cytoadherent IRBCs from two different cloned isolates had large (Mr greater than 2.4 x 10(5) radioiodinatable proteins that differed in size between the isolates but had in common the biochemical properties of trypsin sensitivity and insolubility with Triton X-100. The proteins were not detected with uninfected erythrocytes, indicating that they were parasite determined, nor were they detected with IRBCs containing parasites cultured for many months without selection. With continued selection for the cytoadherent phenotype, additional IRBC surface proteins with larger molecular sizes (Mr 2.9 x 10(5) and 3.2 x 10(5] appeared. A sequence of reversible changes in the cytoadherence phenotype of cloned parasites was accompanied by variation in the molecular size of the IRBC surface protein. Increased cytoadherence was correlated with expression of larger proteins and decreased cytoadherence was correlated with expression of smaller proteins; there was no change in the molecular size of two other parasite proteins associated with the IRBC membrane. The results indicate that the expression of this family of proteins is closely linked to the cytoadherence phenotype of the parasites, suggesting that the members of the protein family have a role in mediating cytoadherence between IRBCs and endothelial cells.


Scapular dysfunction in throwers with pathologic internal impingement.
Case control group study. To compare scapular position and orientation between baseball players with and without pathologic internal impingement. Scapular dysfunction has been implicated as a contributor to throwing-related pathologic internal impingement of the shoulder due to its role in increasing the contact between the greater tuberosity and posterior-superior glenoid, thereby impinging the posterior rotator cuff tendon(s) and labrum. However, to date, no definitive data demonstrate this scapular dysfunction in throwing athletes. The purpose of this study was to assess, in a controlled laboratory environment, whether scapular position and orientation would be different in throwing athletes diagnosed with pathologic internal impingement than in a control group of throwing athletes. Eleven throwing athletes diagnosed with pathologic internal impingement, using both clinical examination and a magnetic resonance arthrogram, were demographically matched with a control group of 11 throwers with no history of upper extremity injury. An electromagnetic tracking device was used to measure scapular internal/external rotation, anterior/posterior tilt, upward/downward rotation, sternoclavicular protraction/retraction, and elevation/depression during humeral elevation within the scapular plane. Comparisons were made between groups with analysis of variance models (P<.05). The individuals in the pathologic internal impingement group demonstrated statistically significant increased sternoclavicular elevation when elevating their humerus from 30 degrees to 120 degrees (P = .002) and from 60 degrees to 120 degrees (P = .003), compared to the control group. Furthermore, these patients also had increased posterior scapular tilt position (P = .016). No statistically significant differences were present in any other scapular variables measured. Based on the results of this study, throwing athletes diagnosed with pathologic internal impingement present with statistically significant increases in sternoclavicular elevation and scapular posterior tilt position during humeral elevation in the scapular plane.


Class 1 (unique) tumor antigens of human melanoma: partial purification and characterization of the FD antigen and analysis of a mouse polyclonal antiserum.
Serum antibodies from melanoma patient FD were previously shown to detect a unique antigenic specificity (FD) expressed only on the autologous tumor cells (SK-MEL-131) in culture. The FD determinant is carried by a Mr 90,000 glycoprotein (gp90) that binds to concanavalin A but not to lentil lectin or wheat germ agglutinin. After treatment with endo-N-acetylglucosaminidase H, the antigen no longer bound to concanavalin A. These and other properties indicate the gp90 carries mainly high mannose or hybrid N-linked carbohydrate chains. gp90 was partially purified from a detergent-solubilized membrane preparation by chromatography on DEAE-Sepharose, hydroxylapatite, chelating Sepharose, and lectin-agarose columns. Two-dimensional electrophoresis of the final preparation revealed three major components, one of which was identified as the FD antigen since it was specifically removed by precipitation with serum from patient FD. Immunization with the partially purified antigen preparation elicited anti-gp90 antibodies in two of four mice as demonstrated by sequential radioimmunoprecipitation experiments. Absorption experiments demonstrated that the mouse antibodies could, unlike human FD serum, be absorbed by a number of different cell types. Based on these results it is proposed that gp90 in SK-MEL-131 cells has two distinct epitopes, one, unique, detected by autologous FD serum, and another, common epitope or epitopes, detected by the polyclonal mouse sera. The common epitope(s) is present on gp90 in a variety of cells, including allogeneic melanomas and FD-B cells. These findings, which are compared with those on mouse tumor rejection antigens, have clear implications for the understanding of the nature of tumor antigens.


Mapping mouse hemangioblast maturation from headfold stages.
The mouse posterior primitive streak at neural plate/headfold stages (NP/HF, ~7.5 dpc-8 dpc) represents an optimal window from which hemangioblasts can be isolated. We performed immunohistochemistry on this domain using established monoclonal antibodies for proteins that affect blood and endothelial fates. We demonstrate that HoxB4 and GATA1 are the first set of markers that segregate independently to endothelial or blood populations during NP/HF stages of mouse embryonic development. In a subset of cells, both proteins are co-expressed and immunoreactivities appear mutually excluded within nuclear spaces. We searched for this particular state at later sites of hematopoietic stem cell emergence, viz., the aorta-gonad-mesonephros (AGM) and the fetal liver at 10.5-11.5 dpc, and found that only a rare number of cells displayed this character. Based on this spatial-temporal argument, we propose that the earliest blood progenitors emerge either directly from the epiblast or through segregation within the allantoic core domain (ACD) through reduction of cell adhesion and pSmad1/5 nuclear signaling, followed by a stochastic decision toward a blood or endothelial fate that involves GATA1 and HoxB4, respectively. A third form in which binding distributions are balanced may represent a common condition shared by hemangioblasts and HSCs. We developed a heuristic model of hemangioblast maturation, in part, to be explicit about our assumptions.


Gianotti-Crosti syndrome: a study of 26 cases.
We have studied 26 patients presenting with a symmetrical papular or papulovesicular acrolocated eruption of more than 10 days duration. Mean age at onset was 2 years (range 10 months to 5.75 years). Lymphadenopathy was noted in eight cases, and hepatomegaly in one case. In 12 cases, histopathology and direct immunofluorescence were non-contributory. Cytolytic hepatitis occurred in one case and was associated with HBs antigenemia. A history of recent immunization was given in two cases. There was serological evidence of recent Epstein-Barr virus infection in seven out of 13 cases tested. Coxsackie B viruses were isolated from three patients, and cytomegalovirus was probably associated with the syndrome in one case. We conclude that the Gianotti-Crosti syndrome is not rare in France, and that non-hepatitis B virus (HBV)-associated cases are more frequent than the classical HBV-associated papular acrodermatitis of childhood.


The potentially poor response to outpatient diabetes care in urban African-Americans.
HbA1c levels can be reduced in populations of diabetic patients, but some individuals may exhibit little improvement. To search for reasons underlying differences in HbA1c outcome, we analyzed patients managed in an outpatient diabetes clinic. African-Americans with type 2 diabetes were categorized as responders, intermediate responders or poor responders according to their HbA1c level after 1 year of care. Logistical regression was used to determine baseline characteristics that distinguished poor responders from responders. Therapeutic strategies were examined for each of the response categories. The 447 patients had a mean age and disease duration of 58 and 5 years, respectively, and BMI of 32 kg/m2. Overall, the mean HbA1c level fell from 9.6 to 8.1% after 12 months. Mean HbA1c levels improved from 8.8 to 6.2% in responders, and from 9.5 to 7.9% in intermediate responders. In poor responders, the average HbA1c level was 10.8% on presentation and 10.9% at 1 year. The odds of being a poor responder were significantly increased with longer disease duration, higher initial HbA1c level, and greater BMI. Although doses of oral agents and insulin were significantly higher among poor responders at most visits, the acceleration of insulin therapy did not occur until late in the follow-up period. Clinical diabetes programs need to devise methods to identify patients who are at risk for persistent hyperglycemia. Whereas patient characteristics explain some heterogeneity of HbA1c outcome (and may aid in earlier identification of patients who potentially may not respond to conventional treatment), insufficient intensification of therapy may also be a component underlying the failure to achieve glycemic goals.


Exploring multifractal-based features for mild Alzheimer's disease classification.
Multifractal applications to resting state functional MRI (rs-fMRI) time series for diagnosing Alzheimer's disease (AD) are still limited. We aim to address two issues: (I) if and what multifractal features are sufficiently discriminative to detect AD from the healthy; (II) if AD classification could be further improved by combining multifractal features with traditional features in this field. Rs-fMRI data of 25 AD patients and 38 normal controls were analyzed. A set of multifractal features were systematically investigated. Traditional features in monofractal, linear, and network-based categories were also extracted for comparison and combination. Both support vector machines and multiple kernel learning (MKL) were used to perform classification with individual and combined features. We identified a multifractal feature, Δf, which has the strongest discriminative power among all the features in our study. Moreover, we found that the classification accuracy could be significantly improved from 69% (by Δf only) to up to 76%, when nonsparse MKL is used to combine Δf with the monofractal feature, Hurst. Finally, we showed that incorporating other multifractal features, α(0), Δα and Pc, could also improve traditional-feature-based AD classification. Our work demonstrated the potential usefulness of multifractal analysis for AD research, especially when combining with the traditional rs-fMRI features. It contributes to distinguishing AD from NC subjects. Magn Reson Med 76:259-269, 2016. © 2015 Wiley Periodicals, Inc.


A fast iterative convolution weighting approach for gridding-based direct Fourier three-dimensional reconstruction with correction for the contrast transfer function.
We describe a fast and accurate method for the reconstruction of macromolecular complexes from a set of projections. Direct Fourier inversion (in which the Fourier Slice Theorem plays a central role) is a solution for dealing with this inverse problem. Unfortunately, the set of projections provides a non-equidistantly sampled version of the macromolecule Fourier transform in the single particle field (and, therefore, a direct Fourier inversion) may not be an optimal solution. In this paper, we introduce a gridding-based direct Fourier method for the three-dimensional reconstruction approach that uses a weighting technique to compute a uniform sampled Fourier transform. Moreover, the contrast transfer function of the microscope, which is a limiting factor in pursuing a high resolution reconstruction, is corrected by the algorithm. Parallelization of this algorithm, both on threads and on multiple CPU's, makes the process of three-dimensional reconstruction even faster. The experimental results show that our proposed gridding-based direct Fourier reconstruction is slightly more accurate than similar existing methods and presents a lower computational complexity both in terms of time and memory, thereby allowing its use on larger volumes. The algorithm is fully implemented in the open-source Xmipp package and is downloadable from http://xmipp.cnb.csic.es.


Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo.
Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.


Mechanism of lncRNA DUXAP8 in promoting proliferation of bladder cancer cells by regulating PTEN.
To evaluate the lncRNA DUXAP8 expression in bladder cancer and its mechanism. Clinical specimens were analyzed. The expression of lncRNA in bladder cancer and adjacent tissues was detected using qRT-PCR. The χ2-test analysis was used to analyze the relationship between lncRNA DUXAP8 expression and clinicopathological information in patients with bladder cancer. The tumor cell activity and cell proliferation were measured by cell counting kit-8 (CCK8) and colony formation assay. We utilized polymerase chain reaction (PCR) to access PTEN expression in bladder cancer and adjacent tissues. Pearson correlation analysis was utilized for evaluating the relationship between PTEN and lncRNA DUXAP8. Western blot was used for detecting protein expression. LncRNA DUXAP8 expression was higher in bladder cancer tissues; it was in a positive correlation with the TNM stage and tumor size, but negatively correlated with the total survival time. Knockdown of DUXAP8 decreased cell viability and cellular proliferation. Lower expression of PTEN gene was found in bladder cancer compared with that in adjacent tissues. Pearson correlation analysis showed that PTEN was negatively correlated with DUXAP8; knockdown of DUAP8 increased the expression of PTEN. Overexpressing DUAP8 increased protein level of PTEN, but decreased cell viability. Our results pointed out that lncRNA DUXAP8 was overexpressed in bladder cancer tissues, which can promote the progression of bladder cancer through inhibiting PTEN.


State-of-the-art PET/CT of the pancreas: current role and emerging indications.
Fused positron emission tomography (PET)/computed tomography (CT) is a recently developed technology that couples the functional information of PET with the anatomic details of CT. Integrated PET/CT scanners produce both PET and contrast material-enhanced CT images of the entire body in one setting. Typically, the amount of fluorine 18 (18F) fluorodeoxyglucose (FDG) uptake in normal pancreatic parenchyma is insignificant compared with that of the liver. However, both malignant (eg, adenocarcinoma) and benign (eg, acute pancreatitis) pancreatic conditions may demonstrate intense FDG uptake. PET/CT provides an opportunity to depict pancreatic tumors and distant metastases, perform preoperative staging, and monitor response to treatment, and it has proved useful in distinguishing postoperative fibrosis from recurrence. In selected cases, PET/CT findings may be used to help diagnose autoimmune pancreatitis mimicking a mass by depicting systemic involvement. PET/CT may also be used to direct biopsy to sites more likely to yield representative tumor tissue. Novel radiolabeled molecules, such as sigma-receptor ligands and 18F-3'-fluoro-3'-deoxy-l-thymidine (FLT), may play an even greater role in distinguishing tumor recurrence from postoperative fibrosis or inflammation.


C-Reactive protein upregulates receptor for advanced glycation end products expression in human endothelial cells.
The receptor for advanced glycation end products (RAGE) may play an important role in inflammatory processes and endothelial activation, likely to accelerate the processes of coronary atherosclerotic development, especially in diabetic patients. The factors that regulate arterial expression of RAGE are not completely clear. C-reactive protein (CRP) is identified as a key proinflammatory cytokine in patients with atherosclerosis. Therefore, we tested the hypothesis that RAGE expression in endothelial cells can be upregulated by CRP. Human saphenous vein endothelial cells were incubated with human recombinant CRP, free of sodium azide and endotoxin. RAGE protein expression was measured by flow-cytometric analysis and Western blotting. CRP caused a significant increase in RAGE protein expression at a dose as low as 5 mug/mL, with expression peaking at 24 to 48 hours after CRP incubation. The effects of modified monomeric CRP on RAGE protein expression were comparable with that of native pentameric CRP. At the mRNA level, CRP not only increased RAGE gene expression but also attenuated the degradation of RAGE mRNA. Furthermore, RNA interference of RAGE gene expression significantly decreased the level of macrophage chemoattractant protein 1, a key downstream mediator of CRP activity. Therefore, CRP at concentrations known to predict future vascular events upregulates RAGE expression in human endothelial cells at both the protein and mRNA level. Silencing of the RAGE gene prevents CRP-induced macrophage chemoattractant protein 1 activation. These data reinforce the mechanistic links among inflammation, endothelial dysfunction, and atherothrombosis.


Biomechanical Evaluation of Suture Anchor Versus Transosseous Tunnel Quadriceps Tendon Repair Techniques.
To evaluate the biomechanical fixation strength of suture anchor and transosseous tunnel repair of the quadriceps tendon in a standardized cadaveric repair model. Twelve "patella-only" specimens were used. Dual-energy X-ray absorptiometry measurement was performed to ensure equal bone quality amongst groups. Specimens were randomly assigned to either a suture anchor repair of quadriceps tendon group (n = 6) or a transosseous tunnel repair group (n = 6). Suture type and repair configuration were equivalent. After the respective procedures were performed, each patella was mounted into a gripping jig. Tensile load was applied at a rate of 0.1 mm/s up to 100 N after which cyclic loading was applied at a rate of 1 Hz between magnitudes of 50 to 150 N, 50 to 200 N, 50 to 250 N, and tensile load at a rate of 0.1 mm/s until failure. Outcome measures included load to failure, displacement at 1st 100 N load, and displacement after each 10th cycle of loading. The measured cyclic displacement to the first 100 N, 50 to 150 N, 50 to 200 N, and 50 to 250 N was significantly less for suture anchors than transosseous tunnels. There was no statistically significant difference in ultimate load to failure between the 2 groups (P = .40). Failure mode for all suture anchors except one was through the soft tissue. Failure mode for all transosseous specimens but one was pulling the repair through the transosseous tunnel. Suture anchor quadriceps tendon repairs had significantly decreased gapping during cyclic loading, but no statistically significant difference in ultimate load to failure when compared with transosseous tunnel repairs. Although suture anchor quadriceps tendon repair appears to be a biomechanically superior construct, a clinical study is needed to confirm this technique as a viable alternative to gold standard transosseous techniques. Although in vivo studies are needed, these results support the suture anchor technique as a viable alternative to transosseous repair of the quadriceps tendon.


Procedural volume and outcomes with radial or femoral access for coronary angiography and intervention.
The study sought to evaluate the relationship between procedural volume and outcomes with radial and femoral approach. RIVAL (RadIal Vs. femorAL) was a randomized trial of radial versus femoral access for coronary angiography/intervention (N = 7,021), which overall did not show a difference in primary outcome of death, myocardial infarction, stroke, or non-coronary artery bypass graft major bleeding. In pre-specified subgroup analyses, the hazard ratios for the primary outcome were compared among centers divided by tertiles and among individual operators. A multivariable Cox proportional hazards model was used to determine the independent effect of center and operator volumes after adjusting for other variables. In high-volume radial centers, the primary outcome was reduced with radial versus femoral access (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.28 to 0.87) but not in intermediate- (HR: 1.23; 95% CI: 0.88 to 1.72) or low-volume centers (HR: 0.83; 95% CI: 0.52 to 1.31; interaction p = 0.021). High-volume centers enrolled a higher proportion of ST-segment elevation myocardial infarction (STEMI). After adjustment for STEMI, the benefit of radial access persisted at high-volume radial centers. There was no difference in the primary outcome between radial and femoral access by operator volume: high-volume operators (HR: 0.79; 95% CI: 0.48 to 1.28), intermediate (HR: 0.87; 95% CI: 0.60 to 1.27), and low (HR: 1.10; 95% CI: 0.74 to 1.65; interaction p = 0.536). However, in a multivariable model, overall center volume and radial center volume were independently associated with the primary outcome but not femoral center volume (overall percutaneous coronary intervention volume HR: 0.92, 95% CI: 0.88 to 0.96; radial volume HR: 0.88, 95% CI: 0.80 to 0.97; and femoral volume HR: 1.00, 95% CI: 0.94 to 1.07; p = 0.98). Procedural volume and expertise are important, particularly for radial percutaneous coronary intervention. (A Trial of Trans-radial Versus Trans-femoral Percutaneous Coronary Intervention [PCI] Access Site Approach in Patients With Unstable Angina or Myocardial Infarction Managed With an Invasive Strategy [RIVAL]; NCT01014273).


Silicones as nonocclusive topical agents.
Silicone excipients are commonly used ingredients because of their emollient and skin-conditioning effects, and their ability to form uniform, water-resistant, yet permeable films. Based on comparisons with organic materials and conflicting knowledge from silicones used in scar treatment, the misconception still exists that silicone topical excipients are occlusive substances that may block the passive loss of water through the upper skin layers. Therefore, 3 types of common silicone excipients and 3 water-in-(oil-plus-silicone) or W/(O + Si) creams, containing 10% (w/w) of the respective silicones, were investigated as a function of time and compared to petrolatum. Transepidermal water loss (TEWL) and skin hydration measurements were carried out after a single topical application on forearm skin of 26 healthy young female volunteers. Both petrolatum and silicones significantly decreased TEWL 15 min after application, but the measurements for the silicones were not significantly different from the untreated control values. The tested silicones did not moisturize the skin. Petrolatum formed an occlusive layer, creating an increase in skin hydration for more than 4 h. The results measured for the W/(O + Si) creams indicated that they moisturized the skin, without any effect on TEWL. A clear difference was shown between the skin occlusive properties of petrolatum and the water vapor permeability of the common silicone excipient materials.


[Intraneural synovial cyst of the peroneal nerve. Case report].
The authors report the case of an intraneural synovial cyst of the peroneal nerve. The initial symptom was pain and weakness of dorsiflexion and eversion of the right foot. The patient was operated on and the cyst was totally resected. The authors discuss the pathogenesis, clinical diagnosis as well as the treatment of that uncommon lesion.


A high performance lithium-ion-sulfur battery with a free-standing carbon matrix supported Li-rich alloy anode.
Although the lithium-sulfur battery exhibits high capacity and energy density, the cycling performance is severely retarded by dendrite formation and side-reactions of the lithium metal anode and the shuttle effect of polysulfides. Therefore, exploring lithium rich-alloy (or compound) anodes and suppressing the shuttling of polysulfides have become practical technical challenges for the commercialization of lithium-sulfur batteries. Here, a lithium ion sulfur full battery system combining a lithium-rich Li-Si alloy anode and sulfurized polyacrylonitrile (S@pPAN) cathode has been proposed. The free-standing CNF matrix supported Li-Si alloy anode is prepared by a simple and effective method, which is practical for scale-up production. The obtained Li-Si alloy anode demonstrates high cycling stability without dendrite growth, while the use of the S@pPAN cathode avoids the shuttle effect in carbonate electrolytes. The constructed Li-Si/S@pPAN battery could be cycled more than 1000 times at 1C and 3000 times at 3C, with a capacity fading rate of 0.01% and 0.03% per cycle. The exceptional performance should originate from the stable integrated anode structure and the excellent compatibility of the S@pPAN cathode and Li-Si alloy anode with carbonate electrolytes.


Biomechanical response of the pediatric abdomen, part 1: development of an experimental model and quantification of structural response to dynamic belt loading.
The abdomen is the second most commonly injured region in children using adult seat belts, but engineers are limited in their efforts to design systems that mitigate these injuries since no current pediatric dummy has the capability to quantify injury risk from loading to the abdomen. This paper develops a porcine (sus scrofa domestica) model of the 6-year-old human's abdomen, and then defines the biomechanical response of this abdominal model. First, a detailed abdominal necropsy study was undertaken, which involved collecting a series of anthropometric measurements and organ masses on 25 swine, ranging in age from 14 to 429 days (4-101 kg mass). These were then compared to the corresponding human quantities to identify the best porcine representation of a 6-year-old human's abdomen. This was determined to be a pig of age 77 days, and whole-body mass of 21.4 kg. The sub-injury, quasistatic response to belt loading of this porcine model compared well with pediatric human volunteer tests performed with a lap belt on the lower abdomen. A test fixture was designed to produce transverse, dynamic belt loading on the porcine abdomen. A detailed review of field cases identified the following test variables: loading location (upper/lower), penetration magnitude (23%-68% of initial abdominal depth), muscle tensing (yes/no), and belt penetration rate (quasistatic, dynamic 2.9 m/s - 7.8 m/s). Dynamic tests were performed on 47 post-mortem subjects. Belt tension and dorsal reaction force were cross-plotted with abdominal penetration to generate structural response corridors. Subcutaneous stimulation of the anterior abdominal muscle wall stiffened the quasistatic response significantly, but was of negligible importance in the dynamic tests. The upper abdomen exhibited stiffer response quasistatically, and also was more sensitive to penetration rate, with stiffness increasing significantly over the range of dynamic rates tested here. In contrast, the lower abdomen was relatively rate insensitive. To our knowledge, this is the only dynamic structural characterization study on a comprehensively developed experimental model of the 6-year-old human abdomen. The structural corridors developed here should lead to the development of both mechanical (i.e., crash dummies) and computational pediatric models that are more useful for assessing injurious levels of belt penetration into the abdomen.


Quantification of plume opacity by digital photography.
The United States Environmental Protection Agency (USEPA) developed Method 9 to describe how plume opacity can be quantified by humans. However, use of observations by humans introduces subjectivity, and is expensive due to semiannual certification requirements of the observers. The Digital Opacity Method (DOM) was developed to quantify plume opacity at lower cost, with improved objectivity, and to provide a digital record. Photographs of plumes were taken with a calibrated digital camera under specified conditions. Pixel values from those photographs were then interpreted to quantify the plume's opacity using a contrast model and a transmission model. The contrast model determines plume opacity based on pixel values that are related to the change in contrast between two backgrounds that are located behind and next to the plume. The transmission model determines the plume's opacity based on pixel values that are related to radiances from the plume and its background. DOM was field tested with a smoke generator. The individual and average opacity errors of DOM were within the USEPA Method 9 acceptable error limits for both field campaigns. Such results are encouraging and support the use of DOM as an alternative to Method 9.


Taxonomic annotation of 16S rRNA sequences of pig intestinal samples using MG-RAST and QIIME2 generated different microbiota compositions.
Environmental microbiome studies rely on fast and accurate bioinformatics tools to characterize the taxonomic composition of samples based on the 16S rRNA gene. MetaGenome Rapid Annotation using Subsystem Technology (MG-RAST) and Quantitative Insights Into Microbial Ecology 2 (QIIME2) are two of the most popular tools available to perform this task. Their underlying algorithms differ in many aspects, and therefore the comparison of the pipelines provides insights into their best use and interpretation of the outcomes. Both of these bioinformatics tools are based on several specialized algorithms pipelined together, but whereas MG-RAST is a user-friendly webserver that clusters rRNA sequences based on their similarity to create Operational Taxonomic Units (OTU), QIIME2 employs DADA2 in the construction of Amplicon Sequence Variants (ASV) by applying an error model that considers the abundance of each sequence and its similarity to other sequences. Taxonomic compositions obtained from the analyses of amplicon sequences of DNA from swine intestinal gut and faecal microbiota samples using MG-RAST and QIIME2 were compared at domain-, phylum-, family- and genus-levels in terms of richness, relative abundance and diversity. We found significant differences between the microbiota profiles obtained from each pipeline. At domain level, bacteria were relatively more abundant using QIIME2 than MG-RAST; at phylum level, seven taxa were identified exclusively by QIIME2; at family level, samples processed in QIIME2 showed higher evenness and richness (assessed by Shannon and Simpson indices). The genus-level compositions obtained from each pipeline were used in partial least squares-discriminant analyses (PLS-DA) to discriminate between sample collection sites (caecum, colon and faeces). The results showed that different genera were found to be significant for the models, based on the Variable Importance in Projection, e.g. when using sequencing data processed by MG-RAST, the three most important genera were Acetitomaculum, Ruminococcus and Methanosphaera, whereas when data was processed using QIIME2, these were Candidatus Methanomethylophilus, Sphaerochaeta and Anaerorhabdus. Furthermore, the application of differential filtering procedures before the PLS-DA revealed higher accuracy when using non-restricted datasets obtained from MG-RAST, whereas datasets obtained from QIIME2 resulted in more accurate discrimination of sample collection sites after removing genera with low relative abundances (<1%) from the datasets. Our results highlight the differences in taxonomic compositions of samples obtained from the two separate pipelines, while underlining the impact on downstream analyses, such as biomarkers identification.


Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case-control study.
The objective of this study is to examine the association between vitamin D status and risk of breast cancer in an Australian population of women. The study design is observational case-control study, performed at Westmead Breast Cancer Institute, Westmead Hospital, Sydney, Australia. 214 women newly diagnosed with breast cancer were matched to 852 controls, and their blood samples were tested at the same laboratory between August 2008 and July 2010. Circulating 25-hydroxyvitamin D (25(OH)D) concentration, was defined as sufficient (≥75 nmol/L), insufficient (50-74 nmol/L), deficient (25-49 nmol/L) or severely deficient (<25 nmol/L). The difference in median 25(OH)D concentration between cases and controls was reported, and the Mann-Whitney U test was used to determine the significance of the difference. Odds ratios and 95 % confidence intervals for the risk of breast cancer were estimated by Cox regression. Median plasma 25(OH)D was significantly lower in cases versus controls overall (53.0 vs 62.0 nmol/L, P < 0.001) and during summer (53.0 vs 68.0 nmol/L, P < 0.001) and winter (54.5 vs 63.0 nmol/L, P < 0.001). Median 25(OH)D was also lower in cases when stratified by BMI (<30, ≥30) and age group (<50, ≥50 years) compared to matched controls, although the difference failed to reach statistical significance. In a Cox regression model, plasma 25(OH)D was inversely associated with the odds ratio of breast cancer. Compared to subjects with sufficient 25(OH)D concentration, the odds ratios of breast cancer were 2.3 (95 % CI 1.3-4.3), 2.5 (95 % CI 1.6-3.9) and 2.5 (95 % CI 1.6-3.8) for subjects categorised as severely deficient, deficient or insufficient vitamin D status, respectively. The results of this observational case-control study indicate that a 25(OH)D concentration below 75 nmol/L at diagnosis was associated with a significantly higher risk of breast cancer. These results support previous research which has shown that lower 25(OH)D concentrations are associated with increased risk of breast cancer.


Which staging system to use for gynaecological cancers: a survey with recommendations for practice in the UK.
There are two commonly used staging systems for gynaecological cancers, namely Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) and TNM. The authors wished to ascertain which staging system is most commonly used in dealing with gynaecological cancers in the UK. The authors undertook a survey among participants in the National Gynaecological Pathology EQA scheme to investigate whether gynaecological pathologists in the UK use FIGO or TNM staging in their routine reporting of gynaecological cancers. There were 105 respondents out of 278 participants (38%). Of the analysed results, a majority of respondents (64%) use FIGO staging, while 32% use both FIGO and TNM. 80% of respondents stated that their multidisciplinary team meeting uses FIGO staging, while 18% use both FIGO and TNM. Only an extremely small minority of pathologists and multidisciplinary team meetings use TNM alone. A survey of members of the British Gynaecological Cancer Society revealed similar findings. Since FIGO and TNM are not always equivalent, and there may be confusion when more than one staging system is used, it is recommended that FIGO staging be used for gynaecological cancers. The survey revealed support for the use of TNM, as well as FIGO, only for cervical cancer, since FIGO does not take the lymph node status into account. Given the prevalent practice in the UK, the British Association of Gynaecological Pathologists, British Gynaecological Cancer Society and gynaecological clinical reference group of the National Cancer Intelligence Network recommend that FIGO staging be used for gynaecological cancers with recording of the lymph node status for cervical cancer. This may be done by providing a TNM stage for this cancer type only or by recording the lymph-node status at the multidisciplinary team meeting.


Protein kinase CbetaII-mediated phosphorylation of endothelial nitric oxide synthase threonine 495 mediates the endothelial dysfunction induced by FK506 (tacrolimus).
FK506 [tacrolimus; hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxa-azacyclotricosine-1,7,20,21(4H,23H)-tetrone] is used clinically to reduce the incidence of allograft rejection; however, chronic administration leads to endothelial dysfunction and hypertension. We have previously shown that FK506 activates Ca(2+)/diacylglycerol-dependent conventional protein kinase C (cPKC), which phosphorylates endothelial nitric oxide synthase (eNOS) at one of its inhibitory sites, Thr495. However, which cPKC isoform is responsible for phosphorylating eNOS Thr495 is unknown. The aim of the current study was to determine the cPKC isoform that is activated by FK506, leading to decreased endothelial function. FK506 reduced endothelium-dependent relaxation responses, yet had no effect on endothelium-independent relaxation responses in aortas from control mice. Of the various cPKC isoforms, only the administration of a PKCβ(II) isoform-specific peptide inhibitor restored aortic relaxation responses to that of controls. In aortic endothelial cells, FK506 significantly increased PKCβ(II) activation compared with vehicle-treated controls, and this was prevented by a PKCβ(II) isoform-specific peptide inhibitor. In addition, a PKCβ(II) isoform-specific peptide inhibitor prevented the increase in eNOS Thr495 phosphorylation induced by FK506. Taken together, our results indicate that β(II) is the cPKC isoform responsible for phosphorylating eNOS at the inhibitory site Thr495 in response to FK506. PKCβ(II) inhibition could prove beneficial in ameliorating the endothelial dysfunction and hypertension in patients treated with FK506.


Expression of cancer-associated fibroblast-related proteins in thyroid papillary carcinoma.
The purpose of this study was to evaluate the association between expression of cancer-associated fibroblast (CAF)-related proteins in papillary thyroid carcinoma (PTC) and clinicopathologic factors. Using tissue microarray (TMA) constructed from 339 cases of PTC (303 classic type, 36 follicular variant), we performed immunohistochemical staining for podoplanin, prolyl 4-hydroxylase, FAPα, S100A4, PDGFRα, PDGFRβ, NG2, 5-meC, and BRAF V600E and evaluated the association with clinicopathologic parameters. We classified the stroma of PTC as desmoplastic type, sclerotic type, pauci type, or inflammatory type. The expression of prolyl 4-hydroxylase (p = 0.042), FAPα (p = 0.044), PDGFRα (p < 0.001), and 5-meC (p = 0.030) in cancer cells differed according to the histologic subtype, higher in classic type than follicular type. The expression of FAPα (p = 0.034) and 5-meC (p = 0.021) in stromal cells was higher in the classic type than follicular type. PTC with BRAF mutation showed higher expression of podoplanin (p < 0.001), prolyl 4-hydroxylase (p = 0.013), FAPα (p < 0.001), S100A4 (p < 0.001), PDGFRα (p < 0.001), and 5-meC (p < 0.001) in the tumor cell compartment and of FAPα (p = 0.004), S100A4 (p < 0.001), PDGFRα (p = 0.002), PDGFRβ (p < 0.001), and 5-meC (p < 0.001) in the stromal cell compartment. There was also a difference in the expression of CAF-related proteins according to stromal phenotype; the expression of FAPα, S100A4, and PDGFRα was higher in desmoplastic type than in other subtypes, whereas NG2 expression was higher in inflammatory type (p < 0.001). Tumoral podoplanin negativity (p = 0.043) was associated with shorter DFS, and tumoral S100A4 positivity (p = 0.044) and stromal PDGFRβ positivity (p = 0.035) were associated with shorter OS. In conclusion, the expression of CAF-related proteins in cancer cells and stromal cells of PTC was different according to histologic subtype, BRAF V600E mutation, and subtype of stroma, and was related to prognosis.


Vitreous IL-8 and VEGF levels in diabetic macular edema with or without subretinal fluid.
To determine the cytokine levels in vitreous samples of diabetic macular edema (DME) patients in comparison with nondiabetic patients, and to evaluate the effect of subretinal fluid on the cytokine levels of vitreous samples. In this prospective case-control study, 11 eyes of 11 patients with DME and subretinal fluid, 11 eyes of 11 patients with DME without subretinal fluid, and 14 eyes of 14 patients who had undergone vitreoretinal surgery for the epiretinal membrane or a macular hole (control group) were evaluated. The blood glycated hemoglobin (HbA1c) level, vitreous vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) levels were determined. The vitreous VEGF level of patients in DME groups was significantly higher than the control group (p < 0.001) without significant difference between DME patients with and without subretinal fluid (p = 0.796). The vitreous IL-8 level of DME patients with subretinal fluid was significantly higher than both control (p = 0.002) and DME without subretinal fluid groups (p = 0.019). The blood HbA1c level was significantly higher in DME group with subretinal fluid than those without subretinal fluid (8.7 ± 1.32 and 7.1 ± 1.13%, respectively, p = 0.010). The only significant correlation was between vitreous VEGF level and blood HbA1c level in DME patients without subretinal fluid (r = 0.813, p = 0.002). IL-8 level in vitreous samples was higher in DME patients with subretinal fluid than those without subretinal fluid, suggesting that inflammation is an important factor in the progression of DME leading to the subretinal fluid formation in diabetic patients.


Colonic motility and gastric emptying in patients with irritable bowel syndrome. Effect of pretreatment with octylonium bromide.
This study was undertaken to evaluate (1) the colonic response to eating for a prolonged time in healthy subjects and patients with the irritable bowel syndrome (IBS); (2) the effect of octylonium bromide, a new smooth muscle relaxant acting by interfering with calcium ion mobilization, on the postprandial colonic motility; and (3) whether chronic gastric stasis could be responsible for both the dyspeptic symptoms often complained of by IBS patients and the faulty colonic response to eating. The colonic response to a 1000-kcal mixed meal in ten healthy subjects was characterized by two transient (from 0 to 60 and from 120 to 150 min postprandially, respectively) increases in colonic motor activity; ten IBS patients showed a continuous postprandial increase in colonic motor activity that was not terminated 180 min after eating. Treatment of IBS patients with octylonium bromide (80 mg, qid, per os) for 5-7 days reduced their colonic response to eating to a very short increase in colonic motor activity limited to the first 30 min. Finally, gastric emptying was not different in the two groups.


"Brain Connectivity Deviates by Sex and Hemisphere in the First Episode of Schizophrenia"-A Route to the Genetic Basis of Language and Psychosis?
Schizophrenia is genetic in origin and associated with a fecundity disadvantage. The deficits in schizophrenia have been attributed to variation related to the human capacity for language or brain laterality. How sex influences the relative connectivity of the 2 hemispheres is a route to understanding these 2 functions. Using resting-state functional magnetic resonance imaging (fMRI) we searched for sex- and hemisphere-specific changes in whole-brain functional-connectivity in multi-site datasets (altogether 672 subjects including 286 patients, all right-handed) in the first-episode schizophrenia (illness duration ≤ 1 year, mostly drug naive) and in chronic stages of schizophrenia (illness duration > 1 year), respectively. We used meta-analyses to integrate data from different sources concerning individuals at the same illness stage. We found first-episode male patients are predominantly left-lateralized in aberrant connectivity with a focus on Broca's area. Female patients show a lesser degree of lateralization than males, but to the right particularly in orbital frontal cortex. In the chronic stage, the focus of aberrant connectivity shifted from anterior to posterior structures with prominent involvement of the thalamus and pre- and post-central gyri bilaterally and in both sexes. While the "deviant connectivity" is right-sided in both the first-episode and the chronic stages in females, in males there is a shift between stages from the left to the right hemisphere. We hypothesized that the pathophysiology of schizophrenia may lie in the interaction between sex and lateralization, ie, in genetic mechanisms located on the X and Y chromosomes, intrinsic to the evolution of language.


It Runs in the Family: A Study of Political Candidacy Among Swedish Adoptees.
What motivates citizens to run for office? Recent work has shown that early life parental socialization is strongly associated with a desire to run for office. However, parents not only shape their children's political environment, they also pass along their genes to those same children. A growing area of research has shown that individual differences in a wide range of political behaviors and attitudes are linked to genetic differences. As a result, genetic factors may confound the observed political similarities among parents and their children. This study analyzes Swedish register data containing information on all nominated and elected candidates in the ten parliamentary, county council, and municipal elections from 1982 to 2014 for a large sample of adoptees and their adoptive and biological parents. By studying the similarity in political ambition within both adoptive and biological families, our research design allows us to disentangle so-called "pre-birth" factors, such as genes and pre-natal environment, and "post-birth" factors like parental socialization. We find that the likelihood of standing as a political candidate is twice as high if one's parent has been a candidate. We also find that the effects of pre-birth and post-birth factors are approximately equal in size. In addition, we test a number of potential pre- and post-birth transmission mechanisms. First, disconfirming our expectations, the pre-birth effects do not seem to be mediated by cognitive ability or leadership skills. Second, consistent with a role modeling mechanism, we find evidence of a strong transmission in candidacy status between rearing mothers and their daughters.


Preparation of Double-Stranded (Replicative Form) Bacteriophage M13 DNA.
The double-stranded, closed-circular, replicative form (RF) of M13 DNA is present in high copy numbers in infected cells, and its physical characteristics are essentially identical to those of closed-circular plasmid DNAs. Any of the methods commonly used to purify plasmid DNA can therefore be used to isolate M13 RF DNA. This protocol describes the isolation of M13 RF DNA by alkaline lysis from small volumes (1-2 mL) of infected bacterial cultures. The yield of DNA (1-4 mg, depending on the size of the M13 clone) is more than enough for most purposes in molecular cloning. However, should more DNA be needed, the procedure can easily be scaled up.


The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk.
Drug-induced reduction of the rapid delayed rectifier potassium current carried by the human Ether-à-go-go-Related Gene (hERG) channel is associated with increased risk of arrhythmias. Recent updates to drug safety regulatory guidelines attempt to capture each drug's hERG binding mechanism by combining in vitro assays with in silico simulations. In this study, we investigate the impact on in silico proarrhythmic risk predictions due to uncertainty in the hERG binding mechanism and physiological hERG current model. Possible pharmacological binding models were designed for the hERG channel to account for known and postulated small molecule binding mechanisms. After selecting a subset of plausible binding models for each compound through calibration to available voltage-clamp electrophysiology data, we assessed their effects, and the effects of different physiological models, on proarrhythmic risk predictions. For some compounds, multiple binding mechanisms can explain the same data produced under the safety testing guidelines, which results in different inferred binding rates. This can result in substantial uncertainty in the predicted torsade risk, which often spans more than one risk category. By comparison, we found that the effect of a different hERG physiological current model on risk classification was subtle. The approach developed in this study assesses the impact of uncertainty in hERG binding mechanisms on predictions of drug-induced proarrhythmic risk. For some compounds, these results imply the need for additional binding data to decrease uncertainty in safety-critical applications.


Upper limb motor function at 5000 metres: determinants of performance and residual sequelae.
Little is known about the effects of age and symptoms of acute mountain sickness and the potential benefit of short term acclimatisation on fine motor performance at altitude. There is uncertainty about whether time spent at altitude results in permanent neurological sequelae. Nine hole pegboard tests were performed on a group of trekkers at sea level (n=61), after ascending to Kanchenjunga base camp (5100 m; n=46), and 20 weeks after return to sea level (n=43). Comparison of baseline and altitude times showed a mean slowing from 36.2 to 39.0 seconds, a 7. 8% deterioration in performance (p<0.0001), which was greatest in subjects aged 50 years or older (5.04 v 1.93 seconds, p=0.017), those tested within 24 hours of arrival at 5100 m (4.75 seconds, 13. 3% v 0.48 seconds, 1.3% p<0.001), and persons experiencing symptoms of acute mountain sickness (p=0.012), each of which were independent determinants of deterioration. Repeat pegboard testing at sea level after 20 weeks showed no significant change compared with baseline (p=0.68). This confirms the deleterious effects of altitude on fine motor function, emphasises the benefit of acclimatisation, and suggests that older persons and those with symptoms of acute mountain sickness are particularly susceptible. The risk of long term motor dysfunction after exposure to these relatively moderate altitudes seems to be small.


Severe Clostridium difficile infections in intensive care units: Diverse clinical presentations.
Clostridium difficile infections (CDIs) cause significant mortality and morbidity. Critically ill patients are susceptible to CDIs and tend to have severe CDIs, and their clinical presentations are not merely diarrhea. From September 2017 to March 2018, the adults with CDIs in the ICUs were included. Fecal specimens with positive results of glutamate dehydrogenase assay were cultured for C. difficile, and toxinotyping and ribotyping for available C. difficile isolates were done. The CDI cases were categorized into the diarrheal group and ileus group. Difficult-to-treat cases with the presentations of life-threatening complications (bowel perforation or bacteremia), toxic megacolon, and refractory diarrhea, were analyzed. Totally 23 cases, including 6 cases of ileus and 17 of diarrhea, were included. Overall, the incidence of CDI in the ICUs was 10.7 cases per 10,000 patient-days. The ileus group tended to have more severe presentation, shorter ICU stay, higher ICU mortality, and receive initial intravenous metronidazole therapy. Severe and fulminant CDIs accounted for 65.2% (15 cases). The ICU mortality rate was 39.1%, but only one death was directly related to CDI (4.3%). Of nine (39.1%) difficult-to-treat cases, there was only one isolate of RT611 with tcdC deletion and cdtA/cdtB from a case with toxic megacolon. No hypervirulent isolates of RT027 or 078 were detected. Severe CDIs in the ICU were not rare. Clinicians should be aware of abdominal symptoms and signs other than diarrhea, such as ileus, to make timely diagnosis and management of CDI.


Health4Afrika - Implementing HL7 FHIR Based Interoperability.
Supported by the European Commission under Horizon 2020, mHealth4Afrika is co-designing and validating a modular, multilingual, state-of-the-art health information system addressing primary healthcare requirements in resource constrained environments. mHealth4Afrika has co-designed a comprehensive range of functionality and medical programs in partnership with Ministries of Health, district health officers, clinic managers and primary healthcare workers from urban, rural and deep rural health facilities in Ethiopia, Kenya, Malawi and South Africa. This paper provides insights into how mHealth4Afrika is leveraging HL7 FHIR to support standards-based data exchange and interoperability between Electronic Medical Records and DHIS2. This work is currently being validated in the field.


On the origins of diastereoselectivity in the alkylation of enolates derived from N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxamates: chiral Weinreb amide equivalents.
The stereochemical outcome observed upon alkylation of enolates derived from N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxamates (chiral Weinreb amide equivalents) may be rationalized by a chiral relay mechanism. Deprotonation with KHMDS leads to a nonchelated (Z)-enolate in which the oxygen atoms adopt an anti-periplanar conformation. The configuration of the N-1-(1'-naphthyl)ethyl group dictates the conformation of the O-tert-butyl group and the configuration adopted by the adjacent pyramidal nitrogen atom. Highly diastereoselective enolate alkylation then proceeds anti to both the bulky tert-butyl group (sterically driven) and the N-lone pair (stereoelectronically driven).


Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema.
The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme with epoxy hydrolase and aminopeptidase activities. We hypothesize that the LTA4H aminopeptidase activity alleviates neutrophilic inflammation, which contributes to cigarette smoke (CS)-induced emphysema by clearing proline-glycine-proline (PGP), a triamino acid chemokine known to induce chemotaxis of neutrophils. To investigate the biological contributions made by the LTA4H aminopeptidase activity in CS-induced emphysema, we exposed wild-type mice to CS over 5 mo while treating them with a vehicle or a pharmaceutical agent (4MDM) that selectively augments the LTA4H aminopeptidase without affecting the bioproduction of leukotriene B4. Emphysematous phenotypes were assessed by premortem lung physiology with a small animal ventilator and by postmortem histologic morphometry. CS exposure acidified the airspaces and induced localization of the LTA4H protein into the nuclei of the epithelial cells. This resulted in accumulation of PGP in the airspaces by suppressing the LTA4H aminopeptidase activity. When the LTA4H aminopeptidase activity was selectively augmented by 4MDM, the levels of PGP in the bronchoalveolar lavage fluid and infiltration of neutrophils into the lungs were significantly reduced without affecting the levels of leukotriene B4. This protected murine lungs from CS-induced emphysematous alveolar remodeling. In conclusion, CS exposure promotes the development of CS-induced emphysema by suppressing the enzymatic activities of the LTA4H aminopeptidase in lung tissues and accumulating PGP and neutrophils in the airspaces. However, restoring the leukotriene A4 aminopeptidase activity with a pharmaceutical agent protected murine lungs from developing CS-induced emphysema.


Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H₃ receptor antagonist ST-1283.
Previous studies have suggested a potential link between histamine H₃ receptors (H₃R) signaling and anxiolytic-like and antidepressant-like effects. The aim of this study was to investigate the acute effects of ST-1283, a novel H₃R antagonist, on anxiety-related and depression-related behaviors in comparison with those of diazepam and fluoxetine. The effects of ST-1283 were evaluated using the elevated plus maze test, open field test, marbles burying test, tail suspension test, novelty suppressed feeding test, and forced swim test in male C57BL/6 mice. The results showed that, like diazepam, ST-1283 (7.5 mg/kg) significantly modified all the parameters observed in the elevated plus maze test. In addition, ST-1283 significantly increased the amount of time spent in the center of the arena without altering general motor activity in the open field test. In the same vein, ST-1283 reduced the number of buried marbles as well as time spent digging in the marbles burying test. The tail suspension test and forced swim test showed that ST-1283 was able to reduce immobility time, like the recognized antidepressant drug fluoxetine. In the novelty suppressed feeding test, treatment with ST-1283 decreased latency to feed with no effect on food intake in the home cage. Importantly, pretreatment with the H₃R agonist R-α-methylhistamine abrogated the anxiolytic and antidepressant effects of ST-1283. Taken together, the present series of studies demonstrates the novel effects of this newly synthesized H₃R antagonist in a number of preclinical models of psychiatric disorders and highlights the histaminergic system as a potential therapeutic target for the treatment of anxiety-related and depression-related disorders.


Formation and decomposition of distonic o-, m-, and p-benzyne radical cations from photolysis of Mg(+)(o-, m-, p-C(6)H(4)F(2)).
Distonic o-, m-, and p-benzyne radical cations (1-3) have been generated by a novel photolysis reaction of mass-selected Mg(+)-difluorobenzene complexes. The energy required for the formation of these radical cations is within 2.2 eV. The formation of o-benzyne cation is most facile. The benzyne radical cations dissociate further to yield ethyne and 1,3-butadiyne radical cation as major products given a sufficient amount of energy. The whole process involves only a single photon, and is very efficient. The calculated threshold for the formation of 1,3-butadiyne radical cation from Mg(+)(o-C(6)H(4)F(2)) is about 4.6 eV, quite comparable with the experimental estimate.


Increasing Trunk Mass Evokes Lower Extremity Biomechanical Plasticity during Stair Descent.
The purpose of this study was to investigate the influence of simulated changes in body mass on lower extremity joint work and relative joint contributions during stair descent. Ten healthy recreationally active college-age participants performed five stair descent trials in each of five loading conditions: no added load and with an additional 5%, 10%, 15% and 20% of their body weight. Three-dimensional ankle, knee and hip joint powers were calculated using a six degree-of-freedom model in Visual3D (C-Motion Inc., Germantown, MD, USA). Sagittal plane joint work was calculated as the joint power curve integrated with respect to time during the period between initial contact and toe off. Prism 9.0 (GraphPad Inc., San Diego, CA) was used to perform univariate 1 × 5 repeated measures analyses of variance to determine the effect of added mass on absolute and relative joint work values for total and for each lower extremity joint independently. Increasing added mass was associated with greater total lower extremity negative work during the stair descent task (p < 0.001). At the ankle, increasing added mass was associated with increasing magnitudes of negative joint work. Increasing added mass was associated with greater relative contributions of the ankle and reduced knee contributions to total negative lower extremity joint work (p = 0.014 and p = 0.006). The current findings demonstrated increases in ankle joint contributions to total lower extremity work while knee joint contributions to total lower extremity work were reduced in response to increasing added mass.


Microlesion formation in myocardial cells by high-intensity electric field stimulation.
Arrhythmias, S-T segment changes, immediate refibrillation, and other signs of dysfunction are often observed after clinical and experimental transthoracic defibrillation. In vitro studies suggested that shock-induced dysfunction is induced by sarcolemmal dielectric breakdown accompanied by ionic exchanges through transient, shock-induced microlesions in the sarcolemma. To test this hypothesis, cultured chick embryo myocardial cells were shocked in media containing fluorescein isothiocyanate-labeled dextrans (FITC-dextrans) ranging in molecular mass from 4 to 70 kDa, using electric field stimulation 5 ms in duration and ranging in intensity from 0 to 200 V/cm. Results showed that the percentage of cells incorporating 4- to 20-kDa dextrans increased in a dose-dependent manner. The 4- and 10-kDa dextrans were incorporated beginning at intensities of 50-100 V/cm. Dextran incorporation corresponded with shock intensities which produced a shock-induced arrest of spontaneous contraction lasting 1 min. The 20-kDa dextrans were incorporated following 150- and 200-V/cm shocks. Shocks of these intensities also produced a transient postshock contracture. Larger dextrans (40 and 70 kDa) were not incorporated. These results suggest the formation of transient sarcolemmal microlesions having a diameter of 45-60 A during high-intensity electric field stimulation.


Geissospermiculatine, a New Alkaloid from Geissospermum reticulatum Bark.
A new alkaloid, geissospermiculatine was characterized in Geissospermum reticulatum A. H. Gentry bark (Apocynaceae). Here, following a simplified isolation protocol, the structure of the alkaloid was elucidated through GC-MS, LC-MS/MS, 1D, and 2D NMR (COSY, ROESY, HSQC, HMBC, 1H-15N HMBC). Cytotoxic properties were evaluated in vitro on malignant THP-1 cells, and the results demonstrated that the cytotoxicity of the alkaloid (30 μg/mL) was comparable with staurosporine (10 μM). Additionally, the toxicity was tested on zebrafish (Danio rerio) embryos in vivo by monitoring their development (0-72 h); toxicity was not evident at 30 μg/mL.


Antioxidant activity of zein hydrolysates in a liposome system and the possible mode of action.
Maize zein was hydrolyzed for 0.5-5 h by alcalase or papain. Protein solubility increased (P < 0.05) with the degree of hydrolysis (DH) and was higher for alcalase-hydrolyzed zein than for papain-hydrolyzed zein. The zein hydrolysates with both enzymes consisted mostly of small peptides or amino acids nondetectable by 15% acrylamide gel electrophoresis. Alcalase-hydrolyzed zein exhibited a stronger (P < 0.05) antioxidant activity than papain-hydrolyzed zein, as indicated by peroxide and thiobarbituric acid-reactive substance values in a liposome-oxidizing system. Zein hydrolysates possessed strong Cu(2+) chelation ability and marked reducing power, both of which were accentuated with hydrolysis time. The protein hydrolysates also showed strong radical-scavenging ability, which was not influenced by hydrolysis time. The antioxidant activity of alcalase-hydrolyzed zein at some specific low concentrations was close or comparable to those of butylated hydroxyanisole, alpha-tocopherol, and ascorbate. Although intact zein displayed an antioxidative effect, it was far less potent than hydrolyzed zein. The results demonstrated that enzyme-hydrolyzed zein can act as a metal ion chelator or a hydrogen donor, as well as a radical stabilizer to inhibit lipid oxidation. The effectiveness of the protein hydrolysates appeared to depend on both the concentration and the peptide/amino acid composition of the soluble protein fraction.


Revealing HIV epidemic dynamics and contrasting responses in two WHO Eastern European countries: insights from modeling and data triangulation.
In the early 2000s, Estonia and Latvia experienced a rapidly growing HIV epidemic among people who inject drugs (PWID), and had, with Russia, the highest diagnosis rates in Europe. Understanding epidemic dynamics in both countries and how responses to HIV impacted them is essential to ending injection-driven epidemics. Statistical modeling, programmatic data collection, and triangulation. Data on newly diagnosed HIV cases were used in a back-calculation model to estimate, for each country, trends in HIV incidence, time to diagnosis, and undiagnosed infections. Modeled estimates were then triangulated with programmatic data on harm reduction services, HIV testing, and ART. From 2007 to 2016, HIV incidence decreased in Estonia by 61% overall, for all exposure groups, and particularly for male PWID (97%), except men who have sex with men, where it increased by 418%. In Latvia, it increased by 72% overall. Median time to diagnosis decreased for male PWID in Estonia, from 3.5 to 2.6 years, but not in Latvia. In 2016, most new and undiagnosed infections, ∼50% in Latvia and ∼75% in Estonia, affected individuals reporting heterosexual transmission, showing a gradual shift toward heterosexual route as the main reported exposure mode. Coverage of services had been higher in Estonia; for example, by 2016, for PWID, there were >200 needles and syringes distributed per PWID annually, and HIV testing and ART coverage reached ∼50% and 76%, respectively, in Estonia, against respectively less than 100%, 10% and 27% in Latvia. Estonia has turned the tide of its epidemic - large scale-up of prevention and care programs probably contributed to it - whereas in Latvia it remains very active.


Public perceptions of physician - pharmaceutical industry interactions: a systematic review.
Interactions between physicians and the pharmaceutical industry have led to concerns about conflict of interest (COI), resulting in COI guidelines that suggest a threshold beyond which interactions may be considered unacceptable. Guidelines have also outlined the importance of public opinion on the topic. Consequently, we conducted a systematic review to determine the Canadian public's opinions of physician-pharmaceutical industry interactions. A systematic review of the standard health sciences literature as well as grey literature was conducted and a number of experts were contacted. Pre-determined eligibility criteria were used to identify appropriate studies. Meta-analysis of the study findings was not possible owing to the variety of methods of reporting outcomes, the types of interactions studied and the diversity of populations studied. No studies on Canadian opinions were identified. Ten international studies (n=13,637), seven with patient groups and three with public citizens, were identified that examined opinions on aspects of awareness, acceptability, disclosure and perceived effects of physician-pharmaceutical industry interactions. Heterogeneity was observed in the awareness, acceptability and perceived effects of physician-pharmaceutical industry interactions; however, there appeared to be greater acceptability and fewer perceived effects with smaller, less costly interactions that directly benefit patients or a medical practice. Desire for disclosure of these interactions was consistent across studies. Research on the public's perception of physician-pharmaceutical industry interactions has been inadequate internationally and non-existent in Canada, and is urgently needed to help shape policies regarding potential conflict of interest.


Ray delay in gradient waveguides with arbitrary symmetric refractive profile.
This paper deals with the investigation of the ray delay in gradient waveguides with any transverse refractive profile. A perturbation method is used for the calculations. It becomes apparent that the delay differences in the pure gradient medium are very small for any decreasing profile and that they are of an order of magnitude of those found in a monomode waveguide (material dispersion). Larger delay differences do, however, occur when the ray paths are to some extent determined by an outer cladding. These influences must be eliminated to allow the excellent delay time properties of a gradient medium to really be utilized.


DNA relatedness among Pseudomonas strains isolated from natural mineral waters and proposal of Pseudomonas veronii sp. nov.
The taxonomic position of eight strains isolated from mineral water and previously grouped in the authentic pseudomonads on the basis of a phenotypic analysis (cluster Ib of M. Elomari, L. Coroler, D. Izard, and H. Leclerc [J. Appl. Bacteriol. 78:71-81, 1995]) has been further studied by DNA-DNA hybridizations. Using the S1 nuclease method at 60 degrees C and labeled reference DNA from a representative strain, CFML 92-134, we showed that members of cluster Ib constituted a homogeneous group with a relative binding ratio of greater than 80% and changes in melting temperature of less than 1 degree C. With a total of 67 strains representing known or partially characterized species of the genus Pseudomonas, only 4 to 47% DNA hybridization and changes in melting temperature of between 8 and 20 degrees C were found, the highest hybridization values being measured with members of the saprophytic fluorescent pseudomonads. Since cluster Ib could also be clearly differentiated from members of the latter group and from other phenotypic clusters containing isolates from mineral water, we designated the Ib strains members of a new Pseudomonas species for which the name Pseudomonas veronii sp. nov. has been proposed. Members of this species grew on alpha-aminobutyrate, sucrose, butyrate, isobutyrate, erythritol, L-tryptophan, and trigonelline as sole sources of carbon and energy. The average G+C content of the DNA of the eight strains of P. veronii was 61.5 +/- 0.5 mol%. The type strain is CFML 92-134T (CIP 104663T), with a G+C content of 61 mol%. The clinical significance of P. veronii is unknown.


Evaluation of Velopharyngeal Closure Ratio by a New Semi-Automatic Detection Method Based on Nasopharyngoscopy With Image Processing Method.
The goal of this study is to develop and validate a novel semi-automatic detection method (SADM) under nasopharyngoscopy based on the image processing technique, which can assist the evaluation of the velar closure ratio (VCR). After the development of the SADM, 72 patients were enrolled. The reliability of SADM was evaluated by repeated measurements. Velar closure ratio are given by conventional nasopharyngoscopy method and SADM were compared. Velar closure ratios given by SADM were further translated into a trichotomous classification for velopharyngeal function diagnosis, that is, velopharyngeal closure (VPC), marginal VPC (MVPC), and velopharyngeal incomplete. The 2 VCR-thresholds used for the translation were explored and validated. As results shown, SADM was proved to be reliable with an intraclass correlation coefficient of 0.996 (95% confidence interval: 0.993-0.997, P < 0.001). Intraclass correlation coefficient between conventional nasopharyngoscopy method and SADM was 0.954 (95% confidence interval: 0.927- 0.971, P < 0.001). Velar closure ratio-thresholds were set at 0.82 and 0.92 according to the ROC curve. Diagnostic sensitivity and specificity for velopharyngeal incomplete were 1.00 and 1.00. MVPC had 0.58 sensitivity and 0.96 specificities while VPC had 0.92 and 0.79, respectively. No statistically significant difference was found between the diagnosis of SADM and speech pathologists (P > 0.1). In conclusion, this study successfully developed an accurate and reliable semi-automatic method to evaluate VCR, which could help improve the efficacy of VCR evaluation and velopharyngeal function diagnosis.


Treatment of portal vein thrombosis in cirrhosis patients.
Portal vein thrombosis is an uncommon complication in patients with cirrhosis, typically manifesting in the advanced stages of the disease. Although robust evidence is lacking, anticoagulation is indicated in specific patient subgroups, either those with severe portal occlusion or those requiring attempted portal recanalization due to their unique transplant situation. Beyond recanalization, anticoagulation appears to exert a beneficial effect on the natural history of cirrhosis, which raises uncertainties about the appropriateness of discontinuing it once initiated.


Pool size measurements facilitate the determination of fluxes at branching points in non-stationary metabolic flux analysis: the case of Arabidopsis thaliana.
Pool size measurements are important for the estimation of absolute intracellular fluxes in particular scenarios based on data from heavy carbon isotope experiments. Recently, steady-state fluxes estimates were obtained for central carbon metabolism in an intact illuminated rosette of Arabidopsis thaliana grown photoautotrophically (Szecowka et al., 2013; Heise et al., 2014). Fluxes were estimated therein by integrating mass-spectrometric data of the dynamics of the unlabeled metabolic fraction, data on metabolic pool sizes, partitioning of metabolic pools between cellular compartments and estimates of photosynthetically inactive pools, with a simplified model of plant central carbon metabolism. However, the fluxes were determined by treating the pool sizes as fixed parameters. Here we investigated whether and, if so, to what extent the treatment of pool sizes as parameters to be optimized in three scenarios may affect the flux estimates. The results are discussed in terms of benchmark values for canonical pathways and reactions, including starch and sucrose synthesis as well as the ribulose-1,5-bisphosphate carboxylation and oxygenation reactions. In addition, we discuss pathways emerging from a divergent branch point for which pool sizes are required for flux estimation, irrespective of the computational approach used for the simulation of the observable labeling pattern. Therefore, our findings indicate the necessity for development of techniques for accurate pool size measurements to improve the quality of flux estimates from non-stationary flux estimates in intact plant cells in the absence of alternative flux measurements.